CYTOGAM Solution for infusion Ref.[10798] Active ingredients: Cytomegalovirus immunoglobulin

Because CMV-IGIV 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 (CJD) agent. The risk of transmission of recognized blood-borne viruses is considered to be low because of the viral inactivation and removal properties in the Cohn-Oncley cold ethanol precipitation procedure used for purification of immune globulin products.^13-15 Until 1993, cold ethanol manufactured immune globulins licensed in the United States had not been documented to transmit any viral agent. However, during a brief period in late 1993 to early 1994, intravenous immune globulin made by one U.S. manufacturer was associated with transmission of Hepatitis C virus.¹⁶ To further guard against possible transmission of blood-borne viruses, including Hepatitis C, CMV-IGIV is treated with a solvent detergent viral inactivation procedure² known to inactivate a wide spectrum of lipid enveloped viruses, including HIV-1, HIV-2, Hepatitis B, and Hepatitis C.¹⁷ However, because new blood-borne viruses may yet emerge, some of which may not be inactivated by the manufacturing process or by solvent detergent treatment, CMV-IGIV, like any other blood product, should be given only if a benefit is expected.

Immune Globulin Intravenous (Human) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis and death. ^18-25 Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia or patients receiving known nephrotoxic drugs. Especially in such patients, IGIV products should be administered at the minimum concentrations available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many IGIV products, those containing sucrose as a stabilizer (and given at daily doses of 350 mg/kg or greater) account for a disproportionate share of the total number.¹⁸ CYTOGAM contains sucrose as a stabilizer. See PRECAUTIONS and DOSAGE AND ADMINISTRATION sections for important information intended to reduce the risk of acute renal failure.

During administration, the patient’s vital signs should be monitored continuously and careful observation made for any symptoms throughout the infusion. Epinephrine should be available for the treatment of an acute anaphylactic reaction (see PRECAUTIONS section).

Minor reactions such as flushing, chills, muscle cramps, back pain, fever, nausea, vomiting, arthralgia, and wheezing were the most frequent adverse reactions observed during the clinical trials of CYTOGAM, Cytomegalovirus Immune Globulin Intravenous (Human). The incidence of these reactions during the clinical trials was less than 6.0% of all infusions and such reactions were most often related to infusion rates. A decrease in blood pressure was observed in 1 of 1039 infusions in clinical trials of CYTOGAM. If a patient develops a minor side effect, slow the rate immediately or temporarily interrupt the infusion.

Increases in serum creatinine and blood urea nitrogen (BUN) have been observed as soon as one to two days following IGIV infusion. Progression to oliguria or anuria requiring dialysis has been observed. Types of severe renal adverse events that have been seen following IGIV therapy include acute renal failure, acute tubular necrosis, proximal tubular nephropathy and osmotic nephrosis.^18-25

Severe reactions such as angioneurotic edema and anaphylactic shock, although not observed during clinical trials, are a possibility. Clinical anaphylaxis may occur even when the patient is not known to be sensitized to immune globulin products. A reaction may be related to the rate of infusion; therefore, carefully adhere to the infusion rates as outlined under DOSAGE AND ADMINISTRATION. If anaphylaxis or drop in blood pressure occurs, discontinue infusion and use antidote such as diphenhydramine and adrenalin.

Postmarketing

The following adverse reactions have been identified and reported during the post-approval use of IGIV products:³⁸

Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion-Related Acute Lung Injury (TRALI), cyanosis, hypoxemia, pulmonary edema, dyspnea, 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, hemolysis, positive direct antiglobulin (Coombs) test

General/Body as a Whole: Pyrexia, Rigors

Musculoskeletal: Back pain

Gastrointestinal: Hepatic dysfunction, abdominal pain

Because postmarketing reporting of these reactions is voluntary and the at-risk populations are of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to exposure to the product. Such is also the case with literature reports authored independently.

Renal Function

Assure that patients are not volume depleted prior to the initiation of IGIV. Periodic monitoring of renal function tests and urine output is particularly important in patients judged to have a potential increased risk for developing acute renal failure. Renal function, including the measurement of blood urea nitrogen (BUN) and serum creatinine should be assessed prior to the initial infusion of CYTOGAM and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered. The recommended rate of CYTOGAM infusion for prophylaxis of CMV disease in solid organ transplant patients is 60 mg Ig/kg/hr (see DOSAGE AND ADMINISTRATION).

Aseptic Meningitis Syndrome

An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with Immune Globulin Intravenous (Human) (IGIV) treatment.^26-29 The syndrome usually begins within several hours to two days following IGIV treatment. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cu.mm., predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high dose (2 g/kg) IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae.

Hemolysis

Immune Globulin Intravenous (Human) (IGIV) products can contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis.^30-32 Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration³³ (see ADVERSE REACTIONS). IGIV recipients should be monitored for clinical signs and symptoms of hemolysis (see PRECAUTIONS: Laboratory Tests).

Transfusion-Related Acute Lung Injury (TRALI)

There have been reports of noncardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] in patients administered IGIV.³⁴ TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within 1-6 hours after transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support.

IGIV recipients should be monitored for pulmonary adverse reactions. If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum (see PRECAUTIONS: Laboratory Tests).

Thrombotic Events

Thrombotic events have been reported in association with IGIV ^35-37 (see ADVERSE REACTIONS). Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity. The potential risks and benefits of IGIV should be weighed against those of alternative therapies for all patients for whom IGIV administration is being considered. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies (see PRECAUTIONS: Laboratory Tests).

CYTOGAM does not contain a preservative. The vial should be entered only once for administration purposes and the infusion should begin within 6 hours. The infusion schedule should be adhered to closely (see DOSAGE AND ADMINISTRATION: Infusion section). Do not use if the solution is turbid.

Although systemic allergic reactions are rare (see ADVERSE REACTIONS section), epinephrine and diphenhydramine should be available for treatment of acute allergic symptoms. If hypotension or anaphylaxis occur, the administration of the immunoglobulin should be discontinued immediately and an antidote should be given as noted above.

Patients should be instructed to report all infections directly to their physician and to CSL Behring Pharmacovigilance at 1-866-915-6958. The risks and benefits of this product should be discussed with the patient. In addition, patients should be instructed to immediately report symptoms of decreased urine output, sudden weight gain, and/or shortness of breath (which may suggest kidney damage) to their physician.

If signs and/or symptoms of hemolysis are present after IGIV infusion, appropriate confirmatory laboratory testing should be done (see PRECAUTIONS).

If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and the patient serum (see PRECAUTIONS).

Because of the potentially increased risk of thrombosis, baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies (see PRECAUTIONS).

Antibodies present in immune globulin preparations may interfere with the immune response to live virus vaccines such as measles, mumps, and rubella; therefore, vaccination with live virus vaccines should be deferred until approximately three months after administration of CYTOGAM. If such vaccinations were given shortly after CYTOGAM, a revaccination may be necessary. Admixtures of CYTOGAM with other drugs have not been evaluated. It is recommended that CYTOGAM be administered separately from other drugs or medications which the patient may be receiving (see DOSAGE AND ADMINISTRATION section).

Animal reproduction studies have not been conducted with Cytomegalovirus Immune Globulin Intravenous (Human). It is also not known whether Cytomegalovirus Immune Globulin Intravenous (Human) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Cytomegalovirus Immune Globulin Intravenous (Human) should be given to a pregnant woman only if clearly needed.