Privigen Side Effects
Please note - some side effects for Privigen may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.
Side Effects of Privigen - for the Consumer
Privigen
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Privigen:
Seek medical attention right away if any of these SEVERE side effects occur when using Privigen:Back pain; chills; cough; diarrhea; fatigue; flushing; headache; muscle cramps; nausea; pain, swelling, muscle stiffness, or redness at the injection site.
Severe allergic reactions (rash; itching; hives; difficulty breathing or swallowing; tightness in the chest; swelling of the mouth, hands, face, lips, eyes, throat, or tongue; unusual hoarseness); calf pain or tenderness; chest pain or tightness; confusion; coughing up blood; eye pain or sensitivity to light; fainting; fast or irregular heartbeat; numbness of an arm or a leg; one-sided weakness; red, swollen, blistered, or peeling skin; seizures; severe headache, dizziness, or stomach pain; shortness of breath or trouble breathing; speech problems; symptoms of kidney problems (eg, decreased urination, lower back or flank pain, swelling or bloating, sudden weight gain); symptoms of liver problems (eg, yellowing of the skin or eyes, dark urine, pale stools, nausea, stomach pain, loss of appetite, unusual tiredness); symptoms of parvovirus infection (eg, fever, drowsiness, chills, runny nose, rash, joint pain); unusual bruising or bleeding; vision problems; wheezing.
This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.
TopPrivigen Side Effects - for the Professional
Privigen
The most serious adverse reactions observed in clinical study subjects receiving Privigen for PI was hypersensitivity in one subject. The most common adverse reactions observed in >5% of clinical study subjects with PI were headache, pain, nausea, fatigue, chills, vomiting, joint swelling/effusion, pyrexia, and urticaria.
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. Six other subjects 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, pyrexia/hyperthermia, positive DAT, anemia, vomiting, nausea, hyperthermia, bilirubin conjugated increased, bilirubin unconjugated increased, hyperbilirubinemia, 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. 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 adverse events (AEs) 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.
Temporally associated AEs are those occurring during an infusion 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 Privigen infusions temporally associated with one or more AEs was 23.8% (actual proportion: 20.8%). The total number of temporally associated AEs was 397 (a rate of 0.38 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 >5% of subjects, irrespective of causality.
| Adverse Event | Number (%) of Subjects [n=80] |
Number (Rate) of Infusions with Adverse Event [n=1038] |
|---|---|---|
|
||
| Headache | 35 (43.8) | 82 (0.079) |
| Pain | 20 (25.0) | 44 (0.042) |
| Fatigue | 13 (16.3) | 27 (0.026) |
| Nausea | 10 (12.5) | 19 (0.018) |
| Chills | 9 (11.3) | 15 (0.014) |
| Vomiting | 7 (8.8) | 13 (0.013) |
| Pyrexia | 6 (7.5) | 10 (0.010) |
| Cough | 5 (6.3) | 5 (0.005) |
| Diarrhea | 5 (6.3) | 5 (0.005) |
| Stomach discomfort | 5 (6.3) | 5 (0.005) |
Of the 397 temporally associated AEs reported for the 80 subjects with PI, the investigators judged 192 to be at least possibly related to the infusion of Privigen (including 5 serious, severe AEs described below). Of these, 91 were mild, 81 were moderate, 19 were severe, and 1 was of unknown severity.
Table 3 lists the adverse reactions (AEs at least possibly related to the infusion of Privigen) that occurred in >5% of subjects with PI, irrespective of time of occurrence.
| Adverse Reaction | Number (%) of Subjects [n=80] |
Number (Rate) of Infusions with Adverse Reaction [n=1038] |
|---|---|---|
| Headache | 24 (30.0) | 62 (0.060) |
| Pain, all types* | 12 (15.0)† | 26 (0.025) |
| Nausea | 10 (12.5) | 18 (0.017) |
| Fatigue | 9 (11.3) | 16 (0.015) |
| Chills | 9 (11.3) | 15 (0.014) |
| Vomiting | 6 (7.5) | 11 (0.011) |
Sixteen (20%) subjects experienced 41 serious AEs. Five of these AEs (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 AEs related to Privigen treatment (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.
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).
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. 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.
In this study, the proportion of infusions temporally associated with one or more AEs occurring during a Privigen infusion or within 72 hours after the end of an infusion was 15%. The total number of temporally associated AEs, irrespective of causality, was 206 (a rate of 0.27 AEs per infusion), reflecting that some subjects experienced more than one AE during the observation period. Table 4 lists the temporally associated AEs that occurred in >5% of subjects, irrespective of causality.
| Adverse Event* | Number (%) of Subjects [n=55] |
Number (Rate) of Infusions with Adverse Event [n=771] |
|---|---|---|
| Note: The AE 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. | ||
|
||
| Headache | 18 (32.7) | 56 (0.073) |
| Pain, all types† | 14 (25.5)‡ | 31 (0.040) |
| Abdominal pain§ | 3 (5.5) | 4 (0.005) |
| Chest pain | 3 (5.5) | 4 (0.005) |
| Pharyngolaryngeal pain | 3 (5.5) | 4 (0.005) |
| Nausea | 6 (10.9) | 10 (0.013) |
| Pyrexia | 4 (7.3) | 9 (0.012) |
| Chills | 3 (5.5) | 7 (0.009) |
| Influenza-like illness | 3 (5.5) | 4 (0.005) |
Of the 206 temporally associated AEs reported for the 55 subjects with PI, the investigators judged 125 to be at least possibly related to the infusion of Privigen. Of these, 76 were mild, 40 were moderate, and 9 were severe.
Table 5 lists the adverse reactions that occurred in >5% of subjects, irrespective of time of occurrence.
| Adverse Reaction | Number (%) of Subjects [n=55] |
Number (Rate) of Infusions With Adverse Reaction [n=771] |
|---|---|---|
|
||
| Headache | 16 (29.1) | 53 (0.069) |
| Pain, all types* | 11 (20.0)† | 26 (0.034) |
| Abdominal pain‡ | 4 (7.3) | 6 (0.008) |
| Chest pain | 3 (5.5) | 4 (0.005) |
| Chills | 3 (5.5) | 7 (0.009) |
| Fatigue | 3 (5.5) | 5 (0.006) |
| Joint swelling/effusion | 3 (5.5) | 7 (0.009) |
| Pyrexia | 3 (5.5) | 10 (0.013) |
| Urticaria | 3 (5.5) | 4 (0.005) |
Eleven (20%) subjects experienced 17 serious AEs, none of which were considered to be related to Privigen. Three subjects experienced AEs 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. 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 6 lists the temporally associated AEs that occurred in >5% of subjects with chronic ITP during a Privigen infusion or within 72 hours after the end of a treatment cycle (two consecutive infusions) with Privigen, irrespective of causality.
| Adverse Event | Number (%) of Subjects [n=57] |
Number (Rate) of Infusions With Adverse Event [n=114] |
|---|---|---|
|
||
| Headache | 37 (64.9) | 41 (0.360) |
| Pyrexia/hyperthermia | 21 (36.8) | 22 (0.193) |
| Nausea | 6 (10.5) | 6 (0.053) |
| Epistaxis | 6 (10.5) | 6 (0.053) |
| Vomiting | 6 (10.5) | 6 (0.053) |
| Blood unconjugated bilirubin increased | 6 (10.5) | 6 (0.053) |
| Blood conjugated bilirubin increased | 5 (8.8) | 5 (0.044) |
| Blood total bilirubin increased | 4 (7.0) | 4 (0.035) |
| Hematocrit decreased | 3 (5.3) | 3 (0.026) |
Table 7 lists the adverse reactions that occurred in >5% of subjects, irrespective of time of occurrence.
| Adverse Reaction | Number (%) of Subjects [n=57] | Number (Rate) of Infusions With Adverse Reaction [n=114] |
|---|---|---|
| Headache | 37 (64.9) | 52 (0.456) |
| Pyrexia/hyperthermia | 19 (33.3) | 21 (0.184) |
| Positive DAT | 6 (10.5) | 7 (0.061) |
| Anemia | 6 (10.5) | 6 (0.053) |
| Vomiting | 5 (8.8) | 6 (0.053) |
| Nausea | 5 (8.8) | 7 (0.061) |
| Bilirubin conjugated, increased | 5 (8.8) | 5 (0.044) |
| Bilirubin unconjugated, increased | 5 (8.8) | 5 (0.044) |
| Hyperbilirubinemia | 3 (5.3) | 3 (0.026) |
| Blood lactate dehydrogenase increased | 3 (5.3) | 3 (0.026) |
| Hematocrit decreased | 3 (5.3) | 3 (0.026) |
Of the 149 non-serious AEs related to Privigen, 103 were mild, 37 were moderate, and 9 were severe.
Three subjects experienced three serious AEs, one of which (aseptic meningitis) was related to the infusion of Privigen.
One subject withdrew from the study due to gingival bleeding that was not related to Privigen.
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.
Postmarketing Experience
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 and reported during the post-approval use of IGIV products.12
- 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
- Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension
- Neurological: Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome
- Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis
- Hematologic: Pancytopenia, leukopenia, hemolysis, positive DAT (Coombs' test)
- Musculoskeletal: Back pain
- Gastrointestinal: Hepatic dysfunction, abdominal pain
- General/Body as a Whole: Pyrexia, rigors
Side Effects by Body System - for Healthcare Professionals
General
In general, immune globulin intravenous human (IGIV) has been well tolerated. Mild infusion related symptoms of headache, myalgia, backache, fever, pruritus, hypotension/hypertension, tachycardia, chest tightness, chills, flushing, and nausea have been reported. Slowing or temporarily discontinuing the infusion has usually resulted in resolution of symptoms.
Renal
Renal side effects have included acute renal failure, acute tubular necrosis, proximal tubular nephropathy, and osmotic nephrosis, primarily in patients with baseline renal impairment. Some patients have required dialysis. Elevations in creatinine and BUN have been noted within 1 to 2 days following infusion. The incidence of adverse reactions may be greater in products containing sucrose as a stabilizer. Maltose containing products may cause mild diuresis. At least one case of reversible oliguria requiring only supportive care and renal failure requiring transplantation in a patient with baseline renal dysfunction has also been reported.
Twenty cases of IGIV related renal impairment have been reported.
Renal impairment, including renal failure, usually occurred in the first 5 days of therapy and more frequently in patients receiving high IGIV dosages for immune thrombocytopenia purpura.
Spontaneous reports to one manufacturer suggest that diabetic patients over the age of 70 years and patients with lupus nephritis receiving dosages greater than 400 mg/kg/day may be at increased risk of renal impairment. The mechanism has not been fully established, but may be related to renal tubular sucrose-induced osmotic injury or an immune mechanism.
Hypersensitivity
Hypersensitivity side effects have included responses in the form of an inflammatory reaction (fever, chills, nausea, vomiting, hypotension) in 10% of patients with agammaglobulinemia or severe hypogammaglobulinemia who have not received IGIV within 8 weeks or who have never received IGIV. True anaphylaxis, rarely resulting in death, has been reported.
Anaphylaxis has occurred more frequently in patients with previous severe hypersensitivity reactions to IGIV, but has been reported in patients without a history of IGIV allergy. Patients previously sensitized to antibodies, such as IgA, may be at increased risk for immediate hypersensitivity reactions. Epinephrine, oxygen, IV antihistamines, and IV corticosteroids should be immediately available as such reactions can occur seconds to hours after the initiation of the infusion.
Nervous system
Limited data suggest that a history of migraine headaches may be associated with an increased risk of aseptic meningitis syndrome.
Nervous system side effects have been reported rarely. Mild, post infusion headache has been reported in 2% of patients with Immune Thrombocytopenic Purpura (ITP) who received dosages equal to or greater than 0.4 g/kg/day. An Aseptic Meningitis Syndrome (AMS), primarily associated with dosages greater than 2 g/kg, has occasionally been reported. Discontinuation of IGIV has resulted in AMS resolution without sequelae. Rarely, seizures have been reported.
Metabolic
Metabolic side effects have been reported rarely. Hyponatremia has been reported in products containing 10% maltose.
Hematologic
Hematologic side effects have been reported rarely. These have included reports of mild hemolysis due to transfer of blood group antibodies, and thrombotic complications. At least 6 cases of disseminated intravascular coagulation (DIC) associated with acute hemoglinemia or hemoglobinuria following immune globulin intravenous administration have been reported.
A recent report of two women who received high dose IVIg and subsequently developed thromboembolic complications suggests that high-dose IVIg increases blood viscosity that may last for several weeks, which may increase susceptibility to thromboembolism in predisposed patients.
Out of the 6 patients who developed DIC, 1 child recovered without sequelae and 5 adults all died. The attending or consulting physicians assessed that acute hemolysis or DIC caused or contributed to each death.
Cardiovascular
Cardiovascular side effects have included rare reports of cardiovascular and cerebrovascular thrombosis.
Local
IGIV products with a more acidic pH have been reported to cause greater vein irritation.
Local side effects have included injection site reactions. These have included erythema, pain, infection, venous thrombosis, thrombophlebitis, and eczema.
Immunologic
Immunologic side effects have been reported rarely. All U.S. immune globulin products undergo viral inactivation and/or removal. However, no method has been totally effective in removing all risk and the potential exists for the presence of unknown infectious agents.
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