Gammaplex: Package Insert and Label Information (Page 2 of 4)

6 ADVERSE REACTIONS

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%).

6.1 Clinical Trials 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.

Primary Humoral Immunodeficiency Study

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
*
Adverse Reactions (ARs) are defined as adverse events considered by the investigators to have been possibly, probably, or definitely related to administration of GAMMAPLEX.
Headache 7 (14.9) 16
Migraine 3 (6.4) 3
Pyrexia 3 (6.4) 3

Chronic Immune Thrombocytopenic Purpura Study

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
*
Adverse Reactions (ARs) are defined as adverse events considered by the investigators to have been possibly, probably, or definitely related to administration of GAMMAPLEX.
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

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.

GAMMAPLEX 10% Postmarketing Experience

The following adverse reactions have been identified and reported during the postmarketing use of GAMMAPLEX 10%:

  • Cardiovascular: Tachycardia, Thromboembolism, Hypertension, Flushing
  • Gastrointestinal: Nausea
  • General/Body as a Whole: Chills, Chest discomfort, Pyrexia
  • Musculoskeletal: Back pain, Polymyositis
  • Neurological: Headache
  • Respiratory: Dyspnea
  • Integumentary: Rash, Urticaria
  • Investigations: Blood Pressure increased, Blood Pressure diastolic decreased

The following adverse reactions have been identified during postmarketing use of intravenous immune globulins9:

  • Infusion reactions: Hypersensitivity (e.g. anaphylaxis), headache, diarrhea, tachycardia, fever, fatigue, dizziness, malaise, chills, flushing, urticaria or other skin reactions, wheezing or other chest discomfort, nausea, vomiting, rigors, back pain, myalgia, arthralgia, and changes in blood pressure
  • Renal: Acute renal dysfunction/failure, osmotic nephropathy
  • Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm, pulmonary embolism
  • Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension, myocardial infarction
  • Neurological: Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome, migraine
  • Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, dermatitis (e.g. bullous dermatitis)
  • Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs’) test
  • Musculoskeletal: Musculoskeletal pain
  • Gastrointestinal: Hepatic dysfunction, abdominal pain
  • General/Body as a Whole: Pyrexia, rigors

7 DRUG INTERACTIONS

  • Transitory rise of the various passively transferred antibodies in the patient’s blood after infusion of immunoglobulin 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
  • Passive transfer of antibodies may transiently interfere with the immune response to live virus vaccines such as measles, mumps, rubella and varicella.10, 11 Inform the immunizing physician of recent therapy with GAMMAPLEX 10% so that appropriate measures may be taken [see Patient Counseling Information (17)]

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

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

8.2 LACTATION

Risk Summary

Use of GAMMAPLEX 10% has not been evaluated in breast-feeding mothers.

8.4 PEDIATRIC USE

In pediatric subjects 3 years of age and older, the pharmacokinetics, dosage and safety are similar to those in adults.

Treatment of Primary Humoral Immunodeficiency

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)].

Treatment of Chronic Immune Thrombocytopenic Purpura

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)].

8.5 Geriatric Use

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)].

10 OVERDOSAGE

Overdosage may lead to fluid overload and hyperviscosity, particularly in the elderly and in patients with renal impairment.

11 DESCRIPTION

GAMMAPLEX 10% is a ready to use sterile solution of polyclonal human Immunoglobulin G for intravenous administration that contains glycine and polysorbate 80 as stabilizers. Specifically, GAMMAPLEX 10% contains approximately 10 g normal human immunoglobulin and 200-300 mM glycine in 100 mL of buffer solution containing: <30 mM acetate, <30 mM sodium chloride and 1-6 mg polysorbate 80. Immunoglobulin G purity is ≥98%, the pH is in the range of 4.9 to 5.3, and osmolality is not less than 240 mOsmol/kg (typically 280 mOsmol/kg). The distribution of the four IgG subclasses reflects that of normal plasma. The content of IgA is less than 20 micrograms/mL. The anti-D and anti-A/anti-B hemagglutinin content of the drug product is strictly controlled to specification.

GAMMAPLEX 10% contains no reducing carbohydrate stabilizers (e.g. sucrose, maltose) and no preservative.

GAMMAPLEX 10% 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 10% is manufactured from plasma, obtained from healthy US donors, who 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.

All plasma donations are screened for antibody to HIV-1/2 and hepatitis C virus (HCV), and hepatitis B surface antigen (HBsAg). Additional testing of donations is carried out in plasma mini-pools (512 donations per pool) that 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 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. Table 5 presents the contribution of each process step to virus reduction and the overall process reduction.

Table 5: Viral Reduction by Process Step
Virus Type(Envelope/Genome) Size(nm) Process Log10 Reduction of Virus (LRV) over manufacturing step
Solvent Detergent 20 nm filtration Terminal low pH/elevated temperature incubation Total LRV
HIV: Human immunodeficiency virus
SIN: Sindbis virus, model for hepatitis C virus (HCV)
WNV: West Nile Virus
BVDV: Bovine viral diarrhea virus, model for HCV
IBR: Infectious bovine rhinotracheitis, bovine herpes virus model for enveloped DNA viruses including hepatitis B
HAV: Hepatitis A virus
EMC: Encephalomyocarditis, model for HAV
CPV: Canine parvovirus, model for human parvovirus B19
NA: Not applicable, solvent detergent step is limited to the inactivation of enveloped viruses
I: Inactivation by the product intermediate precluded the accurate estimation of the removal of these viruses by the filtration step
NT: Not tested
B19: Viral clearance of human parvovirus B19 was investigated experimentally at the 20 nm filtration step. The estimated Log reduction Factor obtained was 6.0
HIV Env/RNA 80-100 >6.8 I >6.0 >12.8
SIN Env/RNA 70 >6.7 6.2 >6.8 >19.7
WNV Env/RNA 50 >6.4 I NT >6.4
BVDV Env/RNA 40-60 >5.6 I >4.6 >10.2
IBR Env/DNA 200 >5.0 I >5.4 >10.4
HAV Non-Env/RNA 30 NA >4.8 1.3 >6.1
EMC Non-Env/RNA 30 NA >4.8 3.4 >8.2
CPV Non-Env/RNA 18-24 NA 3.2 1.0 4.2

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