Included as part of the "PRECAUTIONS" Section
Severe hypersensitivity reactions may occur, even in patients who had tolerated previous treatment with human immune globulin. If a hypersensitivity reaction occurs, discontinue CUVITRU infusion immediately and institute appropriate treatment.
CUVITRU contains trace amounts of IgA (average concentration of 80 mcg/mL). Patients with known antibodies to IgA have a greater risk of developing potentially severe hypersensitivity reactions, including anaphylaxis, with administration of CUVITRU.
Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis, and death may occur upon use of immune globulin treatment, especially those containing sucrose3,4. CUVITRU does not contain sucrose. Ensure that patients are not volume depleted prior to the initiation of infusion of CUVITRU. In patients who are at risk of developing renal dysfunction because of pre-existing renal insufficiency or predisposition to acute renal failure (such as diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs), monitor renal function and consider lower, more frequent dosing. [See DOSAGE AND ADMINISTRATION]
Periodic monitoring of renal function and urine output is particularly important in patients predisposed to be at increased risk for developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of CUVITRU and again at appropriate intervals thereafter. If renal function deteriorates, consider discontinuation of CUVITRU. [See DOSAGE AND ADMINISTRATION]
Thrombosis may occur following treatment with immune globulin products.5,6 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 CUVITRU 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
BOX WARNING, DOSAGE AND ADMINISTRATION, PATIENT INFORMATION]
Aseptic Meningitis Syndrome (AMS)
AMS has been reported with the use of immune globulin. The syndrome usually begins within several hours to two days following immune globulin treatment. AMS may occur more frequently in female patients.
AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea and vomiting. [See PATIENT INFORMATION] Cerebrospinal fluid (CSF) studies frequently reveal pleocytosis up to several thousand cells per mm3, predominantly from the granulocytic series, and elevated protein levels up to several hundred milligram/dL, but negative culture results. Conduct a thorough neurological examination, including CSF studies, on patients exhibiting such signs and symptoms, to rule out other causes of meningitis. Discontinuation of treatment has resulted in remission of AMS within several days without sequelae.
CUVITRU can contain blood group antibodies that may act as hemolysins and induce in vivo coating of red blood cells (RBC) with immune globulin. This may cause a positive direct antiglobulin test [DAT (Coomb’s test)]7,8. Delayed hemolytic anemia can develop subsequent to CUVITRU therapy due to enhanced RBC sequestration; acute hemolysis, consistent with intravascular hemolysis, can occur7-11.
The following risk factors may be related to the development of hemolysis: high doses (e.g., ≥2 grams/kg, single administration or divided over several days) and non-O blood group7, 11. Underlying inflammatory state in an individual patient may increase the risk of hemolysis7 but its role is uncertain10,12.
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.
Transfusion-Related Acute Lung Injury (TRALI)
Non-cardiogenic pulmonary edema (TRALI) has been reported in patients following treatment with immune globulin products. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically occur within 1 to 6 hours after treatment.
Monitor patients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil and anti-HLA antibodies in both the product and patient serum. TRALI may be managed using oxygen therapy with adequate ventilatory support.
Transmittable Infectious Agents
Because CUVITRU 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 agent. This also applies to unknown or emerging viruses and other pathogens. No confirmed cases of viral transmission or vCJD have been associated with CUVITRU.
All infections thought by a physician to possibly have been transmitted by this product should be reported by the physician or other healthcare provider to Baxalta US Inc., at 1-800-423-2090.
Monitoring: Laboratory Tests
- Periodic monitoring of renal function and urine output is particularly important in patients predisposed to be at increased risk of developing acute renal failure. Assess renal function, including measurement of BUN and serum creatinine, before the initial infusion of CUVITRU and at appropriate intervals thereafter.
- 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, because of the potentially increased risk of thrombosis3,5.
- If signs and/or symptoms of hemolysis are present after an infusion of CUVITRU, perform appropriate laboratory testing for confirmation.
- If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies and anti-HLA antibodies in both the product and patient’s serum.
Interference With Laboratory Tests
- After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield false positive serological test 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.
- Administration of CUVITRU can lead to false positive readings in assays that depend on detection of beta-D-glucans for diagnosis of fungal infections; this may persist during the weeks following infusion of the product.
Patient Counseling Information
- Advise patients to read the FDA-approved patient labeling (Information for Patients and Instructions for Use).
- Prior to starting CUVITRU ask about a history of IgA deficiency, allergic reactions to immune globulin or other blood products. Patients with a history of allergic reactions should not be treated subcutaneously at home until several treatments have been administered and tolerated under medical supervision. [See WARNINGS AND PRECAUTIONS]
- Inform patients to immediately report the following signs and symptoms to their healthcare provider:
- Decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath. [See WARNINGS AND PRECAUTIONS]
- Instruct patients to immediately report symptoms of thrombosis. These symptoms may include pain and/or swelling of an arm or leg with warmth over the affected area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one side of the body. [See WARNINGS AND PRECAUTIONS]
- Severe headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movements, nausea, and vomiting. [See WARNINGS AND PRECAUTIONS]
- Increased heart rate, fatigue, yellowing of the skin or eyes, and dark-colored urine. [See WARNINGS AND PRECAUTIONS]
- Trouble breathing, chest pain, blue lips or extremities, or fever that can occur 1 to 6 hours after an infusion of CUVITRU. [See WARNINGS AND PRECAUTIONS]
- Inform patients that CUVITRU is made from human plasma and may contain infectious agents that can cause disease (e.g., viruses and, theoretically, the vCJD agent). The risk of CUVITRU transmitting an infectious agent has been reduced by screening plasma donors for prior exposure, testing donated plasma, and inactivating or removing certain viruses during manufacturing. Patients should report any symptoms that concern them which might be caused by virus infections. [See WARNINGS AND PRECAUTIONS]
- Inform patients that CUVITRU can interfere with their immune response to live viral vaccines such as measles, mumps, rubella and varicella, and instruct patients to notify their healthcare professional of this potential interaction when they are receiving vaccinations. [See DRUG INTERACTIONS]
If self-administration is deemed to be appropriate by the physician, clear instructions and training on subcutaneous infusion should be given to the patient/caregiver, and the demonstration of their ability to independently administer subcutaneous infusions should be documented.
- Ensure the patient understands the importance of consistent subcutaneous infusions to maintain appropriate steady IgG levels.
- Inform the patient to start the infusion promptly after drawing CUVITRU into the syringe. Ensure the patient understands that it is suggested to complete the administration within 2 hours due to the potential formation of particles caused by siliconized syringes.
- Instruct the patient to keep a treatment diary/log book. This diary/log book should include information about each infusion such as, the time, date, dose, lot number(s), infusion sites, and any reactions.
- Inform the patient that mild to moderate local infusion-site reactions (e.g., pain, redness and itching) are a common side effect of subcutaneous treatment, but to contact their healthcare professional if a local reaction increases in severity or persists for more than a few days.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No animal studies were conducted to evaluate the carcinogenic or mutagenic effects of CUVITRU or its effects on fertility.
Use In Specific Populations
No human data are available to indicate the presence or absence of drug-associated risk. Animal reproduction studies have not been conducted with CUVITRU. It is also not known whether CUVITRUcan cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Immune globulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation. CUVITRU should be given to a pregnant woman only if clearly indicated. 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 CUVITRU and any potential adverse effects on the breastfed infant from CUVITRU or from the underlying maternal condition.
CUVITRU was evaluated in 21 pediatric subjects with PI (2 to 16 years of age) in a multicenter clinical study. The safety and efficacy profiles were similar to adult subjects. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels.
Safety and effectiveness of CUVITRU has not been evaluated in neonates or infants <2 years old.
CUVITRU was evaluated in 9 subjects over the age of 65 years. No differences in safety or efficacy were observed for this group.
Monitor patients who are at an increased risk for developing renal failure or thrombotic events. Do not exceed the recommended dose, and infuse at the minimum infusion rate practicable. [See
BOX WARNING, WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION]
1. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Transfusion Med Rev. 2003;17:241-251.
2. Dantal J. Intravenous immunoglobulins: in-depth review of excipients and acute kidney injury risk. Am J Nephrol. 2013;38(4):275-84.
3. Katz U, Sheonfeld Y. Review: intravenous immunoglobulin therapy and thromboembolic complications. Lupus 2005;14:802-8.
4. Ramírez E, Romero-Garrido JA, López-Granados E, Borobia AM, Pérez T, Medrano N, Rueda C, Tong HY, Herrero A, Frías J. Symptomatic thromboembolic events in patients treated with intravenous-immunoglobulins: results from a retrospective cohort study. Thromb Res. 2014 Jun;133(6):1045-51.
5. Wilson JR, Bhoopalam N, Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle Nerve 1997;20:1142-1145.
6. Kessary-Shoham H, Levy Y, Shoenfeld Y, Lorber M, Gershon H. In vivo administration of intravenous immunoglobulin (IVIg) can lead to enhanced erythrocyte sequestration. J Autoimmun 1999;13:129-135.
7. Daw Z, Padmore R, Neurath D, Cober N, Tokessy M, Desjardins D, et al. Hemolytic transfusion reactions after administration of intravenous immune (gamma) globulin: a case series analysis. Transfusion. 2008; 48:1598-601.
8. Copelan EA, Strohm PL, Kennedy MS, Tuschka PJ, Hemolysis following intravenous immune globuline therapy. Transfusion 1986;26:410-412.
9. Berg R, Shebl A, Kimber MC, Abraham M, Schreiber GB. Hemolytic events associated with intravenous immune globulin therapy: a qualitative analysis of 263 cases reported to four manufacturers between 2003 and 2012. Transfusion. 2015 Jul;55 Suppl 2:S36-46.
10. Kahwaji J, et al.; Acute hemolysis after High-Dose Intravenous Immunoglobin Therapy in Highly HLA Sensitized Patients. Clin J Am Soc Nephrol; 2009 (4):1993-97.