Source: FDA, National Drug Code (US) Revision Year: 2020
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 10%. In patients who are at risk of developing renal dysfunction, because of pre-existing renal insufficiency, predisposition to acute renal failure (such as diabetes mellitus, hypovolemia, overweight, use of concomitant nephrotoxic medicinal products or age >65 years), administer GAMMAPLEX 10% 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 10% and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing GAMMAPLEX 10%.
Thrombosis may occur following treatment with immune globulin products, including GAMMAPLEX 10% 2. 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 GAMMAPLEX 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 [see Boxed Warning, Dosage and Administration (2.3), Patient Counseling Information (17)].
Severe hypersensitivity reactions may occur [see Contraindications (4)]. In case of hypersensitivity, discontinue GAMMAPLEX 10% infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions.
GAMMAPLEX 10% contains trace amounts of IgA (<20 micrograms/mL) [see Description (11)]. Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. GAMMAPLEX 10% is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction [see Contraindications (4)].
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 events2.
AMS may occur 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 sequelae3.
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 (17)]. 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.
GAMMAPLEX 10% may contain blood group antibodies that can act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin test (DAT) (Coombs' test) result and hemolysis4. Delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration; acute hemolysis, consistent with intravascular hemolysis, has been reported5. Cases of severe hemolysis-related renal dysfunction/failure or disseminated intravascular coagulation have occurred following infusion of IGIV.
The following risk factors may be associated with the development of hemolysis following IGIV administration: high doses (e.g. ≥2 g/kg), given either as a single administration or divided over several days, and non-O blood group6. Other individual patient factors, such as an underlying inflammatory state (as may be reflected by, for example, elevated C-reactive protein or erythrocyte sedimentation rate), have been hypothesized to increase the risk of hemolysis following administration of IGIV7, but their role is uncertain. Hemolysis has been reported following administration of IGIV for a variety of indications, including ITP and PI4.
Closely monitor patients for clinical signs and symptoms of hemolysis, particularly patients with risk factors noted above. Consider appropriate laboratory testing in higher risk patients, including measurement of hemoglobin or hematocrit prior to infusion and within approximately 36 to 96 hours post infusion. If clinical signs and symptoms of hemolysis or a significant drop in hemoglobin or hematocrit have been observed, perform 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.
Noncardiogenic pulmonary edema may occur in patients following IGIV treatment8. 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.
Carefully consider the relative risks and benefits before prescribing the high dose regimen (for chronic ITP) in patients at increased risk of volume overload.
As GAMMAPLEX 10% is made from human blood, it may carry a risk of transmitting infectious agents, e.g. viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. No cases of transmission of viral diseases or CJD have been associated with the use of GAMMAPLEX 10%. All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare providers to BPL Inc. 1-844-427-5872 or MedInfo@BPL-US.com.
Before prescribing GAMMAPLEX 10%, the physician should discuss the risks and benefits of its use with the patient [see Patient Counseling Information (17)].
The safety information for GAMMAPLEX 10% is based on the clinical trial evaluating the bioequivalence of GAMMAPLEX 10% to GAMMAPLEX 5% in subjects with PI. The safety of GAMMAPLEX 10% has not been established in patients with ITP. However, the safety profile for GAMMAPLEX 5% has been studied in subjects with ITP, and it is anticipated that the safety profile for both formulations are comparable for ITP patients. Hence adverse reaction (AR) information is presented for GAMMAPLEX 5% where relevant. ARs are adverse events that were deemed by the investigators as causally related to GAMMAPLEX 10%.
There were no serious ARs observed with GAMMAPLEX 10% in the clinical trial in adult or pediatric subjects with PI.
Serious ARs observed with GAMMAPLEX 5% clinical trial subjects with ITP were headache, vomiting and dehydration. In addition, following a review of the data, 4 subjects (11%) were considered to have experienced asymptomatic suspected treatment-emergent hemolysis [see Clinical Trials Experience (6.1)].
The following potential serious ARs are described above and/or elsewhere in the labeling:
The most common ARs occurring in ≥5% of adult subjects receiving GAMMAPLEX 10% in the PI clinical trial were headache (4 subjects, 12.5%), migraine (2 subjects, 6.3%) and pyrexia (2 subjects, 6.3%) and for pediatric subjects 3 years of age and older, in the same study, headache (3 subjects, 20.0%); other ARs occurred in a single pediatric subject. Overall, ARs which occurred in ≥5% of the adult and pediatric subjects combined are shown in Table 2.
The most common ARs occurring in ≥5% of adult subjects receiving GAMMAPLEX 5% in the chronic ITP clinical trial were headache (10 subjects, 28.6%), vomiting (6 subjects, 17.1%), pyrexia (5 subjects, 14.3%), nausea (3 subjects, 8.6%), arthralgia (2 subjects, 5.7%) and dehydration (2 subjects, 5.7%).
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.
A multicenter, open-label, randomized two-period crossover study (bioequivalence study) evaluated the PK, safety and tolerability of GAMMAPLEX 10% and GAMMAPLEX 5% in 33 adults aged 17 to 55 years with PI. Twenty one (63.6%) subjects were female and 12 (36.4%) were male; 33 (100%) were White, of which 1 (3.0%) was Hispanic or Latino. The safety analysis included all 33 subjects for GAMMAPLEX 5% and 32 subjects for GAMMAPLEX 10%. One subject withdrew consent during the first infusion of GAMMAPLEX 5%, citing inconvenience of the study visits. Thirty two subjects received at least five infusions of each product either on a 28-day or 21-day cycle. The mean doses per infusion for GAMMAPLEX 10% were 491.7 mg/kg and 499 mg/kg respectively, and were similar for GAMMAPLEX 5% [see Clinical Studies (14.1)]. No subjects were on regular systemic corticosteroids at entry to, or during the study. Twelve (36.4%) adult subjects received short courses of corticosteroids, from a single dose to a maximum of 6 days duration, for various clinical conditions. No subjects received corticosteroids as premedications for GAMMAPLEX infusions. The use of local anesthetics, antipyretics, antihistamines, analgesics, and antiemetics before infusion was allowed; three (9.1%) adult subjects received a total of 5 courses of such premedication.
While on GAMMAPLEX 10%, 10 of the adults (31.3%) had an adverse reaction (AR) with a similar proportion (12; 36.4%) when on GAMMAPLEX 5%. Headache was the most commonly reported AR with both formulations of GAMMAPLEX. In total, 166 infusions of GAMMAPLEX 10% and 163 infusions of GAMMAPLEX 5% were given to adults during the study.
Two subjects had a positive direct antiglobulin (Coombs') test (DAT; DCT) result at some stage in the study. For one adult, the test was positive before starting in the study and it remained positive throughout, but without evidence of hemolysis. One other adult had a positive DAT one week after an infusion of GAMMAPLEX 5% but there was no evidence of hemolysis and no positive DAT results when receiving GAMMAPLEX 10%. No other adults had a positive DAT during the study.
In the same study, 15 pediatric subjects with PI, 3 years of age and older, received GAMMAPLEX 10%. All subjects were White, of which 2 (13.3%) were Hispanic or Latino. The mean doses per infusion were 552.9 mg/kg for subjects on the 28-day cycle (n=8) and 514.7 mg/kg for subjects on the 21-day cycle (n=7), overall range 343 to 745 mg/kg. Two subjects were in the 2-5 year age group, 7 were in the 6-11 year age group and 6 were in the 12-15 year age group. Fourteen subjects completed the study with at least 5 infusions of GAMMAPLEX 10% (pediatric subjects only received GAMMAPLEX 10% in this study); 82 infusions were given in total. Two pediatric subjects received IV methylprednisolone as premedication for each infusion. Local anesthetics, antipyretics, antihistamines and analgesics were allowed.
While on GAMMAPLEX 10%, 6 (40%) pediatric subjects had an AR. Headache was the most common with 3 subjects (20%) reporting a total of 4 events. All other ARs were not reported by more than a single pediatric subject. One pediatric subject had a positive direct antiglobulin (Coombs') test without evidence of hemolysis.
Table 2 lists the ARs occurring in at least 5% of all subjects (adult and pediatric combined) with PI treated with GAMMAPLEX 10% in the clinical study.
Table 2. Adverse Reactions (ARs*) Occurring in ≥5% of Subjects with PI Receiving GAMMAPLEX 10% (Adult and Pediatric Subjects Combined):
| Preferred Term | Subjects (%) [n=32] | Events |
|---|---|---|
| Headache | 7 (14.9) | 16 |
| Migraine | 3 (6.4) | 3 |
| Pyrexia | 3 (6.4) | 3 |
* Adverse Reactions (ARs) are defined as adverse events considered by the investigators to have been possibly, probably, or definitely related to administration of GAMMAPLEX.
The safety of GAMMAPLEX 10% has not been established in patients with ITP. However, the safety profile for GAMMAPLEX 5% has been studied in subjects with ITP, and it is anticipated that the safety profile for both formulations are comparable for ITP patients. The following is a summary of the study of GAMMAPLEX 5% in chronic ITP. In a multicenter, open-label, non-randomized clinical trial, 35 subjects with chronic ITP were treated with a nominal dose of 1000 mg/kg on each of two consecutive days (total dose 2000 mg/kg). Doses of GAMMAPLEX 5% ranged from 482 to 1149 mg/kg on an infusion day. The median total dose per subject was 2035 mg/kg. Pre-medication with antihistamine or analgesic drugs was permitted if required, but corticosteroids were not permitted prior to infusion as pre-medication. Ten subjects received corticosteroids for ITP during the trial and one additional subject received corticosteroids as pre-medication in violation of the protocol. All 35 subjects received at least one infusion of clinical trial drug, and all but one subject completed the first course of treatment.
Fifteen subjects (42.9%) reported at least one AR (63 in total); the most commonly reported being headache (10 subjects, 28.6%), vomiting (6 subjects, 17.1%), pyrexia (5 subjects, 14.3%), nausea (3 subjects, 8.6%), arthralgia (2 subjects, 5.7%) and dehydration (2 subjects, 5.7%). Three subjects experienced a total of five serious ARs. Of the five serious ARs, one subject had three concurrently (vomiting, dehydration and headache) and two subjects each had one serious AR (headache). One of these latter two subjects discontinued from the clinical trial because of the severe headache. Table 3 lists the ARs in more than ≥5% of subjects. Based on a review of clinical and laboratory data, 4/35 subjects (11%) with drops in hemoglobin exceeding 2 g/dL following administration of GAMMAPLEX 5% were considered to have experienced suspected treatment-emergent hemolysis. Milder treatment-emergent hemolysis could not be excluded for an additional 7 subjects, giving a total of 11 of 35 subjects (31%) for whom hemolysis could not be excluded (not including an additional two subjects who lacked follow-up testing for hemolysis, so their hemolysis status was considered unassessable). Data for two subjects were consistent with possible intravascular hemolysis, including one subject who may also have had an element of extravascular hemolysis. Nine of the possible hemolysis cases were mild and appeared consistent with possible extravascular hemolysis.
There was no evidence of transmission of HBV, HCV, HIV and parvovirus B19 during this clinical trial.
Table 3. Adverse Reactions (ARs*) Occurring in ≥5% of Subjects with ITP:
| Adverse Reactions | Subjects % [n=35] | Events |
|---|---|---|
| Headache | 10 (28.6) | 19 |
| Vomiting | 6 (17.1) | 8 |
| Pyrexia | 5 (14.3) | 6 |
| Nausea | 3 (8.6) | 3 |
| Arthralgia | 2 (5.7) | 3 |
| Dehydration | 2 (5.7) | 2 |
* Adverse Reactions (ARs) are defined as adverse events considered by the investigators to have been possibly, probably, or definitely related to administration of GAMMAPLEX.
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 and reported during the postmarketing use of GAMMAPLEX 10%:
The following adverse reactions have been identified during postmarketing use of intravenous immune globulins9:
Inform the immunizing physician of recent therapy with GAMMAPLEX 10% so that appropriate measures may be taken [see Patient Counseling Information (17)]
Animal reproduction studies have not been conducted with GAMMAPLEX 10%. It is also not known whether GAMMAPLEX 10% can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. GAMMAPLEX 10% should be given to a pregnant woman only if clearly needed. Immunoglobulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation.12
Use of GAMMAPLEX 10% has not been evaluated in breast-feeding mothers.
In pediatric subjects 3 years of age and older, the pharmacokinetics, dosage and safety are similar to those in adults.
GAMMAPLEX 10% was evaluated in 13 pediatric patients with primary humoral immunodeficiency (2 between ages of 3 to 5, 6 between ages of 6 to 11, and 5 between ages of 12 to 15). No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels [see Clinical Studies (14)]. The safety and pharmacokinetics of GAMMAPLEX 10% were assessed in pediatric subjects 3 years of age and older with PI [see Clinical Studies (14)].
The safety and effectiveness of GAMMAPLEX 10% has not been established in pediatric patients with ITP. GAMMAPLEX 5% was evaluated in three (3) pediatric subjects with chronic ITP (two aged 6 years and one aged 12 years). This number of pediatric patients was too small for separate evaluation from the adult patients for efficacy [see Clinical Studies (14)].
Use caution when administering GAMMAPLEX 10% to patients aged 65 years and over who are judged to be at increased risk of developing renal insufficiency or thrombotic events [see Boxed Warning, Warnings and Precautions (5.1, 5.2)]. Do not exceed recommended doses, and administer GAMMAPLEX 10% at the minimum infusion rate practicable.
No subjects over the age of 55 years were included in the clinical study of GAMMAPLEX 10%. Eight (8) patients with PI at or over the age of 65 years were included within the clinical evaluation of GAMMAPLEX 5%. The number of geriatric patients was too small for separate evaluation from the younger patients for safety or efficacy [see Clinical Studies (14)].
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