Gammaked

GAMMAKED is an immune globulin injection (human) 10% liquid that is indicated for the treatment of:

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)

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)

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.

PI

The most common adverse reactions observed at a rate ≥ 5% in subjects with intravenous treatment in the clinical trials were cough increased, rhinitis, pharyngitis, headache, asthma, nausea, fever, diarrhea, and sinusitis.

PI

The most common adverse reactions observed at a rate ≥ 5% of subjects with subcutaneous treatment in the clinical trials were local infusion site reactions, fatigue, headache, upper respiratory tract infection, arthralgia, diarrhea, nausea, sinusitis, bronchitis, depression, allergic dermatitis, migraine, myalgia, viral infection, and pyrexia.

ITP

The most common adverse reactions observed at a rate ≥ 5% in subjects in the clinical trials were headache, ecchymosis, vomiting, fever, nausea, rash, abdominal pain, back pain and dyspepsia.

CIDP

The most common adverse reactions observed at a rate ≥ 5% in subjects in the clinical trial were headache, pyrexia, hypertension, chills, rash, nausea, arthralgia, and asthenia.

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.

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 2: Adverse Reactions Occurring in ≥ 5% of Subjects

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

Table 3: Adverse Reactions Frequency

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%.

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]

Table 4: Most Frequent Adverse Reactions (≥ 2% of infusions ) by Infusion in the SC Phase

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

Table 5: Most Frequent Adverse Reactions (≥ 5% of subjects ) by Subject and Infusion in the SC Phase

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.

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.

Table 6: Adverse Reactions Occurring in ≥ 5% of Subjects

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%.

In the CIDP efficacy and safety study, 113 subjects were exposed to GAMMAKED and 95 were exposed to Placebo. [see Clinical Studies] 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.

Table 7: Reasons 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.

Table 8: Adverse Reactions Occurring in ≥ 5% of Subjects

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.

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.

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:

Mechanism Of Action

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.

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

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

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].

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

Table 10: PK Parameters Following IV Adminis tration of GAMMAKED™ by Age

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.

Table 11: Summary of AUC of Total IgG at Steady State Following IV or SC Adminis tration of GAMMAKED™ by Age

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

Table 12: Mean Trough Concentrations of Total IgG (mg/mL)

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

Clinical Studies

Intravenous Adminis tration

In a randomized, double-blind, parallel group clinical trial with 172 subjects with primary humoral immunodeficiencies GAMMAKED was demonstrated to be at least as efficacious as GAMIMUNE N, 10% in the prevention of any infection, i.e., validated plus clinically defined, non-validated infections of any organ system, during a nine month treatment period.(25) Twenty-six subjects were excluded from the Per Protocol analysis (2 due to non-compliance and 24 due to protocol violations). The analysis for efficacy was based on the annual rate of bacterial infections, pneumonia, acute sinusitis and acute exacerbations of chronic sinusitis.

Table 13: Efficacy Results Per Protocol Analysis

The annual rate of validated infections (Number of Infections/year/subject) was 0.18 in the group treated with GAMMAKED and 0.43 in the group treated with GAMIMUNE N, 10% (p=0.023). The annual rates for any infection (validated plus clinically-defined, non-validated infections of any organ system) were 2.88 and 3.38, respectively (p=0.300).

A double-blind, randomized, parallel group clinical trial with 97 ITP subjects was carried out to test the hypothesis that GAMMAKED was at least as effective as GAMIMUNE N, 10% in raising platelet counts from less than or equal to 20 x109 /L to more than 50 x109 /L within 7 days after treatment with 2 g/kg IGIV. Twenty-four percent of the subjects were less than or equal to 16 years of age.(26)

GAMMAKED was demonstrated to be at least as effective as GAMIMUNE N, 10% in the treatment of adults and children with acute or chronic ITP.

Table 14: Platelet Response of Per Protocol Analysis

A trial was conducted to evaluate the clinical response to rapid infusion of GAMMAKED in patients with ITP. The study involved 28 chronic ITP subjects, wherein the subjects received 1 g/kg GAMMAKED on three occasions for treatment of relapses. The infusion rate was randomly assigned to 0.08, 0.11, or 0.14 mL/kg/min (8, 11 or 14 mg/kg/min). Pre-medication with corticosteroids to alleviate infusion-related intolerability was not permitted. Pre-treatment with antihistamines, anti-pyretics and analgesics was permitted. The average dose was approximately 1 g/kg body weight at all three prescribed rates of infusion (0.08, 0.11 and 0.14 mL/kg/min). All patients were administered each of the three planned infusions except seven subjects. Based on 21 patients per treatment group, the a posteriori power to detect twice as many drug-related adverse events between groups was 23%. Of the seven subjects that did not complete the study, five did not require additional treatment, one withdrew because he refused to participate without concomitant medication (prednisone) and one experienced an adverse event (hives); however, this was at the lowest dose rate level (0.08 mL/kg/min).

A multi-center, randomized, double-blind, Placebo-controlled trial (The Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified CIDP Efficacy or ICE study) was conducted with GAMMAKED.(27) This study included two separately randomized periods to assess whether GAMMAKED was more effective than Placebo for the treatment of CIDP (assessed in the Efficacy Period for up to 24 weeks) and whether long-term administration of GAMMAKED could maintain longterm benefit (assessed in the 24 week Randomized Withdrawal Period).

In the Efficacy Period, there was a requirement for Rescue (crossover) to the alternate study drug if the subject did not improve and maintain this improvement until the end of the 24 week treatment period. Subjects entering the Rescue phase followed the same dosing and schedule as in the Efficacy period. Any subject who was rescued (crossed over) and did not improve and maintain this improvement was withdrawn from the study.

Subjects who completed 24 weeks treatment in the Efficacy period or Rescue phase and responded to therapy were eligible for entry into a double-blind Randomized Withdrawal Period. Eligible subjects were re-randomized to GAMMAKED or Placebo. Any subject who relapsed was withdrawn from the study.

The Efficacy Period and the Rescue treatment started with a loading dose of 2 g/kg body weight of GAMMAKED or equal volume of Placebo given over 2-4 consecutive days. All other infusions (including the first infusion of the Randomized Withdrawal Period) were given as maintenance doses of 1 g/kg body weight (or equivalent volume of Placebo) every three weeks.

The Responder rates of the GAMMAKED and Placebo treatment groups were measured by the INCAT score. The INCAT (Inflammatory Neuropathy Cause and Treatment) scale is used to assess functional disability of both upper and lower extremities in demyelinating polyneuropathy. The INCAT scale has upper and lower extremity components (maximum of 5 points for upper (arm disability) and maximum of 5 points for lower (leg disability)) that add up to a maximum of 10-points (0 is normal and 10 is severely incapacitated).(28) At the start of the efficacy portion of the study, the INCAT scores were as follows: Upper Extremity mean was 2.2 ± 1.0, and median was 2.0 with a range of 0 to 5; Lower Extremity mean was 1.9 ± 0.9, and median was 2.0 with a range of 1 to 5; Total Overall Score mean was 4.2 ± 1.4, and median was 4.0 with a range of 2 to 9. A Responder was defined as a subject with at least 1-point improvement from baseline in the adjusted INCAT score that was maintained through 24 weeks.

More subjects with CIDP responded to GAMMAKED: 28 of 59 subjects (47.5%) responded to GAMMAKED compared with 13 of 58 subjects (22.4%) administered Placebo (25% difference; 95% CI 7%-43%; p=0.006). The study included both subjects who were IGIV naive and subjects who had previous IGIV experience. The outcome was influenced by the group of subjects who experienced prior therapy with IGIV, as shown by the outcomes table, below.

Time to relapse for the subset of 57 subjects who previously responded to GAMMAKED was evaluated: 31 were randomly reassigned to continue to receive GAMMAKED and 26 subjects were randomly reassigned to Placebo in the Randomized Withdrawal Period. Subjects who continued to receive GAMMAKED experienced a longer time to relapse versus subjects treated with Placebo (p=0.011). The probability of relapse was 13% with GAMMAKED versus 45% with Placebo (hazard ratio, 0.19; 95% confidence interval, 0.05, 0.70).

Table 15: Outcomes in Intent-to-Treat Population Efficacy Period

The following table shows outcomes for the Rescue Phase (which are supportive data):

Table 16: Outcomes in Res cue Phas e

The following Kaplan-Meier curves show the outcomes for the Randomized Withdrawal Period:

Figure 8: Outcome for Randomized Withdrawal Period

REFERENCES

24. Wasserman RL, Irani A-M, Tracy J, et al. Pharmacokinetics and safety of subcutaneous immune globulin (human), 10% caprylate/chromatography purified in patients with primary immunodeficiency disease. Clinical and Experimental Immunology 2011;161:518-26.

25. Roifman CM, Schroeder H, Berger M, et al. Comparison of the efficacy of IGIV-C, 10% (caprylate/chromatography) and IGIV-SD, 10% as replacement therapy in primary immune deficiency. A randomized double-blind trial. Internat Immunopharmacol 2003;3:1325-33.

26. Bussell JB, Eldor A, Kelton JG, et al. IGIV-C, a novel intravenous immunoglobulin: evaluation of safety, efficacy, mechanisms of action and impact on quality of life. Thromb Haemost 2004;91:771-8.

27. Hughes RAC, Donofrio P, Bril V, et al. Intravenous immune globulin (10% caprylate/chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial. Lancet Neurol 2008;7:136-44.

28. Hughes R, Bensa S, Willison H, et al. Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 2001;50(2):195-201.

GAMMAKED™

Immune Globulin Injection (Human), 10% Caprylate/Chromatography Purified

Instructions for Use: Subcutaneous Infusion for Primary Humoral Immunodeficiency

Information for Patients

Please read this information about GAMMAKED carefully before using this medicine. This information does not take the place of talking with your healthcare professional, and it does not include all of the important information about GAMMAKED. If you have any questions after reading this, contact your healthcare professional.

What is the most important information I should know about GAMMAKED?

GAMMAKED should be infused under your skin (in the subcutaneous tissue). DO NOT inject GAMMAKED into a blood vessel or directly into a muscle.

What is GAMMAKED?

GAMMAKED (gam-ked) is an immunoglobulin used to treat primary immune deficiency (PI). Immunoglobulin is another name for the purified antibodies from human plasma that defend the body against infections such as viruses and bacteria. People with PI lack the healthy antibodies needed to fight off these infections. GAMMAKED provides those healthy antibodies and will help lower the number and severity of infections you could get.

Who should NOT take GAMMAKED?

Do not take GAMMAKED if you have known severe allergic reactions or a severe response to Immune Globulin (Human). Tell your doctor if you have had a serious reaction to other medicines that contain immune globulin. Also tell your doctor if you have an immunoglobulin A (IgA) deficiency.

How should I take GAMMAKED?

You will take GAMMAKED through infusions given just below the skin (in the subcutaneous tissue). As directed by your physician, one or more injection sites on your body will be selected. The number and location of the injection sites depends on the amount you need to receive. Typically, adults may use 1 to 4 needles in different locations at one time. You may use up to 8 needles as directed by your doctor. For children, use up to 6 infusion sites simultaneously. For patients of all ages ensure that the infusion sites are at least 2 inches (5 cm) apart. The needles are attached with a tube to the pump. You will need to have infusions once a week.

Instructions for administering GAMMAKED are at the end of this patient Instructions for Use [see "Steps for Administration"]. Only use GAMMAKED by yourself after you have been instructed by your doctor or healthcare professional.

What should I avoid while taking GAMMAKED?

Certain types of vaccines (ones containing a live virus) may not work as well for you if you are also receiving immunoglobulin products like GAMMAKED. The antibodies in GAMMAKED may prevent the vaccine from working. Before you get a vaccine, tell the doctor or nurse that you are taking GAMMAKED.

Tell your doctor or healthcare professional if you are pregnant or plan to become pregnant, or if you are nursing.

What are possible side effects of GAMMAKED?

The most common side effects with GAMMAKED when given under the skin (subcutaneously) are:

• Redness, swelling, and itching at the injection site
• Fatigue
• Headache
• Pain (including pain in the joints, arms, legs)
• Diarrhea
• Nausea
• Migraine
• Fever

Tell your doctor right away or go to the emergency room if you have hives, trouble breathing, wheezing, dizziness, or fainting. These could be signs of a bad allergic reaction.

Tell your doctor right away if you have any of the following symptoms. They could be signs of a rare, but serious problem.

• Decreased urination, sudden weight gain, fluid retention/swelling in your legs, and/or shortness of breath. They could be signs of a serious kidney problem called renal failure.
Pain and/or swelling of an arm or leg with warmth over the affected area, discoloration of an arm or
• leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one side of the body. These could be signs of a blood clot in your body (thrombosis). Immediately report symptoms of thrombosis.
• Severe headache, stiff neck, fatigue, fever, sensitivity to light, painful eye movements, nausea and vomiting. These could be signs of a type of brain inflammation called aseptic meningitis.
• Increased heart rate, fatigue, yellow skin or eyes, and dark colored urine. These could be signs of a type of blood problem called hemolytic anemia.
• Chest pains, trouble breathing, blue lips or extremities, and fever. These could be signs of a lung problem called TRALI (transfusion-related acute lung injury).
• Fever over 100°F (37.8°C). This could be a sign of an infection.

Tell your doctor about any side effects that concern you. You can ask your doctor to give you the full prescribing information available to healthcare professionals.

Steps for Administration

Infuse GAMMAKED only after you have been trained by your doctor or healthcare professional. Below are step-by-step instructions to help you remember how to use GAMMAKED. Ask your doctor or healthcare professional about any instructions you do not understand.

Before Using GAMMAKED

• GAMMAKED comes in single-use vials. Do not let it freeze. Keep it refrigerated. If needed, GAMMAKED can be stored at room temperature for up to 6 months but you must use it within that time or you must throw it away.
• Do not shake the vials.
• Prior to use, allow the solution to come to room temperature (68-77°F or 20-25°C). This can take 60 minutes or longer.
• Do not use the vial if:
  • the solution is cloudy, discolored or contains particles. The solution should be clear to opalescent, and colorless to pale yellow.
  • the protective cap or plastic shrink band around the cap is missing, or there is any evidence of tampering. Tell your healthcare provider immediately.
  • the expiration date has passed.
• Sanitize your infusion set-up area by preparing a clean, flat, non-porous surface such as a kitchen counter. Avoid using porous surfaces such as wood. Clean the surface with an alcohol wipe using a circular motion from the center outward.

Step 1:

Wash and dry your hands thoroughly before administering GAMMAKED

• Your healthcare provider may recommend that you use antibacterial soap or that you wear gloves.

Step 2:

Remove the protective cap and sanitize the stopper

• Remove the protective cap from the vial to expose the central portion of the stopper.
• Wipe the stopper with alcohol and allow to dry.

Step 3:

Use aseptic technique when preparing and administering GAMMAKED

• Do not allow your fingers or other objects to touch the inner stem of the plunger, the syringe tip, or other areas that will come in contact with your GAMMAKED solution. This is called aseptic technique and is designed to prevent transmission of germs.
• Using aseptic technique, attach each needle to the syringe tip.

Step 4:

Prepare the syringe and draw GAMMAKED solution into syringe

• Remove cap from needle.
• Pull the syringe plunger back to the level matching the amount of GAMMAKED to be withdrawn from the vial.
• Place the GAMMAKED bottle on a clean flat surface and insert the needle into the center of the vial stopper.
• Inject air into the vial. The amount of air should match the amount of GAMMAKED to be withdrawn.
• Turn the vial upside down and withdraw the correct amount of GAMMAKED. If multiple vials are required to achieve the correct dose, repeat Step 4.

Step 5:

Fill the pump reservoir and prepare the infusion pump

• Follow the pump manufacturer’s instructions for filling the pump reservoir and preparing the infusion 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. To prime, hold the syringe in one hand and the administration tubing’s capped needle in the other. Gently squeeze on the plunger until you see a drop of GAMMAKED exit from the needle.

Example Equipment

Step 6:

Select the number and location of infusion sites

• Select one or more infusion sites as directed by your healthcare provider.
• The number and location of injection sites depends on the volume of the total dose.

Step 7:

Prepare the infusion site

• Cleanse the infusion 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 2 inches apart.

Step 8:

Insert the needle

• Grasp the skin between two fingers and insert the needle into the subcutaneous tissue.

Step 9:

Do not inject GAMMAKED into a blood vessel

• After inserting each needle into tissue (and before your infusion), make sure that a blood vessel has not been accidentally entered. To do this, attach a sterile syringe to the end of the primed administration tubing. Pull back on the syringe plunger and watch for any blood flowing back into administration tubing.
• If you see any blood, remove and discard the needle and administration tubing.
• 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.

Step 10:

Repeat for other sites, as needed

• If using multiple, simultaneous infusion sites, use Y-site connection tubing and secure to the administration tubing.

Step 11:

Infuse GAMMAKED following the pump manufacturer’s instructions for the infusion pump

Step 12:

After infusion, turn off pump and dispose of used supplies

• Follow manufacturer’s instructions to turn off pump.
• Undo and discard any dressing or tape.
• Gently remove the inserted needle(s) or catheter(s).
• Discard any unused solution in an appropriate waste container as instructed.
• Discard any used administration equipment in an appropriate waste container.
• Store your supplies in a safe place.
• Follow manufacturer's instructions to care for the infusion pump.

Step 13:

Record each infusion

• Remove the peel-off label with the product lot number from the GAMMAKED vial and use this to complete the patient record.
• Remember to bring your journal with you when you visit your physician or healthcare provider.

Be sure to tell your doctor about any problems you have doing your infusions. Your doctor may ask to see your journal, so be sure to take it with you each time you visit the doctor’s office.

Call your doctor for medical advice about side effects. You can also report side effects to FDA at 1- 800-FDA-1088 or www.fda.gov/medwatch.