Source: FDA, National Drug Code (US) Revision Year: 2021
Severe hypersensitivity reactions may occur (See Contraindications (4)). 1 In case of hypersensitivity, discontinue PANZYGA infusion immediately and institute appropriate treatment. Have epinephrine available for immediate treatment of severe acute hypersensitivity reactions.
PANZYGA contains trace amounts of IgA (average 100 µg/mL in a 10% solution). IgA-deficient patients with antibodies against IgA are at greater risk of developing severe hypersensitivity and anaphylactoid reactions when administered PANZYGA (See Contraindications (4)).
Renal dysfunction, acute renal failure, osmotic nephropathy, and death may occur upon use of PANZYGA in predisposed patients.
Ensure that patients are not volume depleted prior to the initiation of the infusion of PANZYGA.
For patients at risk of renal dysfunction because of pre-existing renal insufficiency or predisposition to acute renal failure (such as individuals with diabetes mellitus, age greater than 65 years, volume depletion, sepsis, paraproteinemia, or those receiving known nephrotoxic drugs), administer PANZYGA at the minimum infusion rate practicable (See Boxed Warning, and Dosage and Administration (2)).
Periodic monitoring of renal function tests and urine output is particularly important in patients judged to be at risk of developing acute renal failure. Assess renal function, including a measurement of blood urea nitrogen (BUN)/serum creatinine, prior to the initial infusion of PANZYGA and again at appropriate intervals thereafter. If renal function deteriorates, consider discontinuation of the product.
Hyperproteinemia, increased serum viscosity and hyponatremia may occur in patients receiving PANZYGA therapy. It is clinically critical to distinguish true hyponatremia from pseudohyponatremia 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 higher risk of thromboembolic events. 2
Thrombosis may occur following treatment with immune globulin products, including PANZYGA. Risk factors 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 thrombotic events, administer PANZYGA 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 [3-5] (See BOXED WARNING, DOSAGE and ADMINSTRATION 2, PATIENT COUNSELING INFORMATION 17).
Aseptic meningitis syndrome (AMS) may occur with PANZYGA treatment. Discontinuation of treatment has resulted in remission of AMS within several days without sequelae. The syndrome usually begins within several hours to two days following infusion with PANZYGA. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting. 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 in patients exhibiting such symptoms and signs, including CSF studies, to rule out other causes of meningitis. Patients with a history of migraine may be more susceptible.6
AMS may occur more frequently following high doses (≥2 g/kg) and/or rapid infusion of IGIV.
PANZYGA 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 hemolysis. Delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration and acute hemolysis, consistent with intravascular hemolysis, has been reported. 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 or more), given either as a single administration or divided over several days, and non-O blood group.7 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 IGIV 8, but their role is uncertain. Hemolysis has been reported following administration of IGIV for a variety of indications, including ITP.
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, including direct antiglobulin test. 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 [Transfusion-Related Acute Lung Injury (TRALI)] may occur in patients administered IGIV.9 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Signs and symptoms typically appear within 1 to 6 hours after transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support.
Monitor recipients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-HLA and anti-neutrophil antibodies in both the product and patient’s serum.Elevations of systolic blood pressure to 180 mm Hg or more and/or of diastolic blood pressure to more than 120 mm Hg (hypertensive urgency) can be observed during and/or shortly following infusion of IGIV. Such elevations are reported more often among patients with a history of hypertension. Check patients for a history of hypertension and current antihypertensive medication use. Monitor blood pressure prior to, during, and following PANZYGA infusion.
Carefully consider the relative risks and benefits before prescribing the high dose regimen (for chronic ITP) in patients at increased risk of volume overload.
Because PANZYGA is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses and theoretically, the variant Creutzfeldt-Jakob disease and Creutzfeldt-Jakob disease (CJD) agent. The risk of infectious agent transmission has been reduced by screening plasma donors and by including virus inactivation/removal steps in the manufacturing process of PANZYGA. Report all infections thought by a physician or other healthcare provider to have been possibly transmitted by this product to Pfizer Inc. at 1-800-438-1985. Discuss the risks and benefits of PANZYGA with the patient before prescribing or administering this product.
PI: The most common adverse reactions observed at a rate of more than 5% in subjects in clinical trials were: headache, abdominal pain, fever, nausea, and fatigue.
Chronic ITP in adults: The most common adverse reactions observed at a rate of more than 5% in subjects in clinical trials were: headache, fever, nausea, vomiting, dizziness, and anemia.
CIDP in adults: The most common adverse reactions observed at a rate of more than 5% in subjects in clinical trials were: headache, fever, dermatitis and blood pressure increased.
The most serious adverse reaction observed with PANZYGA treatment during clinical trials was aseptic meningitis in one subject.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a product cannot be directly compared to rates in the clinical trials of another product and may not reflect the rates observed in clinical practice.
In a prospective, open-label, single-arm, multicenter study in 51 children and adults with PI, subjects received PANZYGA at a dose between 200 to 800 mg/kg body weight every 3 or 4 weeks. Subjects participated in the study for a mean of 360 days. Infusions were initiated at a rate of 1 mg/kg/minute for the first 30 minutes, and, if tolerated, could be advanced to a maximum tolerated rate not exceeding 8 mg/kg/minute. The mean age of subjects was 26.8 years (range: 2 to 65 years).
This study was followed by an extension study that evaluated the safety of PANZYGA administered at higher infusion rates in 21 subjects that successfully had completed the first study. Nineteen of the 21 enrolled patients received PANZYGA up to the maximum allowed infusion rate of 14 mg/kg/minute. In the extension study, medication-related adverse events were reported in 4 of 21 subjects (19%). Adverse reactions occurring in more than 5% of subjects were nausea (9.5%) and headache (9.5%).
In the study in PI, infusion-related adverse events (during or within 72 hours after the end of infusion) were reported in 16 patients (76%) enrolled in the 3-weeks treatment schedule and in 22 patients (73%) in the 4-weeks treatment schedule. Overall, 38 infusions (5%) had at least one adverse event considered related to study medication: 5 infusions (3%) in children, 4 infusions in adolescents (2%), and 29 infusions (8%) in adults. Study medication-related (possible or probable) infusion-related adverse reactions were associated with 35 infusions (5%) (overall); study medication-related headache was noted in 21 infusions (3%).
Table 1. Adverse Reactions* Occurring in more than 5% of Subjects with PI:
| Adverse Reaction | No. of Subjects with Adverse Reaction(percentage of subjects) |
|---|---|
| Headache | 11 (22%) |
| Abdominal pain (upper) | 7 (14%) |
| Fever | 7 (14%) |
| Nausea | 5 (10%) |
| Sinusitis | 4 (8%) |
| Fatigue | 3 (6%) |
| Bronchitis | 3 (6%) |
* Any infusional and any study medication related adverse events.
In a prospective, open-label, single-arm, multicenter study, 40 adult subjects with chronic ITP received PANZYGA at a dose of 2 g/kg, administered daily as 1 g/kg intravenous infusions on 2 consecutive days. 3/40 subjects did not receive a second infusion of PANZYGA due to infusion reactions, including chills, headache, fever and nausea. All subjects except 1 received at least 1 infusion with the highest rate of 8 mg/kg/minute. Pre-medication to alleviate potential adverse drug reactions was not allowed in the study.
There were 67 treatment emergent adverse events (TEAEs) reported in 24 (60%) subjects that were related to administration of PANZYGA. 55 of these adverse events (82%) were infusional adverse events that occurred within 72 hours after start of the infusion. Seven of these adverse events in 2 subjects were severe. These included headache, nausea, vomiting and chills.
When analyzed by infusion, infusion-related adverse events were reported in 33 of the 77 infusions (43%).
Table 2. Adverse Reactions* Occurring in more than 5% of Subjects with Chronic ITP in Adults:
| Adverse Reaction | No. of Subjects with Adverse Reaction(percentage of subjects) |
|---|---|
| Headache | 20 (50%) |
| Fever | 9 (23%) |
| Nausea | 7 (18%) |
| Vomiting | 4 (10%) |
| Dizziness | 4 (10%) |
| Anemia | 4 (10%) |
* Any infusional and any study medication related adverse events.
One out of 40 subjects with ITP treated with PANZYGA developed aseptic meningitis on Day 2 of the infusion. This subject was managed with antibiotics and supportive care with recovery.
Baseline direct Coomb’s test was performed in 39/40 subjects that were treated with PANZYGA. 10/39 (26%) subjects subsequently developed positive Coomb’s test. One subject was not tested at baseline but had positive results on all 3 subsequent visits. Four of these subjects (10%) developed hemolytic anemia after receiving PANZYGA. These resolved spontaneously without any intervention.
In a prospective, double-blind, randomized, multicenter study, 142 adult subjects with CIDP aged between 18 and 83 years were enrolled and randomized 1:2:1 to receive first a loading dose of 2 g/kg and then 0.5 g/kg, 1.0 g/kg or 2.0 g/kg PANZYGA for 7 maintenance infusions at 3-week intervals during the 24-week Dose-evaluation Phase (mean doses administered – including loading and rescue doses – were 0.91, 1.24 and 1.97 g/kg for 0.5, 1 and 2g/kg group, respectively).
All 142 subjects in this study received at least 1 dose of PANZYGA. The median maximum infusion rate was 0.12 mL/kg/min throughout the study in all dose groups. Seventy-three out of the 142 subjects experienced a total of 209 adverse reactions (AR). Table 3 summarizes the most frequent ARs that occurred in more than 5% of subjects. Generally, the incidence of ARs was similar across the dose groups; the only AR where a dose effect was evident was headache, with an incidence of 2.9% in the 0.5 g/kg group, 14.5% in the 1.0 g/kg group and 23.7% in the 2.0 g/kg group. Pre-medication for AEs was only allowed in subjects who had adverse events during 2 consecutive infusions. During the study 11 subjects (7.75%) received premedication.
Table 3. Adverse Reactions* Occurring in more than 5% of Adult Subjects with CIDP:
| Adverse Reaction | No. of Subjects with Adverse Reaction (percentage of subjects) |
|---|---|
| Headache | 21 (14.8 %) |
| Fever | 20 (14.1%) |
| Dermatitis | 14 (9.9%) |
| Blood Pressure Increased | 11 (7.7%) |
* Any infusional and any study medication related adverse events.
Two serious adverse reactions (headache and vomiting) were reported in one subject but did not lead to discontinuation of PANZYGA.
The following adverse reactions have been identified during post-approval use of PANZYGA. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
| Blood and lymphatic system disorders Leucopenia, hemolysis, pancytopenia |
| Immune system disorders Hypersensitivity (e.g., anaphylaxis), anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, allergic reaction, angioedema, face edema |
| Metabolic and nutritional disorders Fluid overload, (pseudo)hyponatremia |
| Psychiatric disorders Agitation, confusional state, anxiety, nervousness |
| Nervous system disorders Coma, loss of consciousness, seizures, (acute) encephalopathy, cerebrovascular accident, stroke, aseptic meningitis, migraine, speech disorder, paraesthesia, hypoesthesia, photophobia, tremor |
| Cardiac disorders Myocardial infarction, cardiac arrest, angina pectoris, tachycardia, bradycardia, palpitations, cyanosis |
| Vascular disorders Hypotension, (deep vein) thrombosis, peripheral circulatory failure/collapse, hypertension, phlebitis, pallor |
| Respiratory, thoracic and mediastinal disorders Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, respiratory failure, pulmonary embolism, pulmonary edema, bronchospasm, dyspnea, hypoxia, wheezing, cough |
| Gastrointestinal disorders Diarrhea, hepatic dysfunction, abdominal discomfort |
| Skin and subcutaneous tissue disorders Eczema, urticaria, rash (erythematous), pruritus, alopecia, Stevens-Johnson syndrome, epidermolysis, skin exfoliation, erythema (multiforme), dermatitis (e.g., bullous dermatitis) |
| Musculoskeletal and connective tissue disorders Back pain, arthralgia, myalgia, musculoskeletal pain, muscle stiffness, pain in extremity, neck pain, muscle spasm |
| Renal and urinary disorders Acute renal failure, osmotic nephropathy, renal pain |
| General disorders and administration site conditions Injection site reaction, chills, chest pain or discomfort, hot flush, flushing, flu-like illness, feeling cold or hot, edema, hyperhidrosis, malaise, asthenia, lethargy, burning sensation |
| Investigations Hepatic enzymes increased, oxygen saturation decreased, falsely elevated erythrocyte sedimentation rate, positive direct antiglobulin (Coombs') test |
Clinical studies have not evaluated mixtures of PANZYGA with other drugs and intravenous solutions. It is recommended that PANZYGA is administered separately from other drugs or medications which the patient may be receiving. Do not mix the product.
Do not mix PANZYGA with IGIVs from other manufacturers.
Passively transferred antibodies in immunoglobulin preparations can confound the results of serological testing, e.g. false positive Treponema pallidum testing might occur.
Antibodies in PANZYGA may interfere with the response to live viral vaccines, such as measles, mumps, and rubella. Inform physicians of recent therapy with PANZYGA, so that administration of live viral vaccines, if indicated, can be appropriately delayed for 3 or more months from the time of PANZYGA administration.
No human data are available to indicate the presence or absence of drug-associated risk. Animal reproduction studies have not been conducted with PANZYGA. It is also not known whether PANZYGA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Immune globulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
No human data are available to indicate the presence or absence of drug-associated risk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PANZYGA and any potential adverse effects on the breastfed infant from PANZYGA or from the underlying maternal condition.
PANZYGA was evaluated in 25 pediatric subjects (age range: 2-15 years). Twenty-five percent of PI subjects exposed to PANZYGA were children (between 2 and 12 years of age). Pharmacokinetics, efficacy and safety were similar to those in adults. No specific dose requirements were necessary to achieve the targeted serum IgG levels in the pediatric subjects.
The safety and effectiveness of PANZYGA have not been established in pediatric patients with ITP.
The safety and effectiveness of PANZYGA have not been established in pediatric patients with CIDP.
Clinical studies of PANZYGA in PID and ITP did not include sufficient numbers of subjects older than 65 years to determine whether they respond differently from younger subjects.
In the clinical study the safety and effectiveness of PANZYGA in subjects with CIDP older than 65 years was similar to those 65 years of age and younger. A total of 36 subjects older than 65 years were included in the clinical trial.
Patients older than 65 years of age may be at increased risk for developing adverse reactions such as thromboembolic events and acute renal failure (See Boxed Warnings and Thrombotic Events (5.4) and Renal Failure (5.2). Do not exceed recommended doses in this population, and apply the minimum practicable infusion rate.
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