Cytomegalovirus immune globulin (CMV-IGIV) is a parenteral, intravenously administered globulin fraction of human plasma, primarily immunoglobulin G. CMV-IGIV is obtained, purified and standardized from human plasma. Cytomegalovirus immune globulin is used to attenuate primary CMV disease associated with renal transplantation. Specifically, CMV-IGIV is given to CMV-seronegative patients receiving a kidney from a CMV-seropositive donor. When used prophylactically in renal allograft recipients, CMV-IGIV has been shown to reduce the incidence of virologically confirmed CMV-associated syndromes, including episodes of CMV pneumonitis. Leukopenia was reduced, and there were no reports of fungal or parasitic superinfections in the CMV-IGIV recipients.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Solution should be colorless, free of particulate matter, and not turbid.
Intravenous Administration
-Cytomegalovirus immune globulin (Cytogam) is administered intravenously.
-Admixtures of CytoGam with other drugs have not been evaluated. It is recommended that CytoGam be administered separately from other parenteral drugs or medications that the patient may be receiving.
Reconstitution:
-Reconstitute the lyophilized powder with 50 mL of sterile water for injection.
-Do not shake the vials; avoid foaming.
-Rotate vial gently to wet all undissolved powder; allow 30 minutes for dissolving powder.
IV infusion:
-Begin infusion within 6 hours of reconstitution and complete within 12 hours.
-Administer through a separate IV line using an administration set that contains an in-line filter (pore size 15 microns) and a constant infusion pump (i.e., IVAC pump or equivalent). A smaller in-line filter (0.2 microns) is also acceptable.
-Solution may be piggybacked, if necessary, into preexisting line running 0.9% Sodium Chloride injection, 5% Dextrose injection, or 5% Dextrose and 0.9% Sodium Chloride injection combinations. Do not dilute CMV-IGIV more than 1:2 dilution.
-The initial infusion rate should be 15 mg/kg/hour. If no adverse reactions occur after 30 minutes, increase dose to 30 mg/kg/hour. If no adverse reactions occur after 30 more minutes, increase dose to 60 mg/kg/hour. Total volume should not exceed 75 mL/hour.
Anaphylactoid reactions, including angioedema and anaphylactic shock, may occur with cytomegalovirus immune globulin. Patients who are IgA deficient and have known antibodies to IgA may be at greater risk for developing severe hypersensitivity reactions. Closely adhere to infusion rate recommendations during therapy as reactions may be related to rate of administration. Epinephrine and diphenhydramine should be immediately available during cytomegalovirus immune globulin infusions. If a hypersensitivity reaction or hypotension occurs, immediately discontinue the infusion.
Minor adverse reactions, such as flushing, chills, muscle cramps, back pain, fever, nausea, vomiting, arthralgia, and wheezing were the most common adverse reactions observed during clinical trials of cytomegalovirus immune globulin, occurring in less than 6% of all infusions. A decrease in blood pressure was observed in approximately 0.1% of infusions. These adverse reactions were most often related to infusion rates. Closely adhere to infusion rate recommendations during therapy. Slow the infusion rate immediately or temporarily discontinue the infusion if a patient develops a minor adverse reaction during therapy.
Transfusion-related acute lung injury (TRALI) is a life-threatening and potentially fatal complication of blood product administration; it has been reported rarely after IVIG administration. TRALI is characterized by severe respiratory distress, hypoxemia (hypoxia), fever, normal left ventricular function, and severe non-cardiogenic pulmonary edema. Symptoms typically begin 1 to 2 hours after administration and manifest fully within 1 to 6 hours. The clinical presentation may be subtle or significant. Radiographs show bilateral pulmonary infiltrates without evidence of cardiac compromise or fluid overload. Respiratory support may be necessary. Diuretics are not effective in TRALI as the cause involves microvascular injury, rather than fluid overload. The etiology of TRALI may be attributable to the presence of anti-HLA antibodies and/or anti-granulocyte antibodies in the plasma of multiparous females or donors who have received previous transfusions who serve as donors for the plasma-derived product. Recipients of IVIG should be monitored for pulmonary adverse events. If TRALI is suspected, both the product and the patient need to be tested for the presence of anti-neutrophil and anti-HLA antibodies. Other respiratory adverse reactions reported with IVIG products in post-marketing surveillance include apnea, acute respiratory distress syndrome (ARDS), cyanosis, dyspnea, and bronchospasm.
Thromboembolism, cerebrovascular accident (stroke), transient ischemic attack, thrombo-phlebitis, deep vein thrombosis, vena cava thrombosis, arterial thrombosis, retinal thrombosis, and pulmonary embolism have all been associated with IVIG. Signs and symptoms include numbness or weakness (paresis) on one side of the body, pain, swelling, discoloration, and/or warmth of the arms or legs, and unexplained shortness of breath. Additional adverse events associated with thrombosis include chest pain (unspecified), pallor, decreased heart rate, vascular collapse, myocardial infarction, and cardiac arrest. These can occur in patients without any known risk factors; however, patients most at risk include age older than 65, multiple cardiovascular risk factors, impaired cardiac output, prolonged immobilization, diabetes mellitus, obesity, coagulation disorders, a history of vascular disease, atherosclerosis, previous thromboembolic event, and/or known or suspected hyperviscosity. Ensure that patients are not volume depleted prior to the initiation of cytomegalovirus immune globulin. For patients judged to be at risk for developing thrombotic events, use the minimum recommended dose of cytomegalovirus immune globulin administered at the minimum practicable rate. Monitor all patients receiving cytomegalovirus immune globulin during and after each infusion and encourage patients to report any signs and symptoms of thrombosis.
Antibodies present in IVIG may act as hemolysins and induce immunoglobulin adherence to red blood cells, causing a positive direct antiglobulin test (DAT, Coombs' test), and rarely, hemolysis. Hemolytic anemia can develop after IVIG therapy due to enhanced red blood cell sequestration. Monitor patients receiving cytomegalovirus immune globulin for signs and symptoms of hemolysis. Pancytopenia and leukopenia have also been reported with IVIG products in post-marketing surveillance.
Renal dysfunction, including oliguria, anuria, acute renal failure (unspecified), osmotic nephrosis (osmotic nephropathy), acute renal tubular necrosis, and proximal tubular nephropathy, has been reported in patients receiving IVIG. Increases in BUN (azotemia) and serum creatinine have been observed as soon as 1 to 2 days after infusion of IVIG. Progression to oliguria and anuria requiring dialysis has been observed. Ensure that patients are adequately hydrated prior to cytomegalovirus immune globulin therapy. Monitor renal function, including BUN, serum creatinine, and urine output at baseline and appropriate intervals thereafter. If renal function deteriorates, consider IVIG therapy discontinuation.
Aseptic meningitis syndrome (AMS) has been reported rarely in association with IVIG therapy. Signs and symptoms appear within several hours to 2 days and include severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and emesis. AMS may be more frequent after high-dose (2 g/kg/dose) or rapid infusion IVIG treatment. Patients presenting with signs and symptoms should undergo a thorough neurological evaluation, including cerebrospinal fluid (CSF) studies; the CSF is often positive for pleocytosis and elevated protein levels. Discontinuation of IVIG treatment may result in remission of AMS within several days without sequelae Other neurologic adverse reactions, such as coma, loss of consciousness, seizures, and tremor, have also been reported with IVIG products in post-marketing surveillance.
Abdominal pain and hepatic dysfunction have been reported with IVIG products in post-marketing surveillance.
Dermatologic reactions, such as Stevens-Johnson syndrome, epidermolysis, erythema multiforme, and bullous rash, have been reported with IVIG products in post-marketing surveillance.
Cytomegalovirus immune globulin (CMV-IGIV) is contraindicated for use by patients with a history of a prior severe reaction associated with the administration of CMV-IGIV or other human immunoglobulin (Ig) preparations (human immunoglobulin hypersensitivity). Persons with selective IgA deficiency have the potential for developing antibodies to immunoglobulin A and could have anaphylactic reactions to subsequent administration of blood products that contain immunoglobulin A such as CMV-IGIV. Use caution in patients with sucrose hypersensitivity because CMV-IVIG contains sucrose.
No well-controlled studies have been conducted in pregnant women and it is not known if cytomegalovirus immune globulin (CMV-IGIV) can cause female harm or affect the reproductive system. According to the Advisory Committee on Immunization Practices, administration of immune globulin during pregnancy results in no known risk to the fetus. Administer CMV-IGIV to pregnant women only if clearly needed.
No data are available from the manufacturer regarding use of cytomegalovirus immune globulin (CMV-IGIV) during breast-feeding and it is not known if CMV-IGIV is excreted in breast milk. Case reports of two nursing mothers receiving intravenous immune globulin therapy suggest transfer of IgG and IgM into the colostrum and breast milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.
Patients with agammaglobulinemia or severe hypogammaglobulinemia are at an increased risk of developing immune-mediated adverse reactions if they have not received immunoglobulins in the preceding 8 weeks or if they have never received CMV-IGIV.
For primary cytomegalovirus (CMV) disease prophylaxis after organ transplantation, including kidney, lung, liver, pancreas, and heart transplantation:
NOTE: Cytomegalovirus immune globulin has been designated an orphan drug by the FDA for this indication.
-In CMV seronegative recipients of a renal allograft from a CMV seropositive donor:
Intravenous dosage:
Adults: 150 mg/kg by IV infusion administered within 72 hours posttransplant. Subsequent single IV doses of 100 mg/kg are administered at 2, 4, 6, and 8 weeks posttransplant. Then, the dosage is decreased to 50 mg/kg IV as a single dose during weeks 12 and 16 posttransplant.
-In CMV seronegative recipients of a heart, liver, lung, or pancreas allograft from a CMV seropositive donor:
Intravenous dosage:
Adults: 150 mg/kg IV given within 72 hours of transplant. Subsequent single doses of 150 mg/kg IV are given 2, 4, 6, and 8 weeks following transplantation. Then, the dosage is decreased to 100 mg/kg IV as a single dose during weeks 12 and 16 posttransplant. The manufacturer recommends consideration of adding ganciclovir in these patients. The efficacy of CMV-IVIG in preventing CMV and related infections was studied in a trial of patients receiving CMV-positive liver transplants. CMV-IVIG reduced the incidence of severe CMV-associated disease, including CMV pneumonia, multiorgan CMV disease, and invasive fungal disease in all serologic groups, regardless of recipient/donor CMV serologic status, except for the CMV-seropositive donor/CMV-seronegative recipient group.
-In CMV seronegative recipients of a bone marrow allograft from a CMV seropositive donor*:
Intravenous dosage:
Adults: In 1 study, bone marrow transplant patients were randomized to receive CMV-IVIG 200 mg/kg IV on days 8 and 6 pretransplant, on the day after marrow infusion, and on days 7, 14, 21, 28, 42, 56, and 70 for a total of 10 doses or no CMV-IVIG as primary prophylaxis of CMV infection. Although CMV viremia and excretion were less in the active drug group, there was no difference between groups with regard to clinical CMV disease.
For the treatment of cytomegalovirus (CMV) pneumonitis* as adjunctive therapy:
NOTE: Cytomegalovirus immune globulin has been designated an orphan drug by the FDA for use in conjunction with ganciclovir sodium for the treatment of cytomegalovirus pneumonia in bone marrow transplant patients.
Intravenous dosage:
Adults: 150 mg/kg/dose IV twice weekly or 400 mg/kg/dose IV every other day for 3 to 5 doses as adjunctive therapy in combination with IV ganciclovir. Guidelines in hematopoietic stem cell transplant (HSCT) recipients and other oncology patients recommend consideration of adjunctive intravenous immunoglobulin (IVIG) for CMV pneumonia. For solid organ transplant recipients, adjunctive immunoglobulin therapy is not routinely recommended.
Maximum Dosage Limits:
-Adults
150 mg/kg/dose IV; higher doses of 400 mg/kg IV have been given off-label for the treatment of CMV pneumonitis.
-Elderly
150 mg/kg/dose IV; higher doses of 400 mg/kg IV have been given off-label for the treatment of CMV pneumonitis.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) Do not give immune globulin including varicella zoster immune globulin concurrently with the varicella-zoster virus vaccine, live. Because of the potential inhibition of the immune response to vaccination by passively transferred antibodies, it is advisable not to give varicella-zoster virus vaccine, live to any patient who has received blood (except washed red blood cells), plasma transfusions, or immunoglobulins within the previous 5 months. After varicella vaccination, the CDC recommends that immune globulin products should not be given for 3 weeks, unless the benefit outweighs the risk; the manufacturer recommends waiting 2 months before administering immunoglobulins. In the case that IgG products are administered within 3 weeks of vaccination, the vaccinee should be either revaccinated at 5 months or tested for immunity and revaccinated if seronegative. Consult current CDC guidelines for recommendations. (Major) Rubella Virus Vaccine or Measles/mumps/rubella vaccines, MMR should not be given for at least 3 months following administration of immunoglobulins because antibodies in these products can neutralize the vaccine.
Measles/Mumps/Rubella Vaccines, MMR: (Major) Rubella Virus Vaccine or Measles/mumps/rubella vaccines, MMR should not be given for at least 3 months following administration of immunoglobulins because antibodies in these products can neutralize the vaccine.
Rotavirus Vaccine: (Major) Defer vaccination with live virus vaccines such as Rotavirus Vaccine until approximately 3 months after Cytomegalovirus immune globulin administration. Inform the immunizing physician of recent therapy with the immune globulin so that appropriate measures can be taken. The efficacy of live attenuated virus vaccines such as Rotavirus Vaccine may be impaired by Cytomegalovirus immune globulin administration; revaccination may be necessary. The passive transfer of antibodies from the immune globulin may impair the efficacy of live attenuated virus vaccines.
Varicella-Zoster Virus Vaccine, Live: (Major) Do not give immune globulin including varicella zoster immune globulin concurrently with the varicella-zoster virus vaccine, live. Because of the potential inhibition of the immune response to vaccination by passively transferred antibodies, it is advisable not to give varicella-zoster virus vaccine, live to any patient who has received blood (except washed red blood cells), plasma transfusions, or immunoglobulins within the previous 5 months. After varicella vaccination, the CDC recommends that immune globulin products should not be given for 3 weeks, unless the benefit outweighs the risk; the manufacturer recommends waiting 2 months before administering immunoglobulins. In the case that IgG products are administered within 3 weeks of vaccination, the vaccinee should be either revaccinated at 5 months or tested for immunity and revaccinated if seronegative. Consult current CDC guidelines for recommendations.
Cytomegalovirus immune globulin (CMV-IGIV) raises the relevant CMV antibodies to concentrations sufficient to attenuate or reduce the incidence of serious CMV disease. CMV-IGIV is primarily comprised of immunoglobulin G (IgG), specifically subclasses IgG1 and IgG3. IgG1 and IgG3 are involved in viral neutralization, as well as, tissue protection and complement activation. Immunoglobulins, such as CMV-IGIV, inhibit the ability of extracellular viruses to infect their target cells. Viral neutralization limits the capacity of viruses to spread from an extracellular focus to an intracellular location. CMV-IGIV inhibits infection of cells with CMV because the virus cannot fix to key cell membrane targets, or because of interference with uncoating or entry.
Pharmacokinetics:
Cytomegalovirus immune globulin (CMV-IGIV) is administered intravenously. CMV-IGIV is primarily comprised of immunoglobulin G (IgG), specifically subclasses IgG1 and IgG3. IgG is distributed from the plasma to other body compartments. Immunoglobulin catabolism occurs primarily in the plasma, but the liver may also have a role. IgG metabolism appears to be a multicompartmental, first-order process. Higher IgG concentrations increase the rate of metabolism and the shorten the half-life. The mean half-life of IgG is dependent on the subclass of the immunoglobulin. IgG1 has a half-life of 23-25 days, whereas, the half-life of IgG3 is only 9 days.
-Route-Specific Pharmacokinetics
Intravenous Route
Protection derived from Cytomegalovirus immune globulin (CMV-IGIV) has a rapid onset, imparting relevant CMV antibody concentrations immediately after infusion. The duration of action of CMV-IGIV is 1-3 months.