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human immunoglobulin g injection, solution
FULL PRESCRIBING INFORMATION
WARNING: ACUTE RENAL DYSFUNCTION and ACUTE RENAL FAILURE
1 INDICATIONS AND USAGE
Gammaplex is an Immune Globulin Intravenous (Human), 5% Liquid indicated for the replacement therapy of primary humoral immunodeficiency (PI). This includes, but is not limited to, the humoral immune defect in common variable immunodeficiency, X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.
2 DOSAGE AND ADMINISTRATION
For Intravenous Use Only
2.1 Preparation and Handling
2.2 Recommended Dose
As there are significant differences in the half-life of IgG among patients with PI, the frequency and amount of immunoglobulin therapy may vary from patient to patient. The proper amount can be determined by monitoring clinical response.
The recommended dose of Gammaplex for patients with PI is 300 to 800 mg/kg (6 to 16 mL/kg), administered every 3 to 4 weeks. Adjust the dosage over time to achieve the desired serum trough levels and clinical responses. If a patient misses a dose, administer the missed dose as soon as possible, and then resume scheduled treatments every 3 or 4 weeks, as applicable.
Monitor vital signs throughout the infusion. Slow or stop the infusion if adverse reactions occur. If symptoms subside promptly, the infusion may be resumed at a lower rate that is comfortable for the patient.
The observation time of patients after Gammaplex administration may vary. If the patient (a) has not received Gammaplex or another IgG product, (b) is switched from an alternative IGIV product or (c) has had a long interval since the previous infusion, prolong the observation time for adverse reactions after Gammaplex infusion.
Certain severe adverse drug reactions may be related to the rate of infusion. Slowing or stopping the infusion often allows the reaction to disappear promptly.
Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients judged to be at risk for renal dysfunction or thrombotic events, administer Gammaplex at the minimum infusion rate practicable, and discontinue Gammaplex administration if renal function deteriorates (see Boxed Warning, Warnings and Precautions [5.2]).
5 WARNINGS AND PRECAUTIONS
Severe hypersensitivity reactions may occur (see Contraindications ). In case of hypersensitivity, discontinue Gammaplex infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions.
Gammaplex contains trace amounts of IgA (<10 μg/mL) (see Description ). Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Gammaplex is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction (see Contraindications ).
5.2 Renal Dysfunction/Failure
Acute renal dysfunction/failure, osmotic nephropathy, and death1 may occur upon use of human IGIV products. Ensure that patients are not volume depleted before administering Gammaplex. In patients who are at risk of developing renal dysfunction, because of pre-existing renal insufficiency or predisposition to acute renal failure (such as diabetes mellitus, hypovolemia, overweight, use of concomitant nephrotoxic medicinal products or age of >65 years), administer Gammaplex at the minimum infusion rate practicable (see Dosage and Administration [2.3]).
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 blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Gammaplex and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing Gammaplex.
5.3 Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia
Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IGIV therapy. It is critical to clinically distinguish true hyponatremia from a pseudohyponatremia that is associated with or causally related to hyperproteinemia 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 thrombotic events.2
5.4 Thrombotic Events
Thrombotic events may occur following treatment with Gammaplex and other IGIV products.2,3 Patients at risk include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and/or known/suspected hyperviscosity.
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 judged to be at risk of developing thrombotic events, administer Gammaplex at the minimum rate of infusion practicable (see Dosage and Administration [2.3]).
5.5 Aseptic Meningitis Syndrome (AMS)
AMS may occur infrequently with IGIV treatment. AMS usually begins within several hours to 2 days following IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae.4
AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting (see Patient Counseling Information ). Cerebrospinal fluid (CSF) studies frequently reveal pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL, but negative culture results. Conduct a thorough neurological examination on patients exhibiting such signs and symptoms, 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.
IGIV products can contain blood group antibodies that may act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis5-7. Delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration8, and acute hemolysis, consistent with intravascular hemolysis, has been reported.
Monitor patients for clinical signs and symptoms of hemolysis (see Patient Counseling Information ). If these are present after Gammaplex infusion, perform appropriate confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis.
5.7 Transfusion-related Acute Lung Injury (TRALI)
Noncardiogenic pulmonary edema may occur in patients following IGIV treatment9. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours following treatment.
Monitor patients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and the patient's serum.
TRALI may be managed using oxygen therapy with adequate ventilatory support.
5.8 Transmissible Infectious Agents
Gammaplex is made from human plasma. Based on effective donor screening and product manufacturing processes (see Description ), Gammaplex carries an extremely remote risk of transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered to be extremely remote. No cases of transmission of viral diseases or CJD have been associated with the use of Gammaplex. 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 FFF on behalf of Bio Products Laboratory (800) 843-7477. Before prescribing Gammaplex, the physician should discuss the risks and benefits of its use with the patient (see Patient Counseling Information ).
5.9 Monitoring: Laboratory Tests
5.10 Interference with Laboratory Tests
6 ADVERSE REACTIONS
Two serious adverse reactions, thrombosis and chest pain, were observed in a clinical study subject receiving Gammaplex.
The most common adverse reactions to Gammaplex (reported in >5% of clinical trial subjects) were headache, fatigue, nausea, pyrexia, hypertension, myalgia, pain, and vomiting.
6.1 Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
In a multicenter, open-label, non-randomized clinical study, 50 subjects with primary humoral immunodeficiency received doses of Gammaplex ranging from 279 to 799 mg/kg every 21days (mean dose 465 mg/kg) or 28 days (mean dose 458 mg/kg), for up to 12 months (see Clinical Studies [14.1]). Routine premedication was not allowed. Of the 703 infusions administered, 2 (4%) subjects received premedication (antipyretic, antihistamine, or antiemetic agent) prior to 2 courses of treatment, because of experience with consecutive infusion-related adverse reactions.
All 50 subjects had an adverse event at some time during the study. Twenty-four subjects (48.0%) had an adverse reaction at some time during the study that was considered product-related. More subjects with the 21-day infusion cycle had at least one adverse reaction (14 of 22 subjects, 63.6%) than subjects with the 28-day infusion cycle (10 of 28 subjects, 35.7%). Of these 24 subjects who showed adverse reactions, only 3 subjects had adverse reactions that were considered definitely related to Gammaplex: headache, pyrexia, tachycardia, chest discomfort, and hypertension.
The most common adverse reactions observed in this clinical trial were headache (18 subjects, 36.0%), fatigue (6 subjects, 12.0%), nausea (6 subjects, 12.0%), pyrexia (6 subjects, 12.0%), hypertension (3 subjects, 6.0%), myalgia (3 subjects, 6.0%), pain (3 subjects, 6.0%), and vomiting (3 subjects, 6.0%).
Temporally associated adverse events (AEs) are those occurring during or within 72 hours after the end of an infusion, irrespective of causality. In this study, the upper bound of the 1-sided 97.5% confidence interval for the proportion of Gammaplex infusions temporally associated with one or more AEs was 24.2% (actual proportion: 21.2%). This is below the target of 40% for this safety endpoint. The total number of temporally associated AEs was 237 (a rate of 0.34 AEs per infusion), reflecting that some subjects experienced more than one AE during the observation period.
Table 2 lists the temporally associated AEs that occurred in more than 5% of subjects during a Gammaplex infusion or within 72 hours after the end of an infusion, irrespective of causality.
Of the 237 temporally associated AEs reported for the 50 subjects, the investigators judged 115 to be related to the infusion of Gammaplex. The most common temporally associated AEs judged to be related to Gammaplex infusion were headache (32% of subjects), pyrexia (8% of subjects), and nausea (8% of subjects).
Five subjects (10%) experienced seven serious AEs. Two of these serious AEs were considered related to Gammaplex treatment (thrombosis and chest pain). Three other subjects withdrew from the study due to the following AEs: paresthesia, bronchospasm, and pregnancy.
Forty-seven of the 50 subjects enrolled in this study had a negative direct antiglobulin test (DAT) at baseline. Of these 47 subjects, 4 (8.5%) developed a positive DAT at some time during the study. However, no subjects showed evidence of hemolytic anemia.
During this study, no subjects tested positive for infection due to human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or B19 virus (B19V).
6.2 Postmarketing Experience
Because adverse reactions are voluntarily reported post-approval from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. The following adverse reactions have been identified during post-approval use of intravenous immune globulins10:
7 DRUG INTERACTIONS
Passive transfer of antibodies may transiently interfere with the immune response to live virus vaccines such as measles, mumps, rubella and varicella.11,12 Inform the immunizing physician of recent therapy with Gammaplex so that appropriate measures may be taken (see Patient Counseling Information ).
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category C. Animal reproduction studies have not been conducted with Gammaplex. It is also not known whether Gammaplex can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Gammaplex should be given to a pregnant woman only if clearly needed. Immunoglobulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation13, 14
8.4 Pediatric Use
Six (6) pediatric patients with primary humoral immunodeficiency (2 between ages of 9 and 10, and 4 between ages 12 and 16) were included within the clinical evaluation of Gammaplex. This number of pediatric patients was too small for separate evaluation from the adult patients for safety or efficacy (see Clinical Studies ).
8.5 Geriatric Use
Use caution when administering Gammaplex to patients age 65 and over who are judged to be at increased risk of developing renal insufficiency or thrombotic events (see Boxed Warning, Warnings and Precautions [5.2, 5.4]). Do not exceed recommended doses, and administer Gammaplex at the minimum infusion rate practicable.
Eight (8) patients with primary humoral immunodeficiency at or over the age of 65 were included within the clinical evaluation of Gammaplex. This number of geriatric patients was too small for separate evaluation from the younger patients for safety or efficacy (see Clinical Studies ).
Gammaplex is a ready to use sterile solution of polyclonal human Immunoglobulin G for IV administration that contains sorbitol, glycine and polysorbate 80 as stabilizers. Specifically, Gammaplex contains approximately 5 g normal human immunoglobulin and 5 g D-sorbitol in 100 mL of buffer solution containing: 0.6 g glycine, 0.2 g sodium acetate, 0.3 g sodium chloride, and ~5 mg polysorbate 80. Immunoglobulin G purity is > 95%, the pH is in the range of 4.8 to 5.1, and osmolality is not less than 240 mOsmol/kg (typically 420 to 500 mOsmol/kg). The distribution of the four IgG subclasses is approximately 64% IgG1, 30% IgG2, 5% IgG3, and 1% IgG4. The content of IgA is lower than 10 µg/mL. The anti-D and anti-A/anti-B hemagglutinin content of the drug product is strictly controlled to specification. Gammaplex contains no reducing carbohydrate stabilizers (e.g. sucrose, maltose) and no preservative.
Gammaplex is prepared from large pools of human plasma by a combination of cold ethanol fractionation and ion exchange chromatography. Fab functions tested include antigen binding activity, and Fc functions tested include complement activation and rubella antibody-mediated hemolysis.
Gammaplex is manufactured from plasma, obtained from healthy US donors, that have passed viral screening tests. All donors are subjected to medical examinations, laboratory tests, and a review of their medical history before being allowed to donate blood or plasma. There are several stages within this manufacturing process that contribute to viral reduction, including management of donors, screening of donations and specific virus removal steps during manufacturing.
All plasma donations are screened for antibody to HIV-1/2 and HCV, and hepatitis B surface antigen (HBsAg). Furthermore, plasma mini-pools (512 donations per pool) undergo nucleic acid amplification testing (NAT) for HIV, hepatitis B virus (HBV), HCV, hepatitis A virus (HAV) and Parvovirus B19. Further testing is carried out on the manufacturing pools for HBsAg, and antibody to HIV-1/2; HCV and Parvovirus B19 are also tested by NAT, with the limit for B19 set to not exceed 104 IU B19 DNA per mL plasma.
There are three processing steps specifically designed to remove or inactivate viruses:
1) Solvent/Detergent treatment is targeted to enveloped viruses;
2) A virus filtration step using Pall Ultipor DV20 is designed to remove small viruses including non-enveloped viruses, on a size exclusion basis; and
3) The terminal low pH incubation step is identified as contributing to the overall viral clearance capacity for enveloped and non-enveloped viruses.
The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model. Overall virus reduction was calculated only from steps that were mechanistically independent from each other. In addition, each step was validated to provide robust virus reduction. The table below presents the contribution of each process step to virus reduction and the overall process reduction.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Gammaplex is a replacement therapy for primary humoral immunodeficiency. It acts through a broad spectrum of opsonic and neutralizing IgG antibodies against pathogens and their toxins involving antigen binding and effector functions15,16. However, the mechanism of action in PI has not been fully elucidated.
In the clinical study assessing safety and efficacy in primary humoral immunodeficiency, the pharmacokinetics of Gammaplex was assessed for 28 days after administration to 24 subjects on 21- or 28-day infusion cycles. Blood samples for pharmacokinetic (PK) analysis were obtained after Infusion 9 for subjects on a 21-day schedule (9 subjects) and after Infusion 7 for subjects on a 28-day schedule (15 subjects), i.e., during the sixth month after initiation of Gammaplex treatment.
The mean dose (range) for those on the 21-day schedule was 476 mg/kg (range: 330 to 721 mg/kg), and it was 468 mg/kg (range: 324 to 799 mg/kg) for those on the 28-day schedule. Table 4 summarizes the PK parameters of Gammaplex, measured as serum concentrations of total IgG.
Assessment of the clinical relevance of half-life measurements in this study should be viewed with caution. Although half-life estimates are provided for total IgG and the specific antibodies, drug elimination half-lives should be measured over a minimum period of at least 3 half-lives. However, the short dosing intervals relative to the long half-life of IgG in this clinical trial do not permit accurate assessment of half-life.
14 CLINICAL STUDIES
In a Phase 3 multicenter, open-label study to evaluate the efficacy, safety, and pharmacokinetics of Gammaplex in primary humoral immunodeficiency, 50 subjects on regular IGIV replacement therapy for at least 3 months prior to participation were treated for 12 months at 21-day (22 subjects) or 28-day (28 subjects) dosing intervals. Out of the 50 subjects, 26 were male and 24 were female, and 46 were Caucasian. They were in the age range of 9 to 78 years.
Doses ranged from 279 mg/kg to 799 mg/kg. The mean dose (range) for the 21-day interval was 465 mg/kg (330 - 693 mg/kg); the mean dose (range) for the 28-day interval was 458 mg/kg (326 - 790 mg/kg). Subjects received a total of 703 infusions of Gammaplex. The maximum infusion rate allowed during this study was 0.08 mL/kg/min.
The primary analysis for efficacy was based on the annual rate of acute serious bacterial infections (aSBIs), defined as pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, visceral abscess, and bacterial meningitis, per subject per year17. Other important clinical analyses for efficacy were based on the annual rate of infections, antibiotic use, days out of work/school/day care or unable to perform normal activities due to illness, and days of hospitalization.
During the 12-month study period, no serious acute bacterial infections occurred in any subject with an onset date between the first infusion of Gammaplex and the first follow-up visit, inclusive. Thus, the mean event rate of serious, acute, bacterial infections per year was zero (with an upper 1-sided 99% confidence interval of 0.101).
Duration of exposure in all tables relating to GMX01 was calculated as the difference between the date of the last visit (first follow-up visit) i.e. approximately 10-14 days following the last dose of Gammaplex and the date of the first Gammaplex infusion (plus one day).
16 HOW SUPPLIED/STORAGE AND HANDLING
Gammaplex is supplied in a single use, clear Type II glass bottle, closed with a stopper (13% natural rubber) and oversealed with a tamper-evident cap.
The following presentations of Gammaplex are available:
Each vial has a label with a peel-off strip showing the product name and batch number.
17 PATIENT COUNSELING INFORMATION
Inform patients to immediately report the following signs and symptoms to their healthcare professional:
Inform patients that Gammaplex is made from human plasma and may contain infectious agents that can cause disease. While the risk that Gammaplex can transmit an infection has been reduced by screening plasma donors for prior exposure, testing donated plasma, and inactivating or removing certain viruses during manufacturing, patients should report any symptoms that concern them (see Warnings and Precautions [5.8]).
Inform patients that Gammaplex can interfere with their immune response to live viral vaccines (e.g., measles, mumps, and rubella), and instruct patients to notify their healthcare professional of this potential interaction when they are receiving vaccinations (see Drug Interactions ).
US License No. 1811
Bio Products Laboratory
DATE OF LEAFLET PREPARATION September 2009
PRINCIPAL DISPLAY PANEL - 100 mL Bottle Carton
SOLUTION FOR INFUSION
FOR INTRAVENOUS USE
PRINCIPAL DISPLAY PANEL - 200 mL Bottle Carton
SOLUTION FOR INFUSION
FOR INTRAVENOUS USE
Revised: 06/2010 BioProducts Laboratory
Reproduced with permission of U.S. National Library of Medicine
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