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Gammaplex: What You Need To Know

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Gammaplex: What You Need To Know

Gammaplex is a highly purified human intravenous immunoglobulin G  (IVIG for short). It is used to prevent infection in primary immunodeficiency diseases (PIDs) and prevent bleeding in immune thrombocytopenic purpura.  Gammaplex drug is provided as intravenous liquid solutions and is available at concentrations of 5 and 10%.

 

What is Gammaplex?

Gammaplex infusion is a highly purified, human immunoglobulin G product that is manufactured using plasma only from paid, healthy US subjects where the plasma of approximately  3,000-10,000  donors is used to obtain human immunoglobulin derivatives (1).

Gammaplex is available in two concentrations, 5 and 10% liquid high pure formulations (>95% for Gammaplex 5% and >98% for Gammaplex 10%) (2).

These formulations differ in the stabilizer utilized. For example, gammaplex 10%  is stabilized with glycine and doesn’t contain reducing carbohydrate stabilizers, whereas Gammaplex 5% is stabilized with sorbitol.

 

Characteristics

The distribution of IgG subclass in gammaplex products reflects that of normal plasma (3).

In addition, the IgA content is very low, reducing the risk of hypersensitivity reactions in IgA-deficient patients.

Anti-D and anti-A/anti-B hemagglutinin contents are very strictly controlled to reduce the risk of hemolytic reactions during gammaplex treatment. 

Moreover, there is very low or undetectable procoagulant activity as shown by testing multiple batches from starting plasma pool to the final product.

 

Overview of IVIG products

There are currently different immune globulin products licensed in the United States. For instance, Gammaplex, Gamunex, Flebogamma, Octagam, bivigam, Gammaked, and Privigen. 

These are different in terms of many aspects including the manufacturing process, their formulation (liquid versus lyophilized (dry powder)), concentration, the stabilizer used, their composition, viral inactivation, pH, volume load, osmolality, sodium content, and method of administration to name a few.

For example, Gamunex is given as either intravenously (IV) abbreviated as (IVIG) or subcutaneously (SC) abbreviated as (SCIG) while gammaplex is given only as intravenous immunoglobulin IVIG infusion.

In terms of formulation, The IVIG products are formulated as either liquid such as gammaplex or Lyophilized (dry powder) like gammagard S/D.

For the manufacturing process, immune globulin products differ in the isolation and purification of IgG, and the antibody fraction.

All these factors affect the final product’s shelf life, efficacy and tolerability and thus may affect the decision of selecting a certain product for a specific population of patients.

For example, patients with cardiovascular risk factors or small infants should be given products with low sodium content and osmolality (4).

Another good example would be that patients with diabetes shouldn’t be given IVIG products that contain glucose and those with preexisting renal conditions shouldn’t be given products that contain sucrose.

 

What Is Gammaplex Used For?

Gammaplex is an FDA approved product for the management of primary humoral immunodeficiency diseases (PIDs) in adults and pediatric patients 2 years of age and older.

Also, gammaplex is indicated for preventing bleeding in idiopathic thrombocytopenic purpura (ITP).

Immunodeficiency disorders result from the absence of a certain element of the immune system or a dysfunctional element and it can be divided into primary or secondary.

The principal clinical manifestation of primary humoral immunodeficiency PI diseases is an increased susceptibility to infection. 

In fact, almost all patients suffered serious or unusual infections and a large population of them reported suffering from permanent functional impairment (5).

 

Primary Humoral Immunodeficiency PI

Primary immunodeficiency is subdivided into several types according to the dysfunctional element and these include:

  • T-cell deficiency, 
  • B-cell deficiency, 
  • both T-cell and B-cell deficiency
  • complement deficiency
  • phagocyte deficiency
  • immunoglobulin A deficiency (6)

Primary Humoral Immunodeficiency PI often has an underlying genetic cause.

For example, in primary immunodeficiency, the B-cell deficiency is an X-linked disorder and is referred to as X- linked agammaglobulinemia (Bruton disease) (7).

Baby patients with X-linked agammaglobulinemia suffer from recurrent bacterial infections including otitis media, bronchitis, septicemia, pneumonia, and arthritis, and giardia lamblia causing intestinal malabsorption.

Administering intravenous immune globulin IVIG such as gammaplex is approved to keep the patient with X- linked agammaglobulinemia alive by replacing the low levels of immunoglobulins. 

Another subdivision of primary humoral immunodeficiency is the T-cell Immunodeficiencies including Hyper-IgM syndrome where immunoglobulin therapy is recommended.

In addition to the immunodeficiency x-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies are among the disorders for which gammaplex is indicated.

 

Chronic Immune Thrombocytopenic purpura (ITP)

Immune thrombocytopenia purpura (ITP) is isolated thrombocytopenia (platelet count <100,000/microL) with normal white blood cells and normal hemoglobin in the setting of a generalized purpuric rash as defined by The American Society of Hematology (8).

 ITP is also known as idiopathic thrombocytopenic purpura or immune thrombocytopenic purpura.

Upon laboratory testing,  the white blood count, hemoglobin concentration, red cell indices, and differential white blood cells are usually normal and the only abnormality seen is a platelet count less than 100,000/microL (9).

The etiology of ITP includes the development of autoantibodies against platelet membrane proteins, leading to thrombocytopenia and an elevated risk of bleeding. It’s an autoantibody-mediated disorder, usually, immunoglobulin G mediated.

The American Society of Hematology 2019 guidelines recommend the use of intravenous immunoglobulin (IVIG) for patients where corticosteroids are contraindicated or not preferred.

Immune globulin intravenous human liquids such as Gammaplex is believed to raise platelet counts for patients with chronic immune thrombocytopenic purpura.

 

Mechanism of Action of Gammaplex

In primary humoral immunodeficiency, gammaplex acts as an IgG replacement therapy by replacing the low level of opsonic and neutralizing IgG antibodies thus boosting the immune system against pathogens and their toxins.

In chronic ITP, gammaplex may act to downregulate antiplatelet antibody production and block  Fc receptors but the exact mechanism has not been fully elucidated (10).

 

Dosing

The dosage of gammaplex infusion varies according to the indication and the concentration administered.

 

Treatment of Primary Humoral Immunodeficiency

For the treatment of primary humoral immunodeficiency disease, the frequency and the dose of immunoglobulin may vary from patient to patient because the half-life of IgG varies among patients.

The proper amount can be adjusted according to the patient’s clinical response.

However, according to gammaplex package insert, gammaplex 5% (100 ml) is given intravenously at a dose of 300-800 mg/kg (6-16 mL/kg) every 3-4 weeks for managing PI.

Gammaplex 10% (50 ml) is administered intravenously at similar doses but this higher concentration allows a 34% reduction in infusion time without compromising safety and tolerability.

 

Treatment of Chronic Immune Thrombocytopenic Purpura

The recommended dose of GAMMAPLEX 5% for patients with ITP is 1 g/kg (20 mL/kg) on 2 consecutive days, providing a total dose of 2 g/kg.

For patients at increased risk of thrombosis, hemolysis, acute kidney injury, or volume overload there should be a careful evaluation of the risks and benefits of prescribing this regimen (1 g/kg/day for 2 consecutive days).

 

Infusion Rates

How to do infusion rates for managing PI using gammaplex 5%?

Initially, the rate of infusion should be 0.5 mg/kg/min for 15 minutes and increase gradually every 15 minutes to 4 mg/kg/min as a maintenance infusion rate.

How to do infusion rates for managing ITP using gammaplex 5%?

Initially, rate of infusion should be 0.5 mg/kg/min for 15 minutes and increase gradually every 15 minutes to 4 mg/kg/min as a maintenance infusion rate until total dose is administered.

What are infusions used to treat PI using gammaplex 10 %?

For managing PI using gammaplex 10%, starting infusion rate is set at 0.5 mg/kg/min for 15 minutes and increases gradually every 15 minutes to 8 mg/kg/min. 

What are infusions used to treat ITP using gammaplex 10%?

For managing ITP, the initial gammaplex infusion rate is set at 0.5 mg/kg/min (0.005 mL/kg/min) for 15 minutes  and increases gradually every 15 minutes to 8 mg/kg/min (0.08 mL/kg/min).

 

Gammaplex Administration

The patient should drink plenty of water to ensure adequate hydration before administering gammaplex infusion.

Monitoring the patient’s vital signs should proceed throughout the infusion session.

If the patient shows any signs of adverse reactions, the infusion rate should be slowed. If the adverse reaction subsides, the infusion should be resumed at a lower rate that is comfortable for the patient.

However, if the adverse reaction persists, the infusion should be stopped.

Ensure that patients with pre-existing renal insufficiency are not volume depleted.

For patients predisposed to renal dysfunction, thrombotic events, or volume overload, gammaplex infusion should be administered at the minimum practicable rate.

Gammaplex Adverse Reactions

The use of IVIG including gammaplex may be accompanied by adverse reactions.  

Actually, it was reported that as many as 21% of patients discontinued their immunoglobulin therapy due to adverse reactions (low tolerability) or concerns about product safety.

Generally speaking, IVIGs are well tolerated, with most adverse reactions are mild in severity, transit, and reversible by slowing or temporarily stopping the infusion.

More specifically, gammaplex IV is well tolerated, as reflected by the low rate of treatment discontinuations due to side effects across the PID studies.

Similarly, patients with ITP  reached and completed  90 of 94 infusions at the maximum recommended rate indicating that gammaplex infusions were well tolerated even at the high dose used.

 

Gammaplex Adverse Reactions Associated With Subjects With Pi

According to gammaplex package insert, The most common adverse reactions reported in primary immune deficiency clinical trials were headache, migraine, and fever.

Gammaplex Adverse Reactions Associated With Subjects With Itp

The most common adverse reactions reported in immune thrombocytopenic purpura clinical trials were headache, vomiting, fever, nausea, joint pain and dehydration.

The frequency of gammaplex adverse reactions tend to be directly proportional to the rate and dose of infusion. 

luckily, most of these side effects tend to be self-limited, mild, and transient.

Usually, these adverse reactions occur during or within 6 h of infusion, specifically after the first infusion session. 

They can also occur in association with rapid infusion rates, administering higher doses, switching to a new product, waiting for longer intervals between infusion sessions and suffering an intercurrent infection.

 

Managing Gammaplex Side Effects

Fortunately, gammaplex side effects can be prevented by conducting simple approaches. 

For example, drinking pretty good amounts of water before or after the end of the infusion session can be enough to minimize the occurrence of adverse reactions (11).

However, if side effects still occur, simple pharmacological approaches can be indicated such as administering paracetamol 500 mg orally or acetylsalicylic acid 500 mg intravenously.

Another option can be administering non-steroidal anti-inflammatory drugs (e.g. ibuprofen 10 mg / kg), second-generation antihistamines or corticosteroids.

However, serious adverse reactions may occur rarely and both patient and health care providers should be aware of. 

These adverse reactions include renal dysfunction/failure, thrombotic events, hypersensitivity, hyperproteinemia, increased serum viscosity, and hyponatremia. 

 

Renal Dysfunction/Failure Adverse Reactions

The risk of renal dysfunction associated with IVIG is perceived to happen mostly due to the stabilizer utilized. 

Renal dysfunction related to IVIGs stabilized with sucrose including acute renal failure, osmotic nephrosis, and renal insufficiency, is well established. However, reports of renal dysfunction with sucrose-free IVIGs are relatively rare.

Patients at risk of developing acute renal failure can be classified into two distinct populations. 

Patients with preexisting conditions or those at increased risk for developing renal insufficiencies such as pre-existing renal insufficiency, diabetes mellitus, elderly (>65 years old), volume depletion (dehydration or hypervolemia), sepsis, paraproteinemia or patients receiving known nephrotoxic drugs.

Since Gammaplex 10% is stabilized with glycine and Gammaplex 5% is stabilized with sorbitol, both products are less prone to cause renal dysfunction or acute renal failure.

 

Minimizing Risk Of Renal Dysfunction Or Acute Renal Failure

However, healthcare authorities including US FDA and clinical experts recommend several precautionary measures to minimize the risk of renal dysfunction or acute renal failure for patients at risk of developing acute renal failure.

Initially, hydrate patients well to ensure that patients aren’t hypovolemic before gammaplex infusion.

Administering gammaplex infusion at the minimum infusion rate practicable should be applied for patients at risk of developing renal dysfunction. 

Those include patients predisposed to acute renal failure (such as diabetes mellitus, hypovolemia, overweight, use of concomitant nephrotoxic medicinal products or age >65 years)

Also, patients at risk of developing renal dysfunction should be assessed periodically for their renal function. Any deterioration in renal function justify discontinuing gammaplex infusion 

 

Thrombotic Adverse Reactions

IVIG products including gammaplex may increase blood viscosity and thus may impair blood flow and trigger a cardiovascular or cerebrovascular thromboembolic event.

In one clinical trial, serum viscosity was measured before and immediately after each of three consecutive monthly infusions of IVIg. Serum viscosity increased after IVIg in all 13 patients who participated in the study (12). 

Although patients at risk of developing thromboembolic events include advanced age patients, those with prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. 

However, thromboembolic events may still occur in the absence of known risk factors.

 

Minimizing Risk Of Thromboembolic Events

Proper hydration of patients should be ensured prior to administration. 

Assess blood viscosity in patients at risk for hyperviscosity including those with high triacylglycerols (triglycerides), patients with cryoglobulins, and those with monoclonal gammopathies. 

For patients at risk of thrombosis, gammaplex infusion should be administered at the minimum dose and infusion rate practicable.

 

Hypersensitivity

Like any other medicinal product, the administration of gammaplex infusion may be accompanied by hypersensitivity adverse reactions. 

 It is well perceived that hypersensitivity reactions may be due to the trace amounts of IgA contained in gammaplex infusions. 

 Patients at risk of developing hypersensitivity and anaphylactic reactions are subjects with known antibodies to IgA so, they should be closely monitored. 

 If hypersensitivity reaction occurred, gammaplex infusion should be discontinued immediately and proper management should have proceeded.

 

Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia

Hyperproteinemia, increased serum viscosity, and hyponatremia are rare adverse reactions that may accompany IVIG infusions. 

Patients should be assessed carefully for signs and symptoms of hyponatremia and distinguish it clinically from pseudohyponatremia. 

Pseudohyponatremia may accompany hyperproteinemia and any management procedure for correction pseudohyponatremia may further deplete volume and increase the risk of thrombotic events.

 

Aseptic Meningitis Syndrome

Aseptic Meningitis Syndrome (AMS) may occur in patients upon IGIV treatment. Especially, in association with high doses (2 g/kg) and rapid infusion rate.

 Aseptic meningitis syndrome (AMS) should be suspected if the following signs and symptoms are initiated within several hours to 2 days following IGIV treatment:  nuchal rigidity, painful eye movements, photophobia, fever, severe headache, drowsiness, nausea, and vomiting. 

However, extensive neurological examination for patients experiencing these signs and symptoms should be initiated to rule out other causes of meningitis.

Fortunately, discontinuation of IVIG treatment usually is enough for the remission of aseptic meningitis syndrome without adverse consequences.

 

Hemolysis

IGIV including gammaplex may cause hemolysis due to the content of blood groups antibodies that can act as hemolysins.

Acute hemolysis may develop into delayed hemolytic anemia which has been reported upon the use of IVIG therapy.

Consequently, severe acute hemolysis may develop into renal dysfunction or disseminated intravascular coagulation which has also been reported.

Some of the main reasons that hemolysis may be developed with the use of IVIG  products are: administering high doses (e.g. ≥2 g/kg) and being other than O blood group.

Hemolysis can develop with either subject with PI or ITP.

 

Minimizing Risk Of Hemolysis

Patients at risk of developing hemolysis should be closely monitored.

Other measurements to minimize the risk of hemolysis should be to perform baseline laboratory testing for patients predisposed to develop hemolysis such as level of hemoglobin and hematocrit. Additionally, these measurements should be done 36 to 96 hours post-infusion.

If hemolysis is suspected, confirmatory laboratory testing should proceed.

Transfusion-related Acute Lung Injury (TRALI):

Transfusion-related acute lung injury is one of the adverse reactions that may accompany transfusing blood products including intravenous immune globulin products. 

Transfusion-related acute lung injury (TRALI) is a clinical syndrome in which there is acute, noncardiogenic pulmonary edema that may occur during or after the transfusion session and is associated with hypoxia.

The signs and symptoms of transfusion-related acute lung injury (TRALI) may include fever, hypotension, and exudative bilateral infiltrates on chest radiograph.

Transfusion-related acute lung injury (TRALI) is suspected when there are other risk factors for acute lung injury and symptoms usually appear within 1 to 6 hours following treatment.

When transfusion-related acute lung injury (TRALI) is suspected,  anti-neutrophil antibodies tests should be performed for both the product and the patient’s serum.

 

Gammaplex Cost

The price for gammaplex intravenous solution 5% is between 890-940$ for a supply of 100 milliliters, depending on the pharmacy you visit (9).

Likewise, gammaplex cost for intravenous solution 10% vial is between 1780-1950$ for a supply of 100 milliliters, depending on the pharmacy you visit.

 

Gammaplex Copay Assistance Programs

There are multiple Patient Assistance Programs (PAPs) that support low income or uninsured and under-insured people to have the medication for free or at discounted prices. 

These programs are sponsored by pharmaceutical companies such as the Patient Access Network Foundation (PAN),  HealthWell Foundation Copay Program, and Bio Products Laboratory BPL Reimbursement Support Program.

In the Bio Products Laboratory reimbursement support program, for example, patients can receive up to $2000 in assistance yearly if they proved that they need financial assistance or they are facing difficulty paying.

 

Gammaplex Manufacturer

Bio Products Laboratory

 

Is Gammaplex The Same As Gammagard?

Basically, both are immune globulin products. However, gammagard infusion differs from gammaplex infusion in that the former can be administered either IV or subcutaneous while gammaplex can’t be given as subcutaneous injection and is only indicated as IV. 

Another difference between these immune globulin products could be their indications. 

Gammaplex is used as replacement therapy for PIDs and for managing ITP.

Gammagard is indicated  also as replacement therapy for PID and as a maintenance therapy to improve muscle strength and disability in adult patients with Multifocal Motor Neuropathy (MMN) 

In terms of cost, gammagard cost generally is lower than that of gammaplex. 

For example, gammagard 10% (100 ml) would cost nearly 1,600$ while a comparable amount of gammaplex 10% would cost 1800$.

What’s more, these products are manufactured differently. Gammaplex manufacturer is Bio Products Laboratory while gammagard manufacturer is Baxalta.

 

Conclusion

Gammaplex is one of the immunoglobulin products currently licensed in the United states with proven safety and efficacy as replacement therapy for primary humoral immunodeficiency (PID) patients and as a management therapy in Chronic Immune Thrombocytopenic Purpura (ITP).

Gammaplex is available at two concentrations 5% and 10%. The higher concentration ensures shorter infusion times.

Gammaplex is a well-tolerated medication with mild, self-limited side effects that can be managed successfully using simple measures. However, caution should be paid for more serious adverse reactions

Gammaplex is not the same as gammagard, each one is formulated in a special manner and has different indications.

 

References:

  1. Gelfand E. W. (2005). Critical decisions in selecting an intravenous immunoglobulin product. Journal of infusion nursing : the official publication of the Infusion Nurses Society, 28(6), 366–374. https://doi.org/10.1097/00129804-200511000-00003
  2. DailyMed – GAMMAPLEX- human immunoglobulin g solution. Dailymed.nlm.nih.gov. (2021). Retrieved 17 July 2021, from https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6c3ce068-59f0-413b-9f93-85fb597d55e5.
  3. Roberts, P. L., Dolan, T., Paddick, M., Stagg, S., & More, J. E. (2015). Development of an intravenous immunoglobulin with improved safety and functional activity. Biologicals : journal of the International Association of Biological Standardization, 43(2), 123–129. https://doi.org/10.1016/j.biologicals.2014.11.005
  4. Saeedian, M., & Randhawa, I. (2014). Immunoglobulin replacement therapy: a twenty-year review and current update. International archives of allergy and immunology, 164(2), 151–166. https://doi.org/10.1159/000363445
  5. Wasserman R. L. (2017). Gammaplex® 5 and 10% in the treatment of primary immunodeficiency and chronic immune thrombocytopenic purpura. Immunotherapy, 9(13), 1071–1088. https://doi.org/10.2217/imt-2017-0071
  6. Justiz Vaillant AA, Qurie A. Immunodeficiency. [Updated 2021 Jun 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK500027/
  7. Hernandez-Trujillo, V. P., Scalchunes, C., Cunningham-Rundles, C., Ochs, H. D., Bonilla, F. A., Paris, K., Yel, L., & Sullivan, K. E. (2014). Autoimmunity and inflammation in X-linked agammaglobulinemia. Journal of clinical immunology, 34(6), 627–632. https://doi.org/10.1007/s10875-014-0056-x
  8. Rodeghiero, F., Stasi, R., Gernsheimer, T., Michel, M., Provan, D., Arnold, D. M., Bussel, J. B., Cines, D. B., Chong, B. H., Cooper, N., Godeau, B., Lechner, K., Mazzucconi, M. G., McMillan, R., Sanz, M. A., Imbach, P., Blanchette, V., Kühne, T., Ruggeri, M., & George, J. N. (2009). Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood, 113(11), 2386–2393. https://doi.org/10.1182/blood-2008-07-162503
  9. Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019;3(23):3829-3866. (2020). Blood advances, 4(2), 252. https://doi.org/10.1182/bloodadvances.2019001380
  10. Jin, F., & Balthasar, J. P. (2005). Mechanisms of intravenous immunoglobulin action in immune thrombocytopenic purpura. Human immunology, 66(4), 403–410. https://doi.org/10.1016/j.humimm.2005.01.029
  11. Šutová, I., Chovancová, Z., & Litzman, J. (2019). Adverse effects of immunoglobulin therapy. Nežádoucí účinky imunoglobulinové léčby. Vnitrni lekarstvi, 65(2), 131–132.
  12. Dalakas M. C. (1994). High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology, 44(2), 223–226. https://doi.org/10.1212/wnl.44.2.223