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نشرة الممارس الصحي نشرة معلومات المريض بالعربية نشرة معلومات المريض بالانجليزية صور الدواء بيانات الدواء
  SFDA PIL (Patient Information Leaflet (PIL) are under review by Saudi Food and Drug Authority)

Information for Patients

Please read this information about GAMUNEX 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 GAMUNEX. If you have any questions after reading this, contact your healthcare professional.

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

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

What is GAMUNEX?

GAMUNEX (Găm-yōō-nĕx) 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. GAMUNEX provides those healthy antibodies and will help lower the number and severity of infections you could get.


Who should NOT take GAMUNEX?

Do not take GAMUNEX 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 GAMUNEX?

You will take GAMUNEX 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, people use 1 to 4 needles in different locations on your body at one time. You may use up to 8 needles as directed by your doctor. The needles are attached with a tube to the pump. You will need to have infusions once a week.

Instructions for administering GAMUNEX are at the end of this patient package insert (see "Steps for Administration"). Only use GAMUNEX by yourself after you have been instructed by your doctor or healthcare professional.

 

What should I avoid while taking GAMUNEX?

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

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

 

Steps for Administration

Infuse GAMUNEX 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 GAMUNEX. Ask your doctor or healthcare professional about any instructions you do not understand.

Before Using GAMUNEX

•       GAMUNEX comes in single-use vials. Do not let it freeze. Keep it refrigerated. If needed, GAMUNEX 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 and colorless to pale yellow.

•       the protective cap or plastic shrink band around the cap is missing.

•       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 GAMUNEX

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

 

Step 2:
Remove the protective cap and sanitize the rubber stopper

•       Remove the protective cap from the vial to expose the central portion of the rubber stopper.

•       Wipe the rubber stopper with alcohol and allow to dry.

 

Step 3:
Use aseptic technique when preparing and administering GAMUNEX

•       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 GAMUNEX 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 GAMUNEX solution into syringe

•       Remove cap from needle.

•       Pull the syringe plunger back to the level matching the amount of GAMUNEX to be withdrawn from the vial.

•       Place the GAMUNEX 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 GAMUNEX to be withdrawn.

•       Turn the vial upside down and withdraw the correct amount of GAMUNEX. 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 GAMUNEX. 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 GAMUNEX 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 GAMUNEX 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 GAMUNEX 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 GAMUNEX 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.


What are possible side effects of GAMUNEX?

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

•       Redness, swelling, and itching at the injection site

•       Headache

•       Fatigue

•       Pain (including pain in the back, joints, arms, legs)

•       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. 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.


Before Using GAMUNEX

•       GAMUNEX comes in single-use vials. Do not let it freeze. Keep it refrigerated. If needed, GAMUNEX 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 and colorless to pale yellow.

•       the protective cap or plastic shrink band around the cap is missing.

•       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.


GAMUNEX consists of 9%–11% protein in 0.16–0.24 M glycine. The buffering capacity of GAMUNEX is 35.0 mEq/L (0.35 mEq/g protein). A dose of 1 g/kg body weight therefore represents an acid load of 0.35 mEq/kg body weight. The total buffering capacity of whole blood in a normal individual is 45–50 mEq/L of blood, or 3.6 mEq/kg body weight. Thus, the acid load delivered with a dose of 1 g/kg of GAMUNEX would be neutralized by the buffering capacity of whole blood alone, even if the dose was infused instantaneously.


GAMUNEX is supplied in single-use, tamper evident vials (shrink band) containing the labeled amount of functionally active IgG. The two larger vial size labels incorporate integrated hangers. The components used in the packaging for GAMUNEX are latex-free. GAMUNEX is supplied in the following sizes: Size Grams Protein 25 mL 2.5 50 mL 5 100 mL 10

Grifols Therapeutics Inc.                                         

Research Triangle Park, NC 27709 USA


This leaflet was approved in 6/2017
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النشرة غير مترجمة للعربية حاليا لأن المستحضر للمستشفيات فقط، سوف يتم اضافة النشرة العربية بعد تقديمها واعتمادها من قبل الهيئة

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النشرة غير مترجمة للعربية حاليا لأن المستحضر للمستشفيات فقط، سوف يتم اضافة النشرة العربية بعد تقديمها واعتمادها من قبل الهيئة

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النشرة غير مترجمة للعربية حاليا لأن المستحضر للمستشفيات فقط، سوف يتم اضافة النشرة العربية بعد تقديمها واعتمادها من قبل الهيئة
 Read this leaflet carefully before you start using this product as it contains important information for you

GAMUNEX® 10%, [ HUMAN IMMUNOGLOBULIN PROTEINS 10%] Solution for Infusion

GAMUNEX consists of 9% - 11% protein in 0.16-0.24 M glycine. Not less than 98% of the protein has the electrophoretic mobility of gamma globulin. GAMUNEX contains trace levels of fragments, IgA (average 0.046 mg/mL), and IgM. The pH of GAMUNEX is 4.0 – 4.5. GAMUNEX contains no preservative and is latex free. The distribution of IgG subclasses is similar to that found in normal serum.

GAMUNEX is a ready-to-use sterile solution of human immune globulin protein for intravenous and subcutaneous (Primary Humoral Immunodeficiency indication only) administration.

4.1.1 Primary Humoral Immunodeficiency (PI)
GAMUNEX is indicated as replacement therapy of primary humoral immunodeficiency.
This includes, but is not limited to, congenital agammaglobulinemia, common variable
immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe
combined immunodeficiencies. 
4.1.2 Idiopathic Thrombocytopenic Purpura (ITP)
GAMUNEX is indicated for the treatment of patients with Idiopathic Thrombocytopenic
Purpura to raise platelet counts to prevent bleeding or to allow a patient with ITP to undergo
surgery. 
4.1.3 Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
GAMUNEX is indicated for the treatment of CIDP to improve neuromuscular disability and
impairment and for maintenance therapy to prevent relapse.

 



GAMUNEX consists of 9%–11% protein in 0.16–0.24 M glycine. The buffering capacity of
GAMUNEX is 35.0 mEq/L (0.35 mEq/g protein). A dose of 1 g/kg body weight therefore represents an acid load of 0.35 mEq/kg body weight. The total buffering capacity of whole
blood in a normal individual is 45–50 mEq/L of blood, or 3.6 mEq/kg body weight. Thus, the
acid load delivered with a dose of 1 g/kg of GAMUNEX would be neutralized by the
buffering capacity of whole blood alone, even if the dose was infused instantaneously.
4.2.1.1 PI
As there are significant differences in the half-life of IgG among patients with primary
humoral immunodeficiencies, the 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 GAMUNEX for patients with PI is 300 to 600 mg/kg body weight (3-6 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
GAMUNEX at the minimum infusion rate practicable.
If a patient routinely receives a dose of less than 400 mg/kg of GAMUNEX 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 GAMUNEX
therapy and serum IgG trough levels. Begin treatment with GAMUNEX one week after the
patient’s last IGIV infusion. See below under “Initial Weekly Dose”. Prior to switching
treatment from IGIV to GAMUNEX, obtain the patient’s serum IgG trough level to guide
subsequent dose adjustments. See below under “Dose Adjustment”.
Establish the initial weekly dose of GAMUNEX 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 GAMUNEX, convert the monthly IGIV dose 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 GAMUNEX, 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 = 1.37 × previous IGIV dose (in grams)
Number of weeks between IGIV doses
To convert the GAMUNEX dose (in grams) to milliliters (mL), multiply the calculated 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 patients 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 the below 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 1000 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 GAMUNEX from another Immune Globulin
Subcutaneous (IGSC) product have not been studied. If a patient on GAMUNEX does not
maintain an adequate clinical response or a serum IgG trough level equivalent to that of the
previous IGSC treatment, the physician may want to adjust the dose. For such patients, the
above also provides guidance for dose adjustment to achieve a desired IGSC trough level.
4.2.1.2 ITP
DO NOT ADMINISTER SUBCUTANEOUSLY
GAMUNEX 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
1g/kg (10 mL/kg) body weight may be withheld.
Forty-eight ITP subjects were treated with 2 g/kg GAMUNEX, divided in two 1 g/kg doses
(10 mL/kg) given on two successive days. With this dose regimen 35/39 subjects (90%)
responded with a platelet count from less than or equal to 20 x109/L to more than or equal to
50 x109/L within 7 days after treatment. 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.
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
GAMUNEX at the minimum infusion rate practicable.
4.2.1.3 CIDP
GAMUNEX 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. GAMUNEX 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.
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
GAMUNEX at the minimum infusion rate practicable.

4.2.2 Method of Administration
Administer intravenously for PI, ITP and CIDP.
GAMUNEX may also be administered subcutaneously for the treatment of PI.
▪ Administer GAMUNEX at room temperature.
▪ Inspect GAMUNEX 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.
4.2.2.1 Intravenous
▪ 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.

GAMUNEX vial sizeGauge of needle to penetrate stopper
25, 50, 100, mL16 gauge


GAMUNEX vial 25, 50, 100, mL size, Gauge of needle to penetrate stopper 16 gauge
▪ Use promptly any vial that has been opened.
▪ Discard partially used vials.
▪ If dilution is required, GAMUNEX may be diluted with 5% dextrose in water (D5/W).
Do not dilute with saline. Infuse GAMUNEX using a separate line by itself, without
mixing with other intravenous fluids or medications the subject might be receiving. The
GAMUNEX infusion line can be flushed with 5% dextrose in water (D5/W) or 0.9%
sodium chloride for injection.
4.2.2.2 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 GAMUNEX for injection.
2. Remove the protective cap from the vial to expose the central portion of the rubber
stopper.
3. Wipe the rubber stopper with alcohol and allow to dry.
4. Using a sterile syringe and needle, prepare to withdraw GAMUNEX by first injecting air
into the vial that is equivalent to the amount of GAMUNEX to be withdrawn. Then
withdraw the desired volume of GAMUNEX. If multiple vials are required to achieve the
desired dose, repeat this step.
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 GAMUNEX.
6. Select the number and location of injection sites.
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.
8. Grasp the skin between two fingers and insert the needle into the subcutaneous tissue.
9. 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.
10. If using multiple, simultaneous injection sites, use Y-site connection tubing and secure to
the administration tubing.
11. Infuse GAMUNEX following the manufacturer’s instructions for the pump.

4.2.2.3 Rate of Administration
Intravenous
Following initial infusion (see 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 GAMUNEX at the minimum
infusion rate practicable and discontinue GAMUNEX if renal function deteriorates.
Subcutaneous for PI Only
For PI, it is recommended that GAMUNEX is infused at a rate of 20 mL/hr per infusion site.
In the SC clinical study, the mean volume administered per infusion site was 34 mL (17-69
mL) and the majority of infusions were administered at a rate of 20 mL/hr per site. Multiple
simultaneous infusion sites were enabled by administration tubing and Y-site connection
tubing. Most subjects utilized 4 infusion sites per infusion with abdomen and thighs being the
most commonly used sites. The maximum number of infusion sites is 8. Injection sites
should be at least 2 inches apart.


4.3.1 Hypersensitivity Reactions to Immune Globulins GAMUNEX is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. 4.3.2 IgA Sensitive Patients with History of Hypersensitivity Reaction GAMUNEX is contraindicated in IgA deficient patients with antibodies against IgA and history of hypersensitivity.

WARNING: THROMBOSIS, RENAL DYSFUNCTION, and ACUTE RENAL
FAILURE
• Thrombosis may occur with immune globulin products, including GAMUNEX. 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.
• For patients at risk of thrombosis, administer GAMUNEX 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.
• Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur with
immune globulin intravenous (IGIV) products in predisposed patients. Patients
predisposed to renal dysfunction include those with any degree of pre-existing renal
insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis,
paraproteinemia, or patients receiving known nephrotoxic drugs.
• Renal dysfunction and acute renal failure occur more commonly in patients receiving
IGIV products containing sucrose. (1) GAMUNEX does not contain sucrose.
• For patients at risk of renal dysfunction or failure, administer GAMUNEX at the
minimum concentration available and the minimum infusion rate practicable.
4.4.1 Hypersensitivity
Severe hypersensitivity reactions may occur with IGIV products, including GAMUNEX. In
case of hypersensitivity, discontinue GAMUNEX infusion immediately and institute
appropriate treatment. Have medications such as epinephrine available for immediate
treatment of acute hypersensitivity reaction.
GAMUNEX 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.
4.4.2 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. (17) GAMUNEX does not contain sucrose. Assure that patients are not
volume depleted prior to the initiation of the infusion of GAMUNEX. 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
GAMUNEX and again at appropriate intervals thereafter. If renal function deteriorates,
consider discontinuation of GAMUNEX. 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 GAMUNEX at the minimum infusion rate
practicable [less than 8 mg IG/kg/min (0.08 mL/kg/min)].

4.4.3 Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia
Hyperproteinemia, increased serum viscosity and hyponatremia may occur in patients
receiving IGIV treatment, including GAMUNEX. 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. (8)
4.4.4 Thrombosis
Thrombosis may occur following treatment with immune globulin products, including
GAMUNEX. 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
GAMUNEX 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.
4.4.5 Aseptic Meningitis Syndrome (AMS)
AMS may occur infrequently with IGIV treatment, including GAMUNEX. 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.
4.4.6 Hemolysis
IGIV products, including GAMUNEX, 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, rarely, hemolysis. (12-14) Delayed
hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC
sequestration, and acute hemolysis consistent with intravascular hemolysis, has been
reported.

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.
(29) Underlying inflammatory state in an individual patient may increase the risk of
hemolysis, but its role is uncertain. (30)
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 approximately 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 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.
4.4.7 Transfusion-Related Acute Lung Injury (TRALI)
Noncardiogenic pulmonary edema may occur in patients following treatment with IGIV
products, including GAMUNEX. (16) 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. 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.
4.4.8 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.
4.4.9 Transmissible Infectious Agents
Because GAMUNEX is made from human blood, it may carry a risk of transmitting
infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.
No cases of transmission of viral diseases or CJD have ever been identified for GAMUNEX.
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 Inc.
[1-800-520-2807]
4.4.10 Hematoma Formation
Do not administer GAMUNEX subcutaneously in patients with ITP because of the risk of
hematoma formation.

4.4.11 Information for Patients
Instruct patients to immediately report the following signs and symptoms to their healthcare
provider:
• Decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of
breath
• Symptoms of thrombosis which may include: 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
• Severe headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye
movements, nausea, and vomiting
• Increased heart rate, fatigue, yellowing of the skin or eyes, and dark-colored urine
• Trouble breathing, chest pain, blue lips or extremities, and fever
Inform patients that GAMUNEX is made from human plasma and may contain infectious
agents that can cause disease. While the risk GAMUNEX can transmit an infectious agent
has been reduced by screening plasma donors for prior exposure, testing donated plasma, and
by inactivating or removing certain viruses during manufacturing, patients should report any
symptoms that concern them.
Inform patients that GAMUNEX can interfere with their immune response to live viral
vaccines such as measles, mumps and rubella. Inform patients to notify their healthcare
professional of this potential interaction when they are receiving vaccinations.
PI: Self-Administration: Subcutaneous Administration Only
Provide the patient with instructions on subcutaneous infusion for home treatment, if the
physician believes that home administration is appropriate for the patient.
• The type of equipment to be used along with its maintenance,
• proper infusion techniques, selection of appropriate infusion sites (e.g., abdomen, thighs,
upper arms, and/or lateral hip),
• maintenance of a treatment diary,
• measures to be taken in case of adverse reactions in the patient instructions.
4.4.12 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 GAMUNEX 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 GAMUNEX,
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.
4.4.13 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.
4.4.14 Pediatric Use
PI: Intravenous
GAMUNEX was evaluated in 18 pediatric subjects (age range 0-16 years). Twenty-one
percent of PI subjects exposed to GAMUNEX 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 GAMUNEX was evaluated in only three pediatric subjects (age range 13-15) with PI.
This number of pediatric subjects was too small for separate evaluation of pharmacokinetics
and safety to determine whether they respond differently from adults. Efficacy and safety in
pediatric patients using the SC route of administration have not been established.
ITP
For treatment of ITP, GAMUNEX must be administered by the intravenous route.
GAMUNEX was evaluated in 12 pediatric subjects with acute ITP. Twenty-five percent of
the acute ITP subjects exposed to GAMUNEX 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 GAMUNEX. The death was judged to be
unrelated to GAMUNEX.
CIDP
The safety and effectiveness of GAMUNEX have not been established in pediatric subjects
with CIDP.

4.4.15 Geriatric Use
Use caution when administering GAMUNEX to patients age 65 and over who are at
increased risk for thrombosis or renal insufficiency. Do not exceed recommended doses, and
administer GAMUNEX at the minimum infusion rate practicable. Clinical studies of
GAMUNEX did not include sufficient numbers of subjects aged 65 and over to determine
whether they respond differently from younger subjects.

 


GAMUNEX may be diluted with 5% dextrose in water (D5/W). Do not dilute with saline.
Admixtures of GAMUNEX with other drugs and intravenous solutions have not been
evaluated. It is recommended that GAMUNEX be administered separately from other drugs
or medications which the patient may be receiving. The product should not be mixed with
IGIVs from other manufacturers.
The infusion line may be flushed before and after administration of GAMUNEX with 5%
dextrose in water (D5/W) or 0.9% sodium chloride for injection.
Avoid simultaneous administration of GAMUNEX and Heparin through a single lumen
delivery device due to GAMUNEX, Heparin incompatibilities. Flush Heparin Lock (Hep-
Lock) through which GAMUNEX was administered with 5% dextrose in water (D5/W), or
0.9% sodium chloride for injection, and do not flush with Heparin.
Various passively transferred antibodies in immunoglobulin preparations can confound the
results of serological testing.
Passive transfer of antibodies may transiently interfere with the immune response to live
virus vaccines such as measles, mumps, rubella and varicella. Inform the immunizing
physician of recent therapy with GAMUNEX so that appropriate measures may be taken.


Pregnancy Category C. Animal reproduction studies have not been conducted with
GAMUNEX. It is not known whether GAMUNEX can cause fetal harm when administered
to a pregnant woman or can affect reproduction capacity. GAMUNEX should be given to a
pregnant woman only if clearly needed. Immunoglobulins cross the placenta from maternal
circulation increasingly after 30 weeks of gestation. (18,19)
Use of GAMUNEX has not been evaluated in nursing mothers.


The ability to drive and operate machines may be impaired by some adverse reactions
associated with GAMUNEX. Patients who experience adverse reactions during treatment
should wait for these to resolve before driving or operating machines..


4.8.1 Postmarketing
Because adverse reactions are voluntary and 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.
GAMUNEX Postmarketing Experience
The following adverse reactions have been identified and reported during the post marketing
use of GAMUNEX:
• Hematologic: Hemolytic anemia
• Infections and Infestations: Aseptic meningitis
The following adverse reactions have been identified and reported during the overall post
marketing use of IGIV products: (17)
• Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS),
TRALI, cyanosis, hypoxemia, pulmonary edema,
dyspnea, bronchospasm
• Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse,
hypotension
• Neurological: Coma, loss of consciousness, seizures/convulsions,
tremor
• Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema
multiforme, bullous dermatitis
• Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct
antiglobulin (Coombs test)
• General/Body as a Whole: Pyrexia, rigors
• Musculoskeletal: Back pain
• Gastrointestinal: Hepatic dysfunction, abdominal pain
4.8.2 Clinical Trials
PI: Intravenous: The most common adverse reactions observed at a rate ≥5% in subjects with
intravenous treatment in the clinical trials were headache, cough, injection site reaction,
nausea, pharyngitis and urticaria.
PI: Subcutaneous: The most common adverse reactions observed at a rate ≥5% of subjects
with subcutaneous treatment in the clinical trials were infusion site reactions, headache,
fatigue, arthralgia and pyrexia.

ITP: The most common adverse reactions observed at a rate ≥5% in subjects in the clinical
trials were headache, vomiting, fever, nausea, back pain and rash.
CIDP: The most common adverse reactions observed at a rate ≥5% in subjects in the clinical
trial were headache, fever, chills, hypertension, rash, nausea and asthenia.


With intravenous administration, overdose of GAMUNEX may lead to fluid overload and
hyperviscosity. Patients at risk of complications of fluid overload and hyperviscosity include
elderly patients and those with cardiac renal impairment.


Immunoglobulins are fractionated blood products made from pooled human plasma.
Immunoglobulins are endogenous proteins produced by B lymphocyte cells. The main
component of GAMUNEX is IgG (≥98%) with a sub-class distribution of IgG1, IgG2, IgG3
and IgG4 of approximately 62.8%, 29.7%, 4.8% and 2.7% respectively.
5.1.1 Mechanism of Action
5.1.1.1 PI
GAMUNEX supplies a broad spectrum of opsonic and neutralizing IgG antibodies against
bacteria, viral, parasitic, mycoplasma agents, and their toxins. The mechanism of action in PI
has not been fully elucidated.
5.1.1.2 ITP
The mechanism of action of high doses of immunoglobulins in the treatment of ITP has not
been fully elucidated.
5.1.1.3 CIDP
The precise mechanism of action in CIDP has not been fully elucidated.
5.1.2 PI: Intravenous Administration
In a randomized, double-blind, parallel group clinical trial with 172 subjects with primary
humoral immunodeficiencies GAMUNEX 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.
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.

 

The annual rate of validated infections (Number of Infection/year/subject) was 0.18 in the
group treated with GAMUNEX 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).
5.1.3 ITP
A double-blind, randomized, parallel group clinical trial with 97 ITP subjects was carried out
to prove the hypothesis that GAMUNEX 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.
GAMUNEX was demonstrated to be at least as effective as GAMIMUNE N, 10% in the
treatment of adults and children with acute or chronic ITP.

                                                     Platelet Response of Per Protocol Analysis

A trial was conducted to evaluate the clinical response to rapid infusion of GAMUNEX in
patients with ITP. The study involved 28 chronic ITP subjects, wherein the subjects received
1 g/kg GAMUNEX 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. Pretreatment
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).
5.1.4 CIDP
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 GAMUNEX. (27) This study included two separately randomized
periods to assess whether GAMUNEX 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 GAMUNEX could maintain long-term 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 GAMUNEX 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 GAMUNEX 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 bw (or equivalent volume of Placebo) every three
weeks.
The Responder rates of the GAMUNEX and Placebo treatment groups was 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 GAMUNEX: 28 of 59 subjects (47.5%) responded to
GAMUNEX 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 GAMUNEX was
evaluated: 31 were randomly reassigned to continue to receive GAMUNEX and 26 subjects
were randomly reassigned to Placebo in the Randomized Withdrawal Period. Subjects who
continued to receive GAMUNEX experienced a longer time to relapse versus subjects treated
with Placebo (p=0.011). The probability of relapse was 13% with GAMUNEX versus 45%
with Placebo (hazard ratio, 0.19; 95% confidence interval, 0.05, 0.70).

                                                        Outcomes in Intent-to-Treat Population Efficacy Period

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

                                                                                                 Outcomes in Rescue Phase

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


5.2.1 Intravenous Administration
Two randomized pharmacokinetic crossover trials were carried out with GAMUNEX in 38
subjects with Primary Humoral Immunodeficiencies given 3 infusions 3 or 4 weeks apart of
test product at a dose of 100-600 mg/kg body weight per infusion. One trial compared the
pharmacokinetic characteristics of GAMUNEX to GAMIMUNE N, 10% and the other trial
compared the pharmacokinetics of GAMUNEX (10% strength) with a 5% concentration of
this product. The ratio of the geometric least square means for dose-normalized IgG peak
levels of GAMUNEX and GAMIMUNE N, 10% was 0.996. The corresponding value for the
dose-normalized area under the curve (AUC) of IgG levels was 0.990. The results of both PK
parameters were within the pre-established limits of 0.080 and 1.25. Similar results were
obtained in the comparison of GAMUNEX 10% to a 5% concentration of GAMUNEX.

The main pharmacokinetic parameters of GAMUNEX, measured as total IgG in study
100152 are displayed below:

                                                PK Parameters of GAMUNEX and GAMIMUNE® N, 10%

The two pharmacokinetic trials with GAMUNEX show the IgG concentration/time curve
follows a biphasic slope with a distribution phase of about 5 days characterized by a fall in
serum IgG levels to about 65-75% of the peak levels achieved immediately post-infusion.
This phase is followed by the elimination phase with a half-life of approximately 35 days.
IgG trough levels were measured over nine months in the therapeutic equivalence trial. Mean
trough levels were 7.8 ± 1.9 mg/mL for the GAMUNEX treatment group and 8.2 ± 2.0
mg/mL for the GAMIMUNE N, 10% control group.
5.2.2 PI: Subcutaneous Administration
In a single sequence, open-label, crossover trial, the pharmacokinetics, safety, and tolerability
of SC administered GAMUNEX in subjects with PI were evaluated. A total of 32 and 26
subjects received GAMUNEX as IV or SC for PK study, respectively. Subjects received
GAMUNEX 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. The PK endpoint
parameter (AUC of total plasma IgG) following IV and SC administration is summarized
below. 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.

5.2.3 Absorption
GAMUNEX is administered by intravenous and subcutaneous infusion.
5.2.3.1 Intravenous:
Absorption is not applicable for intravenous administration.
5.2.3.2 Subcutaneous:
At steady state, plasma concentrations of total IgG remain relatively constant over the 7 day
dosing interval, with small fluctuations between Cmax and Ctrough.
5.2.4 Distribution
5.2.4.1 Intravenous
Human normal immunoglobulin is immediately and completely bioavailable in the
recipient’s circulation after intravenous administration. It is distributed relatively rapidly
between plasma and extravascular fluid, after approximately 3-5 days equilibrium is reached
between the intra- and extravascular compartments. Two pharmacokinetic trials with
GAMUNEX show the IgG concentration/time curve follows a biphasic slope with a distribution phase of about 5 days characterized by a fall in serum IgG levels to about 65-75
percent of the peak levels achieved immediately post infusion.
5.2.4.2 Subcutaneous
A total of 32 adults and adolescent subjects demonstrated the weekly GAMUNEX
subcutaneous dose calculated based on a conversion factor of 1.37 provides comparable
overall exposure to plasma total IgG (AUC) to that produced by the regular IV dose. Weekly
SC administration of GAMUNEX provided a relatively constant steady state trough plasma
concentration of total IgG (11.4 mg/mL) which is approximately 19% higher than that (9.58
mg/mL) obtained after IV administration of GAMUNEX. Data from clinical trials show that
trough levels of GAMUNEX can be maintained by weekly dosing regimens for subcutaneous
administration.
5.2.5 Biotransformation
Immunoglobulins and IgG complexes are broken down in the cells of the mononuclear
phagocytic system.
5.2.6 Elimination
Human normal immunoglobulin has a half-life of about 35 days. This half-life may vary
from patient to patient, in particular in primary immunodeficiency.
5.2.7 Linearity/Non-Linearity
The linearity or non-linearity of GAMUNEX pharmacokinetics has not been investigated.


Immunoglobulins are normal components of the human body. Because administration of
immunoglobulins in animal studies may lead to the formation of antibodies, preclinical safety
data are limited. In the acute and sub-acute animal studies that were performed,
GAMUNEX did not show special risks for humans.


 


If dilution is required, GAMUNEX may be diluted with 5% dextrose in water (D5/W). Do
not dilute with saline. No other drug interactions or compatibilities have been evaluated.
Avoid simultaneous administration of GAMUNEX and Heparin through a single lumen
delivery device due to GAMUNEX, Heparin incompatibilities. Flush Heparin Lock (Hep-
Lock) through which GAMUNEX was administered with 5% dextrose in water (D5/W) or
0.9% sodium chloride for injection, and do not flush with Heparin (see below).


• GAMUNEX may be stored for 36 months at 2 – 8oC (36 – 46oF) from the date of manufacture, AND product may be stored at temperatures not to exceed 25oC (77oF) for up to 6 months anytime during the 36 month shelf life, after which the product must be immediately used or discarded. • Do not use after expiration date.

• Store at 2–8oC (36–46oF).
• DO NOT FREEZE.
• Do not use after expiration date.


GAMUNEX is supplied in single-use, tamper evident vials (shrink band) containing the
labeled amount of functionally active IgG. The larger vial size labels incorporate integrated
hangers. The components used in the packaging for GAMUNEX are latex-free.
GAMUNEX is supplied in the following sizes:


6.6.1 Preparation and Handling
• Visually inspect GAMUNEX for particulate matter and discoloration prior to
administration, whenever solution and container permit. Do not use if turbid and / or if
discoloration is observed.
• Do not freeze. Do not use solutions that have been frozen.
• The GAMUNEX vial is for single use only. GAMUNEX contains no preservative. Use
any vial that has been entered promptly. Discard partially used vials.
• Infuse GAMUNEX using a separate line by itself, without mixing with other intravenous
fluids or medications the subject might be receiving. The
GAMUNEX infusion line can be flushed with 5% dextrose in water (D5/W) or 0.9%
sodium chloride for injection.
• If dilution is required, GAMUNEX may be diluted with 5% dextrose in water (D5/W).
Do not dilute with saline. No other drug interactions or compatibilities have been
evaluated.
• Content of vials may be pooled under aseptic conditions into sterile infusion bags and
infused within 8 hours after pooling.
• Avoid simultaneous administration of GAMUNEX and Heparin through a single lumen
delivery device due to GAMUNEX, Heparin incompatibilities. Flush Heparin Lock (Hep-
Lock) through which GAMUNEX was administered with 5% dextrose in water (D5/W),
or 0.9% sodium chloride for injection and do not flush with Heparin (see below).• Do not mix with immune globulin intravenous (IGIV) products from other
manufacturers.
• Do not use after expiration date.


Grifols Therapeutics Inc., Research Triangle Park, NC 27709, USA

June 2017
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