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Adverse reactions (ARs), as presented below and in Clinical Trials Experience (6.1), are defined as adverse events at least possibly related or events occurring during or within 72 hours of a Privigen infusion or treatment cycle (for ITP).
Primary Humoral Immunodeficiency
The most serious adverse reaction observed in clinical study subjects receiving Privigen for PI was hypersensitivity in one subject [see WARNINGS AND PRECAUTIONS]. The most common adverse reactions observed in > 5% of clinical study subjects with PI were headache, fatigue, nausea, chills, vomiting, back pain, pain, elevated body temperature, abdominal pain, diarrhea, cough, stomach discomfort, chest pain, joint swelling/effusion, influenza-like illness, pharyngolaryngeal pain, urticaria, and dizziness.
Chronic Immune Thrombocytopenic Purpura
The most serious adverse reactions observed in clinical study subjects receiving Privigen for chronic ITP were aseptic meningitis syndrome in one subject and hemolysis in two subjects [see WARNINGS AND PRECAUTIONS]. A total of 8 subjects (14%) in the ITP study experienced hemolysis as documented from clinical laboratory data. The most common adverse reactions observed in > 5% of clinical study subjects with chronic ITP were headache, elevated body temperature, positive DAT, anemia, nausea, epistaxis, vomiting, blood bilirubin unconjugated increased, blood bilirubin conjugated increased, blood total bilirubin increased, hematocrit decreased, and blood lactate dehydrogenase increased.
Clinical Trials Experience
Because different 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.
Treatment Of Primary Humoral Immunodeficiency
In a prospective, open-label, single-arm, multicenter clinical study (pivotal study), 80 subjects with PI (with a diagnosis of XLA or CVID) received Privigen every 3 or 4 weeks for up to 12 months [see Clinical Studies]. All subjects had been on regular IGIV replacement therapy for at least 6 months prior to participating in the study. Subjects ranged in age from 3 to 69; 46 (57.5%) were male and 34 (42.5%) were female.
The safety analysis included all 80 subjects, 16 (20%) on the 3-week schedule and 64 (80%) on the 4-week schedule. The median dose of Privigen administered was 428.3 mg/ kg (3-week schedule) or 440.6 mg/kg (4-week schedule) and ranged from 200 to 888 mg/ kg. A total of 1038 infusions of Privigen were administered, 272 in the 3-week schedule and 766 in the 4-week schedule.
Routine premedication was not allowed. However, subjects who experienced two consecutive infusion-related ARs that were likely to be prevented by premedication were permitted to receive antipyretics, antihistamines, NSAIDs, or antiemetic agents. During the study, 8 (10%) subjects received premedication prior to 51 (4.9%) of the 1038 infusions administered.
Table 2 summarizes the most frequent ARs (defined as adverse events at least possibly related or events occurring during or within 72 hours of a Privigen infusion) that occurred in > 5% of subjects.
Table 2: PI Pivotal Study – ARs* Occurring in > 5%
|AR||Number (%) of Subjects
|Number (Rate) of Infusions with AR
|Headache||36 (45.0)||100 (0.096)|
|Fatigue||13 (16.3)||29 (0.028)|
|Nausea||11 (13.8)||23 (0.022)|
|Chills||9 (11.3)||15 (0.014)|
|Vomiting||9 (11.3)||15 (0.014)|
|Back pain||8 (10.0)||15 (0.014)|
|Pain||7 (8.8)||14 (0.013)|
|Elevated body temperature||7 (8.8)||12 (0.012)|
|Diarrhea||6 (7.5)||6 (0.006)|
|Cough||5 (6.3)||5 (0.005)|
|Stomach discomfort||5 (6.3)||5 (0.005)|
|* Excluding infections.|
Of the 192 ARs reported (including 5 serious, severe ARs described below) 91 were mild (awareness of sign, symptom or event, but easily tolerated), 81 were moderate (discomfort enough to cause interference with usual activity and may have warranted intervention), 19 were severe (incapacitating with inability to do usual activities or significantly affected clinical status, and warranted intervention), and 1 was of unknown severity.
The five serious ARs (hypersensitivity, chills, fatigue, dizziness, and increased body temperature, all severe) were related to Privigen, occurred in one subject, and resulted in the subject's withdrawal from the study. Two other subjects withdrew from the study due to ARs (chills and headache in one subject; vomiting in the other).
Seventy-seven of the 80 subjects enrolled in this study had a negative DAT at baseline. Of these 77 subjects, 36 (46.8%) developed a positive DAT at some time during the study. However, no subjects showed evidence of hemolytic anemia.
An extension of the pivotal study was conducted in 55 adult and pediatric subjects with PI to collect additional efficacy, safety, and tolerability data. This study included 45 subjects from the pivotal study who were receiving Privigen and 10 new subjects who were receiving another IGIV product prior to enrolling in the extension study. Subjects ranged in age from 4 to 81 years; 26 (47.3%) were male and 29 (52.7%) were female.
Subjects were treated with Privigen at median doses ranging from 286 to 832 mg/kg per infusion over a treatment period ranging from 1 to 27 months. Twelve (21.8%) subjects were on a 3¬week treatment schedule with the number of infusions per subject ranging from 4 to 38 (median: 8 infusions); 43 (78.2%) subjects were on a 4-week schedule with the number of infusions ranging from 1 to 31 (median: 15 infusions). A total of 771 infusions were administered in this study.
In this study, subjects who continued from the pivotal study were permitted to receive infusions of Privigen at a rate up to 12 mg/kg/min (as opposed to the maximum of 8 mg/ kg/min allowed in the pivotal study) at the discretion of the investigator based on individual tolerability. Twenty¬three (51%) of the 45 subjects from the pivotal study (41.8% of the 55 subjects in the extension study) received 265 (38.4%) infusions at a maximum rate greater than the recommended rate of 8 mg/kg/min [see Administration]. The median of the maximum infusion rate in this subset was 12 mg/kg/min. However, because the study was not designed to compare infusion rates, no definitive conclusions regarding tolerability could be drawn for infusion rates higher than the recommended rate of 8 mg/kg/min.
Table 3 summarizes the ARs that occurred in > 5% of subjects.
Table 3: PI Extension Study – ARs* Occurring in > 5%
|AR*||Number (%) of Subjects
|Number (Rate) of Infusions with AR
|Headache||18 (32.7)||76 (0.099)|
|Nausea||6 (10.9)||10 (0.013)|
|Elevated body temperature||4 (7.3)||12 (0.016)|
|Abdominal pain†||4 (7.3)||7 (0.009)|
|Chest pain||3 (5.5)||4 (0.005)|
|Chills||3 (5.5)||7 (0.009)|
|Joint swelling/effusion||3 (5.5)||7 (0.009)|
|Pain||3 (5.5)||6 (0.008)|
|Fatigue||3 (5.5)||5 (0.006)|
|Influenza-like illness||3 (5.5)||5 (0.006)|
|Pharyngolaryngeal pain||3 (5.5)||4 (0.005)|
|Urticaria||3 (5.5)||4 (0.005)|
|Dizziness||3 (5.5)||3 (0.004)|
|Note: The AR rates in this study cannot be compared
directly to the rates in other IGIV studies, including the original pivotal
study described earlier in this section, because (1) the extension study used
an enriched population and (2) the selective use of higher infusion rates at
the investigators' discretion in a subset of subjects may have introduced bias.
* Excluding infections.
† Includes abdominal pain, abdominal pain upper, and abdominal pain lower.
Of the 125 reported ARs, 76 were mild (does not interfere with routine activities), 40 were moderate (interferes somewhat with routine activities), and 9 were severe (impossible to perform routine activities).
Three subjects experienced ARs that were considered to be at least possibly related to Privigen: dyspnea and pancytopenia in one subject, a transient ischemic attack 16 days after the infusion in one subject, and mild urticaria in one subject, resulting in the subject's withdrawal from the study.
Treatment Of Chronic Immune Thrombocytopenic Purpura
In a prospective, open-label, single-arm, multicenter clinical study, 57 subjects with chronic ITP and a platelet count of 20 x 109/L or less received a total of 2 g/kg dose of Privigen administered as 1 g/kg infusions daily for 2 consecutive days [see Clinical Studies]. Subjects ranged in age from 15 to 69; 23 (40.4%) were male and 34 (59.6%) were female.
Concomitant medications affecting platelets or other treatments for chronic ITP were not allowed. Thirty-two (56.1%) subjects received premedication with acetaminophen and/or an antihistamine.
Table 4 summarizes the most frequent ARs (adverse events at least possibly related or events occurring during or within 72 hours after the end of a treatment cycle [two consecutive infusions]) that occurred in > 5% of subjects with chronic ITP.
Table 4: Chronic ITP Study – ARs Occurring in > 5%
|AR||Number (%) of Subjects
|Number (Rate) of Infusions with AR
|Headache||37 (64.9)||52 (0.456)|
|Elevated body temperature||21 (36.8)||23 (0.202)|
|Positive DAT||7 (12.3)||8 (0.070)|
|Anemia||6 (10.5)||6 (0.053)|
|Nausea||6 (10.5)||8 (0.070)|
|Epistaxis||6 (10.5)||8 (0.070)|
|Vomiting||6 (10.5)||7 (0.061)|
|Blood bilirubin unconjugated increased||6 (10.5)||6 (0.053)|
|Blood bilirubin conjugated increased||5 (8.8)||5 (0.044)|
|Blood total bilirubin|
|increased||3 (5.3)||3 (0.026)|
|Hematocrit decreased||3 (5.3)||3 (0.026)|
|Blood lactate dehydrogenase increased||3 (5.3)||3 (0.026)|
Of the 149 non-serious ARs, 103 were mild (awareness of sign, symptom or event, but easily tolerated), 37 were moderate (discomfort enough to cause interference with usual activity and may have warranted intervention), and 9 were severe (incapacitating with inability to do usual activities or significantly affected clinical status, and warranted intervention). One subject experienced a serious AR (aseptic meningitis).
Eight subjects, all of whom had a positive DAT, experienced transient drug-related hemolytic reactions, which were associated with elevated bilirubin, elevated lactate dehydrogenase, and a decrease in hemoglobin level within two days after the infusion of Privigen. Two of the eight subjects were clinically anemic but did not require clinical intervention; these cases resolved uneventfully.
Four other subjects with active bleeding were reported to have developed anemia without evidence of hemolysis.
In this study, there was a decrease in hemoglobin after the first Privigen infusion (median decrease of 1.2 g/dL by Day 8) followed by a return to near baseline by Day 29. Fifty-six of the 57 subjects in this study had a negative DAT at baseline. Of these 56 subjects, 12 (21.4%) developed a positive DAT during the 29-day study period.
Because adverse reactions are reported voluntarily post-approval from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.
The following adverse reactions have been identified during postmarketing use of Privigen. This list does not include reactions already reported in clinical studies with Privigen [see Clinical Trials Experience].
- Infusion reactions: Changes in blood pressure, dyspnea, tachycardia, flushing
- Hematologic: hemoglobinuria/hematuria/chromaturia, renal failure
- Neurological: photophobia
- Integumentary: pruritus, rash
In addition, the following adverse reactions have been identified and reported during the post-approval use of immune globulin products.14
- Infusion Reactions: Tachycardia, malaise, flushing, rigors
- Renal: Acute renal dysfunction/failure, osmotic nephropathy
- Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, bronchospasm
- Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension
- Neurological: Coma, loss of consciousness, seizures, tremor
- Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis
- Hematologic: Pancytopenia, leukopenia
- Gastrointestinal: Hepatic dysfunction
Read the Privigen (immune globulin intravenous) Side Effects Center for a complete guide to possible side effects
Live Virus Vaccines
The passive transfer of antibodies with immunoglobulin administration may interfere with the response to live virus vaccines such as measles, mumps, rubella, and varicella [see PATIENT INFORMATION].15
Inform the immunizing physician of recent therapy with Privigen so that appropriate measures can be taken.
14. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Trans Med Rev 2003;17:241-251.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 3/18/2016
Additional Privigen Information
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