Primary humoral immunodeficiency (PI)

Gamunex 10% is indicated for treatment of primary humoral immunodeficiency (PI) 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.

Idiopathic thrombocytopenic purpura (ITP)

Gamunex 10% is indicated for the treatment of adults and children with idiopathic thrombocytopenic purpura (ITP) to raise platelet counts to prevent bleeding or to allow a patient with ITP to undergo surgery.

Chronic inflammatory demyelinating polyneuropathy (CIDP)

Gamunex 10% is indicated for the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) in adults to improve neuromuscular disability and impairment and for maintenance therapy to prevent relapse. 

Treatment should be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency.

Posology

The dose and dose regimen is dependent on the indication. 

The dose may need to be individualized for each patient dependent on the clinical response.  

The following dose regimens are given as a guideline.

Primary humoral immunodeficiency (PI)

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

Intravenous (IV)

The dose of Gamunex 10% for patients with PI is 300 mg/kg to 600 mg/kg body weight
(3 mL/kg to 6 mL/kg) administered every 3 to 4 weeks. The dosage may be adjusted over time to achieve the desired trough levels and clinical responses.

The recommended initial infusion rate is 1 mg/kg/min (0.01 mL/kg/min). If the infusion is well-tolerated, the rate may be gradually increased to a maximum of 8 mg/kg/min
(0.08 mL/kg/min). For patients judged to be at risk for renal dysfunction or thrombosis, administer Gamunex 10% at the minimum infusion rate practicable.

If a patient routinely receives a dose of less than 400 mg/kg of Gamunex 10% 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 10% therapy and serum IgG trough levels. Begin treatment with Gamunex 10% one week after the patient’s last IGIV infusion. See below under “Initial Weekly Dose”. Prior to switching treatment from IGIV to Gamunex 10%, 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 10% 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 10%, convert the monthly IGIV dose (in grams) by multiplying by 1.37, then dividing this dose into weekly doses based on the patient’s previous IGIV treatment interval. Monitor the patient’s clinical response, and adjust dose accordingly. 

Initial weekly dose
To calculate the initial weekly dose of subcutaneous administration of Gamunex 10%, multiply the previous IGIV dose in grams by the dose adjustment factor of 1.37; then divide this by the number of weeks between doses during the patient’s IGIV treatment (i.e., 3 or 4).

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

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

Dose adjustment
Over time, the dose may need to be adjusted to achieve the desired clinical response and serum IgG trough level. To determine if a dose adjustment may be considered, measure the patient’s serum IgG trough level on IGIV and as early as 5 weeks after switching from IGIV to subcutaneous. The target serum IgG trough level on weekly SC treatment is projected to be the last IGIV trough level plus 340 mg/dL. To determine if further dose adjustments are necessary, monitor the 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 following table and the corresponding amount (in mL) by which to increase or decrease the weekly dose based on the patient’s body weight. However, the patient’s clinical response should be the primary consideration in dose adjustment.

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

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

Dosage requirements for patients switching to Gamunex 10% from another Immune Globulin Subcutaneous (IGSC) product have not been studied. If a patient on Gamunex 10% does not maintain an adequate clinical response or a serum IgG trough level equivalent to that of the previous IGSC treatment, adjust the dose accordingly. For such patients, the above table also provides guidance for dose adjustment to achieve a desired IGSC trough level.

Idiopathic thrombocytopenic purpura (ITP)

DO NOT ADMINISTER SUBCUTANEOUSLY

Gamunex 10% 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.

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 10% at the minimum infusion rate practicable. 

Chronic inflammatory demyelinating polyneuropathy (CIDP)

Gamunex 10% 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 10% 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 10% at the minimum infusion rate practicable.

Method of administration

Administer intravenously for PI, ITP and CIDP.

Gamunex 10% may also be administered subcutaneously for the treatment of PI.

• Administer Gamunex 10% at room temperature.
• Inspect Gamunex 10% visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.  
• Do not use if turbid and/or if discoloration is observed.

Intravenous

• Use 16 gauge needles or dispensing pins only. 
• Insert needles or dispensing pins only once and be within the stopper area delineated by the raised ring.
• Penetrate the stopper perpendicular to the plane of the stopper within the ring.

• Use promptly any vial that has been opened. 
• Discard partially used vials.
• If dilution is required, Gamunex 10% may be diluted with 5% dextrose in water (D5/W). Do not dilute with saline. Infuse Gamunex 10% using a separate line by itself, without mixing with other intravenous fluids or medications the subject might be receiving.  The Gamunex 10% infusion line can be flushed with 5% dextrose in water (D5/W) or 0.9% sodium chloride for injection.

Subcutaneous for PI only

Instructions for administration

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

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

Rate of administration

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

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

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

Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients at risk of renal dysfunction or thrombosis, administer Gamunex 10% at the minimum infusion rate practicable and discontinue Gamunex 10% if renal function deteriorates.

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

WARNING: THROMBOSIS, RENAL DYSFUNCTION, and  ACUTE RENAL FAILURE

• Thrombosis may occur with immunoglobulin products, including Gamunex 10%. 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 10% 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. Gamunex 10% does not contain sucrose. 
• For patients at risk of renal dysfunction or failure, administer Gamunex 10% at the minimum concentration available and the minimum infusion rate practicable. 

Hypersensitivity

Severe hypersensitivity reactions may occur with IGIV products, including Gamunex 10%. In case of hypersensitivity, discontinue Gamunex 10% infusion immediately and institute appropriate treatment. Have medications such as epinephrine available for immediate treatment of acute hypersensitivity reaction. 

Gamunex 10% 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.

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. Gamunex 10% does not contain sucrose. Ensure that patients are not volume depleted prior to the initiation of the infusion of Gamunex 10%. 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 10% and again at appropriate intervals thereafter. If renal function deteriorates, consider discontinuation of Gamunex 10%. 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 10% at the minimum infusion rate practicable [less than 8 mg/kg/min (0.08 mL/kg/min)].

Hyperproteinemia, increased serum viscosity, and hyponatremia

Hyperproteinemia, increased serum viscosity and hyponatremia may occur in patients receiving IGIV treatment, including Gamunex 10%. 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. 

Thrombosis

Thrombosis may occur following treatment with immunoglobulin products, including Gamunex 10%. 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 10% 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.

Aseptic meningitis syndrome (AMS)

AMS may occur infrequently with IGIV treatment, including Gamunex 10%. 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.

Hemolysis

Gamunex 10% may contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin reaction and hemolysis.  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.  Underlying inflammatory state in an individual patient may increase the risk of hemolysis, but its role is uncertain.

Closely monitor patients for clinical signs and symptoms of hemolysis, particularly patients with risk factors noted above and those with pre-existing anemia and/ or cardiovascular or pulmonary compromise. Consider appropriate laboratory testing in higher risk patients, including measurement of hemoglobin or hematocrit prior to infusion and within approximately 36 hours and again 7 to 10 days post infusion. If clinical signs and symptoms of hemolysis or a significant drop in hemoglobin or hematocrit have been observed, perform additional confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis.

Transfusion-related acute lung injury (TRALI)

Noncardiogenic pulmonary edema may occur in patients following treatment with IGIV products, including Gamunex 10%. 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.

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.

Hematoma formation

Do not administer Gamunex 10% subcutaneously in patients with ITP because of the risk of hematoma formation.

Transmissible infectious agents

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, and for the non-enveloped viruses HAV and parvovirus B19.

There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19 transmission with immunoglobulins and it is also assumed that the antibody content makes an important contribution to viral safety.

It is strongly recommended that every time Gamunex 10% is administered to a patient, the name and batch number of the product are recorded in order to maintain a record of the batches used.

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 10% is made from human plasma and may contain infectious agents that can cause disease.  While the risk Gamunex 10% can transmit an infectious agent has been reduced by screening plasma donors for prior exposure, testing donated plasma, and by inactivating or removing pathogens during manufacturing, patients should report any symptoms that concern them.

Inform patients that Gamunex 10% can interfere with their immune response to live virus 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

Advise the patient to read the patient leaflet.

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, and
• measures to be taken in case of adverse reactions in the patient instructions.

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 10% 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 10%, 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.

Interference with laboratory tests

After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs) test. 

Pediatric use

PI: Intravenous

Gamunex 10% was evaluated in 18 pediatric subjects (age range 0-16 years). Twenty-one percent of PI subjects exposed to Gamunex 10% 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 10% was evaluated in only three pediatric subjects (age range 13-15 years) with PI along with adults, and separately in a second trial in 11 children and adolescents (age range 2-16 years). Pharmacokinetics and safety were similar to those in adults. No pediatric-specific dose requirements were necessary to achieve circulating IgG levels. Efficacy and safety in pediatric patients under 2 years of age using the SC route of administration have not been established. 

ITP

For treatment of ITP, Gamunex 10% must be administered by the intravenous route.

Gamunex 10% was evaluated in 12 pediatric subjects with acute ITP.  Twenty-five percent of the acute ITP subjects exposed to Gamunex 10% 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 10%. The death was judged to be unrelated to Gamunex 10%.

CIDP

The safety and effectiveness of Gamunex 10% have not been established in pediatric subjects with CIDP.

Geriatric use

Use caution when administering Gamunex 10% to patients age 65 and over who are at increased risk for thrombosis or renal insufficiency.  Do not exceed recommended doses, and administer Gamunex 10% at the minimum infusion rate practicable. Clinical studies of Gamunex 10% did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Gamunex 10% may be diluted with 5% dextrose in water (D5/W). Do not dilute with saline. Admixtures of Gamunex 10% with other drugs and intravenous solutions have not been evaluated. It is recommended that Gamunex 10% 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 10% with
5% dextrose in water (D5/W) or 0.9% sodium chloride for injection.

Avoid simultaneous administration of Gamunex 10% and Heparin through a single lumen delivery device due to Gamunex 10%, Heparin incompatibilities. Flush Heparin Lock (Hep-Lock) through which Gamunex 10% 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 10% so that appropriate measures may be taken.

Fertility

Effect of Gamunex 10% on reproduction and fertility is not known.

Pregnancy

There are no data with Gamunex 10% use in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with Gamunex 10%. It is not known whether Gamunex 10% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Gamunex 10% should be given to a pregnant woman only if clearly needed. 

Lactation

There is no information regarding the presence of Gamunex 10% in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Gamunex 10% and any potential adverse effects on the breastfed infant from Gamunex 10% or from the underlying maternal condition.

The ability to drive and operate machines may be impaired by some adverse reactions associated with Gamunex 10%. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.

Summary of the safety profile

Adverse reactions caused by human normal immunoglobulins (in decreasing frequency) encompass (see also Section 4.4): 

• chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain 
• reversible haemolytic reactions; especially in those patients with blood groups A, B and AB and (rarely) haemolytic anaemia requiring transfusion 
• (rarely) a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration 
• (rarely) transient cutaneous reactions (including cutaneous lupus erythematosus - frequency unknown) 
• (very rarely) thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep vein thromboses 
• cases of reversible aseptic meningitis 
• cases of increased serum creatinine level and/or occurrence of acute renal failure 
• cases of Transfusion Related Acute Lung Injury (TRALI) 

Tabulated list of adverse reactions

The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level). 

Frequencies have been evaluated according to the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse Reactions in 1 or more Subjects associated with IV Infusion of Gamunex 10% in clinical trials 

Adverse Reactions in 2 or more Subjects associated with SC Infusion of Gamunex 10% in clinical trials 

Paediatric population

Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

To report any side effect(s):

Saudi Arabia:

• The National Pharmacovigilance Centre (NPC):

• SFDA Call Center: 19999
• E-mail: npc.drug@sfda.gov.sa
• Website: https://ade.sfda.gov.sa/

With intravenous administration, overdose of Gamunex 10% 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.

Pharmacotherapeutic group: Immunoglobulins, normal human, ATC code: J06BA02.

Gamunex 10% 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.

PI: Intravenous administration

In a randomized, double-blind, parallel group clinical trial with 172 subjects with primary humoral immunodeficiencies Gamunex 10% 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 10% 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).

ITP

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

A double-blind, randomized, parallel group clinical trial with 97 ITP subjects was carried out to test the hypothesis that Gamunex 10% 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 10% was demonstrated to be at least as effective as Gamimune N, 10% in the treatment of adults and children with acute or chronic ITP.

A trial was conducted to evaluate the clinical response to rapid infusion of Gamunex 10% in patients with ITP. The study involved 28 chronic ITP subjects, wherein the subjects received 1 g/kg Gamunex 10% 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).

CIDP

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

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 10%.  This study included two separately randomized periods to assess whether Gamunex 10% 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 10% 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 10% 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 10% 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 Gamunex 10% 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). 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 10% : 28 of 59 subjects (47.5%) responded to Gamunex 10% 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 10% was evaluated: 31 were randomly reassigned to continue to receive Gamunex 10% and 26 subjects were randomly reassigned to Placebo in the Randomized Withdrawal Period. Subjects who continued to receive Gamunex 10% experienced a longer time to relapse versus subjects treated with Placebo (p=0.011). The probability of relapse was 13% with
Gamunex 10% 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):

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

Outcome for Randomized Withdrawal Period

Two pharmacokinetic crossover trials were carried out with Gamunex 10% 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 Gamunex 10% in subjects with PI were evaluated. A total of 32 and 26 subjects received Gamunex 10% as IV or SC for PK study, respectively, of whom 3 were adolescents.  Subjects received Gamunex 10% 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 Gamunex 10% were evaluated in children and adolescents.  The design of the study was essentially the same as above. A total of 11 subjects  received Gamunex 10% as IV and 10 received Gamunex 10% as SC for PK analysis. Age groups were as follows: age 2 to 5 years, [N=1 both phases]; 6 to 11 years, [N = 5 completing IV phase, N=4 evaluated in SC phase]; 12-16 years: [N = 5 both phases].

Intravenous administration

The pharmacokinetic parameters of Gamunex 10%, measured as total IgG for intravenous administration are shown in the below table.

PI: Subcutaneous administration

The PK parameter (AUC of total IgG) following IV and SC administration is summarized in the table below 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 Gamunex 10% in pediatric populations.

The mean trough concentrations (mean C_trough) of total IgG following IV and SC administration are presented for both studies in the table below.

In contrast to plasma total IgG levels observed with monthly IV Gamunex 10% treatment (rapid peaks followed by a slow decline), the plasma IgG levels in subjects receiving weekly SC Gamunex 10% therapy were relatively stable (Figure 7, adult and adolescent trial).

Absorption

Gamunex 10% is administered by intravenous and subcutaneous infusion.

Intravenous - Absorption is not applicable for intravenous administration.

Subcutaneous - At steady state, plasma concentrations of total IgG remain relatively constant over the 7 day dosing interval, with small fluctuations between C_max and C_trough.

Distribution

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 10% 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.

Subcutaneous - In study 060001, a total of 32 adults and adolescent subjects demonstrated the weekly Gamunex 10% 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 10% 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 10%.  

In a second study (T5004-401), 11 children with PI aged 2-16 years participated. This study also demonstrated that a weekly Gamunex 10% subcutaneous dose calculated using a conversion factor of 1.37 provides comparable overall total IgG (AUC) exposure to that produced by IV administration. A relatively constant steady state trough total IgG level was observed. The average steady-state mean total IgG trough determined in the subcutaneous phase in all subjects was 13.25 mg/mL (range: 10.77-16.90 mg/mL), which was approximately 31% higher than the mean IgG trough of 9.97 mg/mL following the regular IV dosing of Gamunex 10%.

Data from clinical trials show that trough levels of IgG can be maintained by weekly dosing regimens of Gamunex 10% for subcutaneous administration.

Biotransformation

Immunoglobulins and IgG complexes are broken down in the cells of the mononuclear phagocytic system.

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.

Linearity/Non-Linearity

The linearity or non-linearity of Gamunex 10% 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 10% did not show special risks for humans.

Glycine

Water for Injection

If dilution is required, Gamunex 10% may be diluted with 5% dextrose in water (D5/W). Do not dilute with saline.

• Keep out of the reach and sight of children.
• Keep the vial in the carton to protect from light.
• Gamunex 10% may be stored for 36 months at 2-8°C from the date of manufacture, AND product may be stored at temperatures not to exceed 25°C for up to 6 months anytime during the 36 month shelf life, after which the product must be immediately used or discarded. 
• Do not freeze. 
• Do not use after expiration date.

Gamunex 10% 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. Gamunex 10% is not made with natural rubber latex.

Gamunex 10% is supplied in the following sizes:

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Preparation and handling

Read instructions carefully before use.

• Visually inspect Gamunex 10% for particulate matter and discoloration prior to administration, whenever solution and container permit.  Do not use if turbid.  
• Do not freeze. Do not use solutions that have been frozen.
• Prior to use, allow the solution to reach ambient room temperature.
• If the packaging shows any signs of tampering, do not use the product.
• The Gamunex 10% vial is for single use only. Gamunex 10% contains no preservative. Use any vial that has been entered promptly.  Discard partially used vials. Do not store after entry into vial.
• Infuse Gamunex 10% using a separate line by itself, without mixing with other intravenous fluids or medications the subject might be receiving.  The Gamunex 10% infusion line can be flushed with 5% dextrose in water (D5/W) or 0.9% sodium chloride for injection.
• If dilution is required, Gamunex 10% may be diluted with 5% dextrose in water (D5/W). Do not dilute with saline. 
• Content of vials may be pooled under aseptic conditions into sterile infusion bags and infused within 8 hours after pooling.
• Avoid simultaneous administration of Gamunex 10% and Heparin through a single lumen delivery device due to Gamunex 10%, Heparin incompatibilities. Flush Heparin Lock (Hep-Lock) through which  Gamunex 10% was administered with 5% dextrose in water (D5/W) or 0.9% sodium chloride for injection, and do not flush with Heparin (see table below).

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