ATC Class:J06BB09
VA Class:IM500
Cytomegalovirus immune globulin IV (CMV-IGIV) is a specific immune globulin (hyperimmune globulin).36 CMV-IGIV contains immunoglobulin G (IgG) prepared from plasma of adults selected for high titers of CMV antibody.1
Cytomegalovirus immune globulin IV (CMV-IGIV) is used to provide passive immunity to cytomegalovirus (CMV) in certain individuals at risk for primary CMV infection or disease or secondary ) CMV disease (reactivation of CMV).1, 4, 5, 6, 7, 8, 10, 11, 13, 16, 17, 18, 19, 20, 40 CMV-IGIV has been designated an orphan drug by the US Food and Drug Administration (FDA) for the prevention or attenuation of primary CMV disease in immunosuppressed organ transplant recipients.14 CMV-IGIV is labeled by the FDA for prophylaxis of CMV disease in CMV-seronegative or CMV-seropositive recipients of kidney, liver, lung, pancreas, or heart transplant.1 With the exception of CMV-seronegative recipients of kidneys from CMV-seropositive donors, CMV-IGIV prophylaxis should be considered in conjunction with ganciclovir.1 CMV-IGIV has been used in an attempt to prevent primary or secondary CMV disease in allogeneic bone marrow transplant (BMT) patients†;17, 18, 41, 45, 49, 57, 62, 63 however, the role of the immune globulin in this patient population is less clearly established than its role in solid organ transplant recipients.17, 18, 56, 57, 62, 63 CMV-IGIV also has been used in conjunction with ganciclovir for the treatment of CMV pneumonitis† in transplant recipients,18, 22, 23, 24, 25 and has been designated an orphan drug by the FDA for use in conjunction with ganciclovir for the treatment of CMV pneumonia in bone marrow transplant recipients.14
Ensuring that CMV-seronegative transplant recipients receive only blood products that have been screened for CMV and organs or bone marrow from CMV-seronegative donors substantially decreases the risk for posttransplant CMV infection and disease in these individuals; however, CMV-seronegative donors may not be available since 40-100% of adults in the US have serologic evidence of CMV infection.9, 10, 18, 43, 47, 61, 65, 66, 67 (See Pharmacology: Cytomegalovirus and Infection.) Therefore, various strategies have been used for CMV prophylaxis in solid organ transplant or BMT patients at risk for primary CMV infection or disease or for reactivation of CMV, including short- or long-term antiviral agent prophylaxis and/or passive immunization with CMV-IGIV or immune globulin IV (IGIV).10, 13, 15, 50, 51, 55, 58, 61, 69, 70, 71, 72, 73, 74, 84, 86 In addition, as an alternative to routine CMV prophylaxis, selective use of preemptive antiviral agent therapy (initiated after transplant based on detection of CMV) with or without CMV-IGIV has been used for the prevention of CMV disease in transplant patients.18, 56, 57, 69, 71, 72, 73, 76, 86 Each of these strategies has certain advantages and disadvantages and all have limited efficacy since no regimen has been found to effectively and consistently prevent active CMV disease in all individuals at risk.10, 13, 15, 50, 51, 55, 58, 61, 69, 71, 72, 73, 84, 86
A meta-analysis of 11 prospective, randomized trials evaluating use of CMV-IGIV for CMV prevention in solid organ transplant recipients indicated that such prophylaxis was associated with reduced CMV disease, reduced all-cause mortality, and reduced CMV-associated deaths (except in those undergoing kidney transplantation), but did not reduce CMV infection and had no effect on the incidence of rejection episodes.85 However, another data analysis of randomized (or quasi-randomized), controlled trials indicated that use of CMV-IGIV or IGIV in solid organ transplant recipients did not reduce the risk of CMV disease, CMV infection, or all-cause mortality compared with placebo or no treatment and that use of CMV-IGIV or IGIV in conjunction with antivirals (acyclovir, ganciclovir) was no more effective than use of the antiviral alone in reducing the risk of CMV disease or all-cause mortality.84 Further study is needed to identify optimum regimens for CMV prophylaxis based on the degree of risk associated with the CMV status of the patient prior to transplant (i.e., CMV-seronegative or -seropositive), the particular transplant procedure (i.e., kidney, liver, lung, heart, bone marrow), and immunosuppressive regimen administered.13, 40, 55, 58, 60, 86 In addition, further study is needed to compare the relative efficacy and safety of routine CMV prophylaxis with that of preemptive CMV therapy and to identify which patients would derive the most benefit from these differing strategies.10, 18, 56, 57, 71, 72, 73, 86
The relative efficacy and safety of CMV-IGIV and IGIV for the prevention of CMV disease in solid organ transplant recipients or allogeneic BMT patients have not been clearly established in prospective, randomized, controlled studies.10, 12, 13, 50, 51, 55, 62, 63, 84 While it is unclear whether CMV-IGIV offers any therapeutic advantage over IGIV, some clinicians suggest that CMV-IGIV may be preferred if an immune globulin is used for CMV prophylaxis in solid organ transplant recipients since it contains a standardized CMV antibody content that is 4-8 times higher than that contained in IGIV.10, 12, 13, 50, 51, 55, 75, 76
Prevention of CMV Disease in Kidney Transplant Recipients
CMV-IGIV is used for CMV prophylaxis in kidney transplant recipients who are at risk for primary CMV infection and disease (i.e., CMV-seronegative recipients of a kidney from a donor who is CMV-seropositive).1, 4, 5, 7, 8, 10, 15 While CMV-IGIV has been used alone for CMV prophylaxis in renal transplant patients at risk for primary infection, CMV-IGIV generally is used in conjunction with an antiviral agent (e.g., acyclovir, ganciclovir) in these patients.10, 13, 15, 70, 75, 76 The role of CMV-IGIV for prevention or attenuation of reactivated CMV infections in CMV-seropositive kidney transplant patients remains to be determined.6, 75, 76
In a randomized, multicenter study that involved CMV-seronegative renal transplant recipients (i.e., pretransplant CMV antibody titers less than 1:8 by indirect hemagglutination assay [IHA]) who received kidneys from CMV-seropositive cadavers or living relatives, CMV-IGIV prophylaxis (initiated within 72 hours of transplantation and continued until 16 weeks posttransplant using a preparation containing a CMV antibody titer of 1:8192 by IHA or 1:8000 by enzyme-linked immunosorbent assay [ELISA]) did not affect the incidence of primary CMV infection since the seroconversion rate was 71% in those who received CMV-IGIV and 77% in those who did not receive the immune globulin.1, 5 However, those who received prophylaxis with CMV-IGIV had a decreased incidence of CMV-associated syndromes and serious CMV disease compared with control patients.1, 5 During the first year following transplantation, 21% of patients who received CMV-IGIV developed virologically confirmed CMV-associated syndromes compared with 60% of control patients.1, 5 The incidence of substantial leukopenia (i.e. leukocytes less than 3000/ mm3) was 4% in patients who received CMV-IGIV and 37% in control patients.1, 5 While there were no fungal or parasitic superinfections in those who received CMV-IGIV, 20% of control patients developed fungal infections (i.e., aspergillosis, candidemia, candida peritonitis, disseminated mucormycosis) or Pneumocystis carinii pneumonia.1, 5 The beneficial effects of CMV-IGIV were not affected by immunosuppressive regimens administered for prophylaxis or treatment of graft rejection (i.e., antilymphocyte serum, antithymocyte globulin, methylprednisolone sodium succinate, monoclonal antibody [muromonab-CD3], plasmapheresis).5 Overall, serious CMV disease (i.e., CMV pneumonia, retinitis, CNS involvement, substantial leukopenia, fungal or parasitic superinfection) developed in 13% of patients receiving CMV-IGIV or 46% of control patients;1, 5 in those who received therapy for rejection, serious CMV disease occurred in 15 or 54%, respectively.5
The beneficial effects of CMV-IGIV demonstrated in the randomized, controlled study were confirmed by a subsequent open-label study that evaluated use of CMV-IGIV in 36 renal transplant recipients at risk for developing primary CMV disease (i.e., CMV-seronegative recipients of a kidney from a CMV-seropositive cadaver or living relative)7 and by analysis of clinical outcomes of 174 similar renal transplant recipients who received CMV-IGIV under treatment IND protocols during 1987-1990.8 In the open-label study, the seroconversion rate in those receiving CMV-IGIV was 67%; however, only 36% developed virologically confirmed CMV-associated syndromes.1, 6, 7 The rates of CMV-associated pneumonia, CMV-associated hepatitis, and concomitant fungal and parasitic superinfections in these patients were similar to those reported in patients who received CMV-IGIV in the randomized, controlled study.1, 5, 6, 7 While data relating to seroconversion rate were not available for renal transplant patients who received CMV-IGIV prophylaxis under the treatment IND protocol, the overall incidence of virologically-confirmed CMV syndromes was 22%.8 Serious CMV disease occurred in 25% of patients who received therapy for rejection and 18% of those who did require such therapy; however, CMV infection was not virologically confirmed in all these patients.8
Prevention of CMV Disease in Liver, Lung, Pancreas, or Heart Transplant Recipients
CMV-IGIV is used for the prevention of CMV disease in liver,1, 16, 20, 54, 60, 61 lung,1, 19, 53, 81 pancreas,1 or heart1, 37, 40, 55 transplant recipients.1, 11, 13, 16, 17, 19, 20, 40, 76 CMV-IGIV usually is used in conjunction with an antiviral agent (e.g., ganciclovir, acyclovir) in these transplant recipients.1, 19, 53, 54, 55, 61, 75, 76, 81 Although CMV-IGIV is included in CMV prophylaxis protocols used at some transplant centers for liver, lung, or heart transplant recipients,13, 58, 76 optimum regimens for CMV prophylaxis based on the type of organ being transplanted and the degree of risk for CMV infection or disease have not been identified, especially for those at greatest risk (e.g., CMV-seronegative recipients of organs from CMV-seropositive donors, patients receiving muromonab-CD3 [OKT3 monoclonal antibodies] or other immunosuppressive therapy).13, 40, 58, 60, 86
Safety and efficacy of CMV-IGIV prophylaxis in liver transplant recipients was evaluated in a prospective, randomized, placebo-controlled study that included 141 children and adults who were CMV-seronegative or -seropositive prior to transplant.16 Patients received either the commercially available CMV-IGIV preparation or placebo (albumin human 1%); those who developed CMV pneumonia or severe CMV disease received treatment with a regimen of ganciclovir used in conjunction with CMV-IGIV.16 CMV-IGIV prophylaxis did not affect the incidence of primary CMV infection in these patients since CMV infection developed in 57% of those who received the immune globulin and 61% of those who received placebo.16 However, while the rate of viremia was similar in both groups, those who received CMV-IGIV had a 50% reduction in the incidence of severe CMV disease (i.e., biopsy-proven CMV disease in more than 1 organ, CMV pneumonia, or invasive fungal disease associated with CMV infection).16 When results were stratified according to the serologic status of the recipient and donor, CMV-IGIV prophylaxis was least effective in CMV-seronegative recipients of liver transplants from CMV-positive donors.16 Most clinicians suggest that CMV prophylaxis in these individuals requires the use of both CMV-IGIV and an antiviral agent (e.g., ganciclovir, acyclovir).54, 61, 75, 76
There is some evidence that CMV prophylaxis that includes both CMV-IGIV and ganciclovir can decrease the incidence of severe CMV disease in CMV-seronegative recipients of a heart and/or lung from a CMV-positive donor,19, 53, 55 and may decrease the incidence and delay the onset of CMV disease in heart and/or lung recipients who are CMV-seropositive prior to surgery.19 CMV-IGIV should be used in conjunction with an antiviral agent and not used alone for CMV prophylaxis in CMV-seronegative or -seropositive heart and/or lung transplant patients.55, 75, 76
Prevention of CMV Disease in Bone Marrow Transplant Recipients
CMV-IGIV has been used in individuals undergoing allogeneic BMT in an attempt to prevent primary CMV infection in those who are CMV-seronegative prior to transplant†17, 18, 41, 45, 49, 57, 62, 63 or to prevent or attenuate secondary CMV disease (reactivation of CMV) in individuals who are CMV-seropositive prior to transplant†.18 However, such use is controversial since the possible benefits of CMV-IGIV prophylaxis in this patient population have not been clearly established.17, 18, 56, 57, 62, 63, 75, 76 Results of published trials evaluating use of CMV-IGIV in allogeneic BMT patients have been conflicting, possibly because of factors related to the specific patient population evaluated (i.e., CMV status, age, preparatory regimen used prior to transplant, medical condition necessitating transplant) or factors related to the specific CMV-IGIV preparation and/or dosing regimen used.17, 18, 57, 62, 63
While several randomized studies in CMV-seronegative individuals who received BMT from a CMV-seronegative or -seropositive donor failed to demonstrate evidence that use of CMV-IGIV for prophylaxis decreased the incidence of posttransplant CMV disease,17, 18, 41 results of other randomized studies that included both CMV-seronegative and -seropositive individuals indicated that those who received CMV-IGIV had a lower incidence of CMV disease following transplant than those who did not receive the immune globulin.18, 49 In a study that included only CMV-seronegative recipients of allogeneic BMT from CMV-seropositive donors, prophylaxis with CMV-IGIV (200-mg/kg doses of a preparation containing a CMV antibody titer of 1:8192 by IHA or 1:25,600 by ELISA given once daily on days 8 and 6 prior to transplant and on days 1, 7, 14, 21, 28, 42, 56, and 70 posttransplant) decreased the incidence of primary CMV infection occurring within 100 days after transplant but did not decrease the incidence of symptomatic CMV disease or provide any survival benefit.45
The most effective regimen for CMV prophylaxis in allogeneic BMT patients at risk for CMV infection and disease has not been established.57 While current Eastern Cooperative Oncology Group (ECOG) recommended guidelines for the management of autologous and allogenic bone marrow transplantation do not specifically address the use of CMV-IGIV for CMV prophylaxis in allogeneic BMT patients, these guidelines do include recommendations regarding the use of IGIV.21 In general, allogeneic BMT patients who are CMV-seronegative and are scheduled to receive marrow from a CMV-seronegative donor are at low risk for CMV infection and do not need to receive CMV prophylaxis with an immune globulin or antiviral agent; however, these individuals should receive only blood products that have been screened and found to be negative for CMV.18, 21, 56 CMV-seronegative individuals who are scheduled to receive BMT from a CMV-seropositive donor and all CMV-seropositive allogeneic BMT recipients are at greater risk and may benefit from CMV prophylaxis.18, 21, 46, 56 ECOG recommends that such individuals receive IGIV for CMV prophylaxis.18, 21 While some clinicians recommend that these individuals receive CMV prophylaxis with an antiviral agent (e.g., acyclovir, ganciclovir), others state that the benefits of antiviral agent prophylaxis in CMV-seropositive recipients do not outweigh the risks associated with such regimens and these clinicians prefer to use preemptive therapy (initiated based on detection of CMV) rather than routine prophylaxis in these individuals.18, 56, 57 ECOG guidelines stipulate that weekly blood, urine, and throat cultures should be obtained from allogeneic BMT patients for the first 120 days after transplant and that those with positive cultures for CMV should receive preemptive therapy with ganciclovir given in conjunction with IGIV.21
Individuals undergoing autologous BMT also are at risk for CMV infection; however, serious CMV disease (including CMV pneumonitis) occurs much less frequently in autologous BMT patients than in allogeneic BMT patients and CMV prophylaxis with an immune globulin and/or antiviral agent is not generally indicated in individuals undergoing autologous BMT.18, 21, 75, 76 CMV prophylaxis in individuals who are CMV-seronegative prior to autologous BMT generally involves ensuring that they receive only CMV-seronegative blood products or, alternatively, leukocyte-filtered blood products.21, 75, 76
Recommendations of the US Centers for Disease Control and Prevention (CDC), Infectious Diseases Society of America (IDSA), and American Society of Blood and Marrow Transplantation (ASBMT) regarding prevention and prophylaxis of opportunistic infections in pediatric and adult autologous and allogeneic hematopoietic stem cell transplant (HSCT) recipients do not address the use of CMV-IGIV in these individuals.78
Treatment of CMV Pneumonitis in Transplant Recipients
CMV-IGIV has been used in conjunction with ganciclovir for the treatment of CMV pneumonitis in allogeneic BMT recipients†.18, 22, 23, 24 The immune globulin also has been used in conjunction with ganciclovir for the treatment of CMV pneumonitis in solid organ transplant recipients† (e.g., liver transplant patients).16, 25 While there is some evidence that regimens that include ganciclovir and either CMV-IGIV11, 18, 22, 23 or IGIV18, 22, 48 may be more effective in the treatment of CMV pneumonitis in allogeneic BMT patients than use of the antiviral agent alone,11, 18, 23 it is unclear whether CMV-IGIV or IGIV is the preferred immune globulin for this use.18, 22, 75, 76 CMV-IGIV should not be used alone for the treatment of CMV pneumonia in BMT patients.18, 44
In a study in allogeneic BMT patients with proven CMV pneumonia who received induction treatment with ganciclovir (2.5 mg/kg every 8 hours for 14 days) given in conjunction with CMV-IGIV (400-mg/kg doses of a preparation containing a CMV antibody titer of 1:6400 by IHA given once daily on days 1, 2, and 7 and a 200-mg/kg dose given on day 14) and, if necessary, continued induction treatment or maintenance treatment with both drugs, 52% survived the initial episode of pneumonitis (based on resolution of respiratory symptoms and hypoxia and eventual hospital discharge) in contrast to the 10-22% (mean: 15%) survival rate obtained at the same institution with other treatment regimens (e.g., antiviral agent therapy alone or in conjunction with corticosteroids or interferon).23 However, CMV pneumonia recurred in some patients23 and further study is needed to determine whether combined ganciclovir and CMV-IGIV therapy has any effect on the long-term survival rate in allogeneic BMT patients who develop CMV pneumonitis.18, 23, 56
Congenital or Neonatal CMV Infection
CMV-IGIV has been used in a limited number of pregnant women with primary CMV infection in an attempt to treat or prevent congenital CMV infection†.38, 79, 83 There is some evidence from a prospective, uncontrolled study that administration of at least 1 dose of CMV-IGIV to pregnant women with confirmed primary CMV infection and with CMV-positive amniotic fluid may decrease the risk of symptomatic congenital CMV disease in their infants.79 There also is some evidence from this uncontrolled study that administration of CMV-IGIV (once monthly for 2-7 months) in pregnant women with primary CMV infection but with unknown fetal CMV infection status (i.e., amniocentesis not performed) may decrease the risk of congenital CMV infection.79 However, CMV-IGIV is not currently recommended for prevention of maternal-fetal transmission of CMV.38, 82 Additional study is needed to evaluate the possible benefits and risks of antenatal CMV-IGIV.79, 80, 82
CMV-IGIV previously was investigated for use in premature neonates at risk for CMV infection who required multiple blood transfusions with products that had not been screened for CMV†.39 However, CMV-IGIV is no longer being investigated for this use since concerns regarding transmission of CMV to neonates via blood transfusions have virtually been eliminated by the current practice of ensuring that premature neonates born to CMV-seronegative mothers receive blood that is CMV-negative or, alternatively, frozen deglycerolized red blood cells or leukodepleted blood.39, 75, 76
CMV Infection in HIV-Infected Individuals
The potential role, if any, for CMV-IGIV in prevention or treatment of CMV infection or disease in individuals with human immunodeficiency virus (HIV) infection† has not been evaluated to date.75, 76 Recommendations from the CDC, National Institutes of Health (NIH), and HIV Medicine Association of the IDSA regarding CMV prophylaxis and treatment in HIV-infected individuals include information on antivirals, but do not address use of CMV-IGIV.68
Cytomegalovirus immune globulin IV (CMV-IGIV) is administered by IV infusion.1 CMV-IGIV should not be administered IM or subcutaneously.1
CMV-IGIV should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.1 The solution should be colorless and should not be used if turbid.1 Vials of CMV-IGIV should not be shaken; formation of foam should be avoided.1 CMV-IGIV contains no preservatives and the manufacturer recommends that vials of the immune globulin be entered only once and that the infusion be initiated within 6 hours and completed within 12 hours after entering the vial.1 To prevent transmission of hepatitis B infection and/or other infectious agents from one individual to another, a different sterile syringe and needle must be used for each individual who is administered CMV-IGIV.1
IV infusions of CMV-IGIV should be administered through an IV line using an administration set that contains in inline filter (pore size 15 µm) and a controlled-infusion device (i.e., IVAC® pump or equivalent) to control the rate of flow.1 The manufacturer states that a smaller inline membrane filter (0.2 µm) also may be used during administration of CMV-IGIV.1 CMV-IGIV should not be diluted prior to IV infusion and preferably should be administered via a separate infusion line.1 CMV-IGIV may be piggy-backed into a preexisting line containing 0.9% sodium chloride injection or 2.5, 5, 10, or 20% dextrose injection (with or without sodium chloride) provided the dilution of immune globulin does not exceed 1:2 with such fluid.1 Information on the physical and/or chemical compatibility of CMV-IGIV with other IV infusion fluids or other drugs is not available, and the manufacturer recommends that CMV-IGIV not be admixed with other drugs.1
Vital signs should be assessed prior to initiating the CMV-IGIV infusion, midway through the infusion, and after completion of the infusion.1 Vital signs also should be assessed before any change is made in the rate of administration and closely monitored during and after the change. In addition, renal function, including measurement of BUN, serum creatinine, and urine output, should be assessed before and at appropriate intervals after administration of CMV-IGIV.1 If renal function decreases, consideration should be given to discontinuing CMV-IGIV.1
The initial dose of CMV-IGIV should be administered at an infusion rate of 15 mg/kg per hour for the first 30 minutes; if this rate is tolerated, the rate can be increased to 30 mg/kg per hour for the next 30 minutes and, if well tolerated, increased to 60 mg/kg per hour for the remainder of the infusion.1
After the initial infusion, subsequent doses of CMV-IGIV can be initiated at an infusion rate of 15 mg/kg per hour for the first 15 minutes; if this rate is tolerated, the rate can be increased to 30 mg/kg for the next 15 minutes and, if well tolerated, increased to 60 mg/kg per hour for the remainder of the infusion.1
The manufacturer states that the infusion rate for initial or subsequent doses of CMV-IGIV should not exceed 60 mg/kg per hour (75 mL/hour) and strict compliance with this maximum rate of infusion is recommended.1 In addition, if CMV-IGIV is used in patients considered at risk of acute renal failure, the drug should be infused at the minimum rate feasible.1 (See Renal Effects under Cautions: Adverse Effects.)
If relatively minor adverse effects (e.g., flushing, back pain, nausea) occur, the rate of infusion should be reduced or the infusion temporarily interrupted until manifestations subside.1 The infusion may then be resumed at the rate that was previously tolerated.76 If anaphylaxis or a drop in blood pressure occurs, the infusion should be discontinued immediately and appropriate therapy (e.g., epinephrine) instituted.1
Prevention of CMV Disease in Kidney Transplant Recipients
For the prevention or attenuation of cytomegalovirus (CMV) disease in kidney recipients, an initial 150-mg/kg dose of CMV-IGIV should be administered within 72 hours after transplantation.1 Additional 100-mg/kg doses of CMV-IGIV should be given once every 2 weeks at 2, 4, 6, and 8 weeks after transplantation, followed by 50-mg/kg doses given once at 12 and 16 weeks after transplantation.1 The manufacturer states that the maximum recommended total CMV-IGIV dosage per infusion is 150 mg/kg.1
Prevention of CMV Disease in Liver, Lung, Pancreas, or Heart Transplant Recipients
For the prevention or attenuation of CMV disease in liver, lung, pancreas, or heart transplant recipients, an initial 150-mg/kg dose of CMV-IGIV should be given within 72 hours after transplantation.1 Additional 150-mg/kg doses of CMV-IGIV should be given once every 2 weeks at 2, 4, 6, and 8 weeks after transplantation, and 100-mg/kg doses given once at 12 and 16 weeks after transplantation.1
Alternatively, liver transplant recipients have received a regimen that consists of an initial 150-mg/kg dose given within 72 hours of transplantation, followed by 100-mg/kg doses given once at 2, 4, 6, and 8 weeks after transplant and 50-mg/kg doses given once at 12 and 16 weeks after transplant.54 Heart transplant recipients have received CMV-IGIV regimens that consist of an initial 150-mg/kg dose given on the day of transplant, followed by 100-mg/kg doses given once on days 2, 7, 14, 22, 28 (or 35), 56, and 77.55, 59 Lung transplant recipients have received a regimen that consists of an initial 150-mg/kg dose given on the day of transplant, followed by 100-mg/kg doses given once on day 15 and 30, and prior to muromonab-CD3 (OKT3 monoclonal antibodies) in conjunction with ganciclovir.19
Adverse reactions to cytomegalovirus immune globulin IV (CMV-IGIV) have been reported in less than 6% of patients receiving the drug in clinical studies.1 Flushing,1, 5, 7, 8 chills,1, 7 muscle cramps,1, 5, 7 back pain,1, 5, 7, 8 fever,1 nausea,1, 5 vomiting,1 arthralgia,1, 8 and wheezing/shortness of breath/chest tightness1, 5, 7, 8 have been reported and often were related to the IV infusion rate.1, 7 The infusion rate should be decreased or the infusion temporarily interrupted if any of these minor adverse effect occur.1 Other adverse effects reported in patients receiving CMV-IGIV include anxiety,5 headache,5 increased or decreased blood pressure,1, 8 metallic taste,5 myalgia,8 palpitations,5 or tachycardia.8
A precipitous fall in blood pressure and clinical manifestations of anaphylaxis have occurred rarely in patients receiving another immune globulin preparation (immune globulin IV; Gamimune® N, 5%), including patients without a history of sensitivity to immune globulin.30 The manufacturer of CMV-IGIV states that, although hypotension did not occur in over 200 infusions of CMV-IGIV and serious reactions such as angioedema or anaphylaxis have not been reported to date in clinical studies, the possibility exists that these reactions could occur in patients receiving CMV-IGIV.1
If anaphylaxis or a change in blood pressure occurs in a patient receiving CMV-IGIV, the infusion should be immediately discontinued and appropriate therapy (e.g., epinephrine) instituted.1
Renal dysfunction, including acute renal failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis, and death have been reported in patients receiving IGIV.1 Increases in serum creatinine and BUN have occurred as soon as 1-2 days following infusion of IGIV with progression to oliguria or anuria (requiring dialysis).1 Patients predisposed to acute renal failure include those who have preexisting renal insufficiency, diabetes mellitus, volume depletion, sepsis, or paraproteinemia and those who are receiving nephrotoxic drugs and/or are 65 years of age or older.1
Available data suggest that IGIV preparations stabilized with sucrose and given in daily dosages of 350 mg/kg or greater are associated with a greater risk of developing IGIV-associated renal dysfunction.1, 77 Because commercially available CMV-IGIV contains 5% sucrose, patients (especially those at increased risk of acute renal failure) should be adequately hydrated prior to CMV-IGIV administration and the drug should be infused at the minimum rate whenever feasible.1 Renal function, including measurement of BUN, serum creatinine and urine output, should be assessed before and at appropriate intervals after administration of CMV-IGIV.1 If renal function decreases, consideration should be given to discontinuation of CMV-IGIV.1 For additional information on IGIV-associated renal dysfunction, see Renal Effects under Cautions: Immune Globulin IV, in Immune Globulin 80:04.
Aseptic meningitis syndrome has been reported rarely in patients receiving IGIV, principally in those receiving high doses of the immune globulin (e.g., 2 g/kg).26, 29 The syndrome usually is evident within several hours to 2 days after administration of IGIV and is characterized by severe headache, nuchal rigidity, drowsiness, lethargy, fever, photophobia, painful eye movements, and nausea and vomiting.1, 26, 27, 28, 29 CSF analysis frequently reveals pleocytosis (up to several thousand cells per mm3), predominantly from the granulocytic series, and protein concentrations up to several hundred mg/dL.1, 26, 27, 28, 29 When IGIV is discontinued, aseptic meningitis syndrome generally resolves within several (3-5) days without sequelae.1, 26, 27, 28, 29 There is some evidence that patients with a history of migraine may be more susceptible to aseptic meningitis syndrome than other patients and may have severe symptoms requiring additional hospitalization and treatment with opiate analgesics.26
The cause of aseptic meningitis syndrome in patients receiving IGIV is not known.26 It has been suggested that the syndrome may result from a hypersensitivity reaction associated with distribution of components of the preparation into the CSF; alternatively, IgG antibodies present in IGIV, which are allogeneic, may accumulate in the CNS and initiate reactions resulting in aseptic meningitis.26 The syndrome has been reported with various commercially available preparations of IGIV and does not appear to be related to a specific formulation.26, 27
Any patient experiencing signs and symptoms of aseptic meningitis syndrome while receiving an immune globulin preparation should receive a thorough neurologic examination, including CSF analysis, to rule out other causes of meningitis.1
IGIV preparations can contain blood group antibodies that may act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis.1 Hemolytic anemia can develop following IGIV therapy because of enhanced RBC sequestration.1
Transfusion-related Acute Lung Injury
Transfusion-related acute lung injury (TRALI; noncardiogenic pulmonary edema) has been reported in patients receiving IGIV preparations.1 TRALI typically occurs within 1-6 hours after IGIV infusion and is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever.1 Patients should be managed using oxygen therapy with adequate ventilatory support.1
Thrombotic events have been reported in patients receiving IGIV.1 Patients at risk for thrombotic events may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity.1
Precautions and Contraindications
CMV-IGIV is contraindicated in individuals who have had a severe reaction to CMV-IGIV or any other human immune globulin preparation.1 Although systemic allergic reactions to immune globulin preparations are rare, epinephrine and diphenhydramine should be available to treat acute allergic manifestations or anaphylactoid reactions if they occur.1
CMV-IGIV is contraindicated in individuals with selective IgA deficiency since these individuals may have antibodies to IgA (or develop such antibodies following administration of CMV-IGIV) and anaphylaxis could result following administration of CMV-IGIV or other blood products containing IgA.1 CMV-IGIV contains trace amounts of IgA.1
The patient should be carefully observed and vital signs monitored during IV infusion of CMV-IGIV.1 While CMV-IGIV generally is well tolerated, some reported adverse effects are related to the IV infusion rate, and the recommended rate of infusion should not be exceeded.1 (See Dosage and Administration: Administration.)
Because commercially available CMV-IGIV contains 5% sucrose, patients (especially those at increased risk of acute renal failure) should be adequately hydrated prior to CMV-IGIV administration, and the drug should be infused at the minimum rate whenever feasible.1 Renal function, including measurement of BUN, serum creatinine, and urine output, should be assessed before and at appropriate intervals after administration of CMV-IGIV.1 If renal function decreases, consideration should be given to discontinuation of CMV-IGIV.1 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 clinician.1
Patients receiving IGIV preparations should be monitored for clinical signs and symptoms of hemolysis during and after therapy and appropriate confirmatory laboratory testing should be performed if necessary.1
Patients receiving IGIV preparations also should be monitored for adverse pulmonary reactions.1 If transfusion-related acute lung injury is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum.1
Because thrombotic events have been reported in association with IGIV, the potential risks and benefits of CMV-IGIV should be weighed against those of alternative therapies for all patients for whom IGIV is being considered.1 In addition, 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.1
Patients should be instructed to report any infections that occur during CMV-IGIV therapy directly to their clinician and to the manufacturer at 866-915-6958.1
Risk of Transmissible Infectious Agents in Plasma-derived Preparations
Because CMV-IGIV is prepared from pooled human plasma and contains albumin human, it is a potential vehicle for transmission of human viruses, including the causative agents of viral hepatitis and human immunodeficiency virus (HIV) infection, and theoretically may carry a risk of transmitting the causative agent of Creutzfeldt-Jakob disease (CJD) or variant CJD (vCJD).1, 31 The risk for transmission of recognized blood-borne viruses is considered to be remote because of the viral inactivation and removal properties inherent in the Cohn cold ethanol precipitation method used for purification of immune globulin preparations.1, 32 In addition, CMV-IGIV undergoes a chemical (solvent/detergent) treatment procedure to reduce viral infectious potential.1 Solvent/detergent inactivation processes apparently can inactivate lipid-enveloped viruses (e.g., hepatitis B, hepatitis C, HIV type 1 and type 2 [HIV-1 and HIV-2]) but are less effective against viruses that do not have a lipid envelope (e.g., hepatitis A, parvovirus B-19).1, 3, 32, 33, 34, 35 Because no purification method has been shown to be totally effective in removing the risk of viral infectivity from plasma-derived preparations and because new blood-borne viruses or other disease agents may emerge which may not be inactivated by the manufacturing process or the chemical (solvent/detergent) treatment procedures currently used, CMV-IGIV should be administered only when a benefit is expected.1 Any infection believed to have been transmitted by CMV-IGIV should be reported to the manufacturer.1
Improper storage or handling of immune globulins may affect efficacy.36
CMV-IGIV that has been mishandled or has not been stored at the recommended temperature should not be administered.36 CMV-IGIV should be stored at 2-8°C and administered shortly after the vial is entered.1 (See Dosage and Administration: Administration.)
All immune globulins should be inspected upon delivery and monitored during storage to ensure that the appropriate temperature is maintained.36 If there are concerns about mishandling, the manufacturer or state or local health departments should be contacted for guidance on whether CMV-IGIV is usable.36
In clinical trials, various CMV-IGIV preparations have been used in pediatric renal transplant recipients5, 7, 8 as young as 1 year of age,75 in liver transplant patients† as young as 4 years of age,54 and in allogeneic bone marrow transplant (BMT) patients† as young as 1-8 years of age17, 22, 23, 44 without unusual adverse effects.16, 44, 75
CMV-IGIV has been used in a limited number of neonates.39 In a controlled study in premature neonates at risk for CMV infection because they required multiple blood transfusions†, CMV-IGIV doses of 150 mg/kg were well tolerated; 2.9% of CMV-IGIV infusions and 4.2% of placebo infusions (1% albumin human) were associated with adverse reactions (i.e., fever, rash, change in blood pressure, increased oxygen requirement, irregular heart beat) which may or may not have been related to the infusions.39
CMV-IGIV should be used with caution in patients older than 65 years of age.1 (See Renal Effects under Cautions: Adverse Effects.)
Pregnancy, Fertility, and Lactation
Animal reproductive studies have not been performed with CMV-IGIV and it is not known whether CMV-IGIV can cause fetal harm when administered to pregnant women.1 CMV-IGIV should be used during pregnancy only when clearly needed.1
The US Public Health Service Advisory Committee on Immunization Practices (ACIP) states there are no known risks for the fetus from use of immune globulin preparations for passive immunization in pregnant women.36 CMV-IGIV has been used in a limited number of pregnant women with primary CMV infection in an attempt to treat and prevent congenital CMV infection.79 (See Uses: Congenital or Neonatal CMV Infection.)
It is not known whether CMV-IGIV can affect fertility.1
Information on the distribution of CMV-IGIV into milk is not available; it is not known if transmission of CMV-IGIV to a nursing infant presents any unusual risk.75, 76
Antibodies present in immune globulin preparations may interfere with immune responses to some live virus vaccines, including measles, mumps, and rubella virus vaccine live (MMR), varicella virus vaccine live, and fixed combination of MMR and varicella virus vaccine live (MMRV).1, 36 (See Measles, Mumps, Rubella, and Varicella Vaccines under Vaccines: Live Vaccines, in Drug Interactions.)
There is no evidence that immune globulin preparations interfere with immune responses to influenza virus vaccine live intranasal, rotavirus vaccine live oral, typhoid vaccine live oral, yellow fever virus vaccine live, or zoster vaccine live.36 When indicated, these live vaccines may be given simultaneously with (at a different anatomic site) or at any interval before or after cytomegalovirus immune globulin IV (CMV-IGIV).36
Measles, Mumps, Rubella, and Varicella Vaccines
Although specific information on CMV-IGIV is not available,75 immune globulin preparations may interfere with immune responses to MMR and varicella virus vaccine live.36 The duration of possible interference between immune globulin preparations and live virus vaccines appears to depend on antibody concentrations in the immune globulin; there is evidence that high doses of certain immune globulin preparations can inhibit the immune response to measles virus vaccine live and rubella virus vaccine live for more than 3 months.36 Although specific information regarding the effect of immune globulin preparations on immune responses to mumps virus vaccine live and varicella virus vaccine live are not available, there is potential for similar interference since immune globulin preparations contain antibodies to these viruses.36
The US Public Health Service Advisory Committee on Immunization Practices (ACIP) recommends that administration of MMR and varicella vaccines be deferred for 6 months following administration of CMV-IGIV.36 If a dose of MMR or varicella vaccine is administered simultaneously with or within 6 months after CMV-IGIV, the ACIP recommends revaccination at least 6 months after the CMV-IGIV dose, unless serologic testing is feasible and indicates an adequate immune response to the vaccine.36 In addition, the fact that revaccination may be necessary in individuals who receive CMV-IGIV shortly after MMR or varicella vaccine should be considered.36 In general, vaccine virus replication and stimulation of immunity occur within 7-14 days after administration of a live virus vaccine.36 Therefore, if CMV-IGIV must be administered less than 14 days after receipt of MMR or varicella vaccine, revaccination is necessary at least 6 months after CMV-IGIV, unless there is serologic evidence of an adequate immune response to the vaccine.36, 76
Inactivated Vaccines and Toxoids
Immune globulins preparations are not expected to have a clinically important effect on immune responses to inactivated vaccines or toxoids; therefore, inactivated vaccines, recombinant vaccines, polysaccharide vaccines, and toxoids may be administered simultaneously with (using different syringes and different injection sites) or at any interval before or after administration of CMV-IGIV.36
Little information is available on acute toxicity of cytomegalovirus immune globulin IV (CMV-IGIV); however, clinical experience with other immune globulin preparations suggests that the major manifestations of acute toxicity would be those associated with fluid overload.1
Cytomegalovirus immune globulin IV (CMV-IGIV) is used to provide passive immunity to cytomegalovirus (CMV).1, 4, 5, 6, 7, 8, 9, 10, 65, 66 When used for CMV prophylaxis in individuals at risk for CMV infection or disease, CMV-IGIV prevents or attenuates CMV disease, but generally does not prevent infection.9, 52, 57, 62, 63, 65, 66, 75, 76
CMV-IGIV contains CMV-specific antibodies and results of in vitro studies and studies in mice indicate that these antibodies can neutralize the virus.55, 65, 66 Therefore, it has been suggested that administration of CMV-IGIV to individuals at risk for primary CMV infection or disease may increase CMV neutralizing antibodies to levels sufficient to inhibit the pathogenic properties of the virus.1, 4, 5, 6, 7, 8, 9, 10, 55, 66, 75 However, CMV is largely a cell-associated virus and antibody-neutralization of the virus alone may not be sufficient to prevent or ameliorate active disease in individuals already infected.42, 55, 63, 65, 75 There is evidence that cell-mediated immunity is important in determining the severity and outcome of CMV disease in immunocompromised individuals and it has been suggested that, in addition to antibody-neutralization, CMV-IGIV may exert some immunomodulating effects (e.g., potentiation of antibody-dependent cell-mediated cytotoxic reactions) that contribute to the prevention or amelioration of CMV disease in these patients.42, 55, 63, 65, 66
CMV is an enveloped DNA virus classified as a member of the Herpesviridae family.9, 42 Like other herpesviruses (e.g., herpes simplex virus, Epstein-Barr virus, varicella-zoster virus), CMV can establish sites of latent infection following primary infection.9, 42 CMV is thought to establish latent infections at multiple sites, including leukocytes and various tissues (e.g., kidney, lung, liver).9, 43 Latency usually persists for life; however, the virus can be reactivated during periods of immunosuppression in the host resulting in CMV disease that can be severe and life-threatening.9, 10, 43 Individuals with altered immunocompetence, including those with malignancies or human immunodeficiency virus (HIV) infection and transplant recipients or others receiving certain immunosuppressive therapies, are at substantial risk for reactivation of latent CMV.9, 10, 43
While primary CMV infection is relatively common, active CMV disease occurring as the result of primary infection or reactivation of latent infection (secondary CMV disease) occurs only rarely in otherwise healthy individuals.9, 10, 43 Studies of the seroprevalence of antibody to CMV indicate that 40-100% of adults in the US have serologic evidence of infection.9, 10, 18, 43, 67 CMV infection usually is defined as direct or indirect evidence of the virus (e.g., seroconversion, a fourfold or greater increase in CMV antibody titer, isolation of the virus from any body site, direct detection of CMV antigen) in an asymptomatic or symptomatic patient.9, 57, 61, 67, 76 Individuals infected with CMV may develop CMV disease which manifests as generalized symptoms (e.g., fever, malaise, leukopenia), various serious site-specific CMV-associated syndromes (e.g., interstitial pneumonitis, hepatitis, gastroenteritis or other GI symptoms, retinitis, meningoencephalitis or other CNS involvement), or as an immunosuppressed state that predisposes the patient to potentially fatal opportunistic infections.9, 10, 43, 57, 60
CMV can be acquired perinatally from a CMV-seropositive mother, through sexual contact with a CMV-positive individual, or by direct inoculation via blood transfusion, organ transplant, or bone marrow transplant (BMT) from a CMV-seropositive donor.1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 42, 43, 60, 61 CMV is a major viral pathogen involved in posttransplant infections in solid organ or allogeneic BMT transplant recipients, and CMV disease results in considerable morbidity and mortality in these individuals.4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 43, 52, 57, 60, 61, 65 Transplant recipients who develop serious CMV disease (usually apparent between 2-16 weeks after transplantation)43, 60, 61, 66 are at risk for transplant rejection and/or death.4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 43, 60
The degree of risk for CMV infection and disease in transplant recipients depends on the particular transplant procedure (e.g., kidney, liver, lung, heart, bone marrow), CMV status of the donor and recipient, and immunosuppressive regimens administered for prophylaxis or treatment of graft rejection.9, 43, 50, 60 Individuals who are CMV-seronegative prior to transplant are at risk of primary CMV infection and serious disease if they receive organs or bone marrow from a CMV-seropositive donor.1, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 47, 58, 61 Individuals who are CMV-seropositive prior to transplant are at risk of reactivation of latent CMV infection during the posttransplant period (when they are immunocompromised) regardless of whether the donor is CMV-seropositive or -seronegative.9, 43, 47 If the donor is CMV-seropositive, recipients also are at risk for reactivation of CMV of donor origin (superinfection).43, 52
Without CMV prophylaxis, approximately 70-90% of CMV-seronegative renal transplant recipients who receive transplants from CMV-seropositive donors would be expected to develop primary CMV infection.1, 43 The overall incidence of CMV infection and disease in lung transplant recipients is higher than that in kidney, liver, or heart transplant recipients,58, 61 possibly because the lungs contain a higher viral load of CMV than other organs.58 In solid organ transplant patients, the incidence of serious posttransplant CMV disease is greater in CMV-seronegative recipients of CMV-seropositive organs than in those who are CMV-seropositive prior to transplant.43, 58, 70 Conversely, in allogeneic BMT patients, the incidence of serious posttransplant CMV disease is greater in those who are CMV-seropositive prior to transplant than in those who are CMV-seronegative.62
The actual serum titer of CMV antibody associated with immunity against primary CMV infection in CMV-seronegative individuals or suppression or amelioration of reactivated infections in CMV-seropositive individuals has not been identified.4, 43 In a study in CMV-seronegative renal transplant patients, administration of CMV-IGIV (a preparation containing a CMV antibody titer of 1:8192 by IHA and 1:4000 by ELISA) in a regimen that consisted of 50-mg/kg doses given once daily for the first 3 days posttransplant and then every 21 days for 4 months, median peak CMV antibody titers were 1:175 by ELISA (range: 55-472).4 The serum half-life of CMV antibody varied from 5-13 days during the first 2 months posttransplant and from 13-45 days during the third to fifth month posttransplant.4 Detectable titers of CMV antibody were present for up to 2 months following the last dose.4
Cytomegalovirus immune globulin IV (CMV-IGIV) is a sterile, nonpyrogenic solution prepared from plasma of healthy adults selected for high titers of antibodies to cytomegalovirus (CMV).1, 5, 6 CMV-IGIV commercially available in the US is standardized to contain a CMV antibody titer1 of greater than 1:7000 by enzyme-linked immunosorbent assay (ELISA).75 This CMV antibody titer is at least 4-8 times higher than that contained in immune globulin IV (IGIV) or immune globulin IM (IGIM).6, 10, 11, 13 Each mL of CMV-IGIV contains 40-60 mg of immunoglobulin composed principally of immunoglobulin G (IgG) with trace amounts of IgA and IgM.1
Commercially available CMV-IGIV meets standards established by the Center for Biologics Evaluation and Research of the US Food and Drug Administration (FDA).75 Plasma used in the preparation of CMV-IGIV has been tested and shown to be negative for hepatitis B surface antigen (HBsAg), antibody to hepatitis C virus, antibody to human immunodeficiency virus type 1 and type 2 (HIV-1 and HIV-2), and HIV p24 antigen by FDA-approved assays, and all plasma donors must have a negative VDRL test and serum ALT (SGPT) concentrations no higher than twice normal.75 In addition, the manufacture of CMV-IGIV includes purification steps (Cohn cold ethanol precipitation) and a chemical (solvent/detergent) inactivation process that reduce the risk of transmission of blood-borne viruses.1, 11, 32, 33, 34, 35 No method, however, has been shown to be totally effective in removing the risk of viral infectivity from preparations derived from pooled human plasma.1 (See Risk of Transmissible Agents in Plasma-derived Preparations under Cautions: Precautions and Contraindications.)
CMV-IGIV occurs as a translucent, colorless solution.1 CMV-IGIV contains 5% sucrose and 1% albumin as stabilizing agents; the solution does not contain thimerosal or any other preservative.1 CMV-IGIV contains 1-1.5 mEq of sodium per 50 mL.1
CMV-IGIV should be refrigerated at 2-8°C.1
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV infusion | 50 ±10 mg (of immunoglobulin) per mL |
1. CSL Behring. CytoGam® (cytomegalovirus immune globulin intravenous [human][CMV-IGIV]) liquid formulation solvent detergent treated prescribing information. Kankakee, IL; 2010 Nov.
3. Horowitz B, Wiebe ME, Lippin A et al. Inactivation of viruses in labile blood derivatives: I. Disruption of lipid-enveloped viruses by tri(n-butyl)phosphate detergent combinations. Transfusion . 1985; 25:516-22. [PubMed 3934801]
4. Snydman DR, McIver J, Leszczynski J et al. A pilot trial of a novel cytomegalovirus immune globulin in renal transplant recipients. Transplantation . 1984; 38:553-7. [PubMed 6093299]
5. Snydman DR, Werner BG, Heinze-Lacey B et al. Use of cytomegalovirus immune globulin to prevent cytomegalovirus disease in renal-transplant recipients. N Engl J Med . 1987; 317:1049-54. [PubMed 2821397]
6. Snydman DR. Prevention of cytomegalovirus-associated diseases with immunoglobulin. Transplant Proc . 1991; 23(Suppl 3):131-5. [PubMed 1648817]
7. Snydman DR, Werner BG, Tilney NL et al. Final analysis of primary cytomegalovirus disease prevention in renal transplant recipients with a cytomegalovirus-immune globulin: comparison of the randomized and open-label trials. Transplant Proc . 1991; 23:1357-60. [PubMed 1846464]
8. Werner BG, Snydman DR, Freeman R et al et al. Cytomegalovirus immune globulin for the prevention of primary CMV disease in renal transplant patients: analysis of usage under treatment IND status. Transplant Proc . 1993; 25:1441-3. [PubMed 8382875]
9. Ho M. Cytomegalovirus. In: Mandell GL, Bennett JE, Dolin R eds. Mandell, Douglas and Bennett's principles and practice of infectious diseases. 4th ed. New York: Churchill Livingstone; 1995:1351-64.
10. Dickinson BI, Gora-Harper ML, McCraney SA et al. Studies evaluating high-dose acyclovir, intravenous immune globulin, and cytomegalovirus hyperimmunoglobulin for prophylaxis against cytomegalovirus in kidney transplant recipients. Ann Pharmacother . 1996; 30:1452-64. [PubMed 8968459]
11. Snydman DR. Cytomegalovirus immunoglobulins in the prevention and treatment of cytomegalovirus disease. Clin Infect Dis . 1990; 12(Suppl 7):S839-48.
12. Snydman DR. Cytomegalovirus prophylaxis strategies in high-risk transplantation. Transplant Proc . 1994; 26(Suppl 1):20-2. [PubMed 7940971]
13. Patel R, Snydman DR, Rubin RH et al. Cytomegalovirus prophylaxis in solid organ transplant recipients. Transplantation . 1996; 61:1279-89. [PubMed 8629285]
14. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website. Accessed 2012 Mar 12. [Web]
15. Bulinski P, Toledo-Pereyra LH, Dalal S et al. Cytomegalovirus infection in kidney transplantation: prophylaxis and management. Transplant Proc . 1996; 28:3310-1. [PubMed 8962286]
16. Snydman DR, Werner BG, Dougherty NN et al et al. Cytomegalovirus immune globulin prophylaxis in liver transplantation: a randomized, double-blind, placebo-controlled trial. Ann Intern Med . 1993; 119:984-91. [PubMed 8214995]
17. Bowden RA, Sayers M, Flournoy N et al. Cytomegalovirus immune globulin and seronegative blood products to prevent primary cytomegalovirus infection after marrow transplantation. N Engl J Med . 1986; 314:1006-10. [PubMed 3007984]
18. Tsinontides AC, Bechtel TP. Cytomegalovirus prophylaxis and treatment following bone marrow transplantation. Ann Pharmacother . 1996; 30:1277-90. [PubMed 8913411]
19. Zamora MR, Fullerton DA, Campbell DN et al. Use of cytomegalovirus (CMV) hyperimmune globulin for prevention of CMV disease in CMV-seropositive lung transplant recipients. Transplant Proc . 1994; 26(Suppl 1):49-51. [PubMed 7940974]
20. Snydman DR, Werner BG, Dougherty NN et al et al. A further analysis of the use of cytomegalovirus immune globulin in orthotopic liver transplant patients at risk for primary infection. Transplant Proc . 1994; 26(Suppl 1):23-7.
21. Rowe JM, Ciobanu N, Ascensao J et al et al. Recommended guidelines for the management of autologous and allogeneic bone marrow transplantation: a report from the Eastern Cooperative Oncology Group (ECOG). Ann Intern Med . 1994; 120:143-58. [PubMed 8256974]
22. Ljungman P, Engelhard D, Link H et al. Treatment of interstitial pneumonitis due to cytomegalovirus with ganciclovir and intravenous immune globulin: experience of European Bone Marrow Transplant Group. Clin Infect Dis . 1992; 14:831-5. [PubMed 1315585]
23. Reed EC, Bowden RA, Dandliker PS et al. Treatment of cytomegalovirus pneumonia with ganciclovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplants. Ann Intern Med . 1988; 109:783-8. [PubMed 2847610]
24. Reed EC, Bowden RA, Dandliker PS et al. Treatment of cytomegalovirus (CMV) pneumonia in bone marrow transplant (BMT) patients (pts) with ganciclovir (GCV) and CMV immunoglobulin (CMV-IG). Blood . 1987; 70(Suppl 1):313.
25. D'Alessandro AM, Pirsch JD, Stratta RJ et al. Successful treatment of severe cytomegalovirus infections with ganciclovir and CMV hyperimmune globulin in liver transplant recipients. Transplant Proc . 1989; 21:3560-1. [PubMed 2545018]
26. Sekul EA, Cupler EJ, Dalakas MC. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern Med . 1994; 121:259-62. [PubMed 8037406]
27. Scribner CL, Kapit RM, Phillips ET et al. Aseptic meningitis and intravenous immunoglobulin therapy. Ann Intern Med . 1994; 121:305-6. [PubMed 8037414]
28. Kato E, Shindo S, Eto Y et al. Administration of immune globulin associated with aseptic meningitis. JAMA . 1988; 259:3269-71. [PubMed 2453686]
29. Casteels-Van Daele M, Wijndaele L, Hunninck K et al. Intravenous immune globulin and acute aseptic meningitis. N Engl J Med . 1990; 323:614-5.
30. Talecris. Gamimune® N, 10% (immune globulin intravenous [human]) 10% solvent/detergent treated prescribing information. Research Triangle Park,NC; 2005 Jan.
31. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research (CBER). Guidance for industry. Revised preventive measures to reduce the possible risk of transmission of Creutzfeldt-Jakob disease (CJD) and variant Creutzfeldt-Jakob disease (vCJD) by blood and blood products. January 2002. From FDA website. [Web]
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33. Centers for Disease Control and Prevention. Outbreak of hepatitis C associated with intravenous immunoglobulin administration—United States, October 1993-June 1994. MMWR Morb Mortal Wkly Rep . 1994; 43:505-9. [PubMed 8022396]
34. Horowitz B, Wiebe ME, Lippin A et al. Inactivation of viruses in labile blood derivatives. I. Disruption of lipid-enveloped viruses by tri(n-butyl)phosphate detergent combinations. Transfusion . 1985; 25:516-22. [PubMed 3934801]
35. Edwards CA, Piet MPJ, Chin S et al. Tri(n-butyl) phosphate/detergent treatment of licensed therapeutic and experimental blood derivatives. Vox Sang . 1987; 52:53-9. [PubMed 3111089]
36. National Center for Immunization and Respiratory Diseases. General recommendations on immunization -- recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep . 2011; 60:1-64.
37. Metselaar HJ, Velzing J, Rothbarth PH et al. A pharmacokinetic study of anti-cytomegalovirus hyperimmunoglobulins in cytomegalovirus seronegative cardiac transplant recipients. Transplant Proc . 1987; 19:4063-5. [PubMed 2823431]
38. American Academy of Pediatrics. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009.
39. Snydman DR, Werner BG, Meissner HC et al. Use of cytomegalovirus immunoglobulin in multiply transfused premature neonates. Pediatr Infect Dis J . 1995; 14:34-40. [PubMed 7715987]
40. Aguado JM, Gomez-Sanchez MA, Lumbreras C et al. Prospective randomized trial of efficacy of ganciclovir versus that of anti-cytomegalovirus (CMV) immunoglobulin to prevent CMV-seropositive heart transplant recipients treated with OKT3. Antimicrob Agents Chemother . 1995;39:1643-5. [PubMedCentral][PubMed 7492123]
41. Ruutu T, Ljungman P, Brinch L et al and the Nordic BMT Group. No prevention of cytomegalovirus infection by anti-cytomegalovirus hyperimmune globulin in seronegative bone marrow transplant recipients. Bone Marrow Transplant . 1997; 19:233-6. [PubMed 9028551]
42. Grundy JE. Virologic and pathogenetic aspects of cytomegalovirus infection. Clin Infect Dis . 1990; 12(Suppl 7):S711-9.
43. Rubin RH. Impact of cytomegalovirus infection on organ transplant recipients. Clin Infect Dis . 1990; 12(Suppl 7):754-66.
44. Reed EC, Bowden RA, Dandliker PS et al. Efficacy of cytomegalovirus immunoglobulin in marrow transplant recipients with cytomegalovirus pneumonia. J Infect Dis . 1987; 156:641-5. [PubMed 3040870]
45. Bowden RA, Fisher LD, Rogers K et al. Cytomegalovirus (CMV)-specific intravenous immunoglobulin for the prevention of primary CMV infection and disease after marrow transplant. J Infect Dis . 1991; 164:483-7. [PubMed 1651360]
46. Filipovich AH, Peltier MH, Bechtel MK et al. Circulating cytomegalovirus (V) neutralizing activity in bone marrow transplant recipients: comparison of passive immunity in a randomized study of four intravenous IgG products administered to CMV-seronegative patients. Blood . 1992; 80:2656-60. [PubMed 1330079]
47. Zaia JA. Prevention and treatment of cytomegalovirus pneumonia in transplant recipients. Clin Infect Dis . 1993; 17(Suppl 2):S392-9. [PubMed 8274605]
48. Emanuel D, Cunningham I, Jules-Elysee K et al. Cytomegalovirus pneumonia after bone marrow transplantation successfully treated with the combination of ganciclovir and high-dose intravenous immune globulin. Ann Intern Med . 1988; 109:777-82. [PubMed 2847609]
49. Condie RM, O'Reilly RJ. Prevention of cytomegalovirus infection by prophylaxis with an intravenous, hyperimmune, native, unmodified cytomegalovirus globulin. Am J Med . 1984; 76(Suppl 3A):134-41. [PubMed 6324587]
50. Glowacki LS, Small FM. Use of immune globulin to prevent symptomatic cytomegalovirus disease in transplant recipients—a meta-analysis. Clin Transplant . 1994; 8:10-8. [PubMed 8136560]
51. Snydman DR. Use of immune globulin to prevent symptomatic cytomegalovirus disease in transplant recipients—a meta-analysis. Clin Transplant . 1995; 9:490-1. [PubMed 8645893]
52. Dunn DL, Gillingham KJ, Kramer MA et al. A prospective randomized study of acyclovir versus ganciclovir plus human immune globulin prophylaxis of cytomegalovirus infection after solid organ transplantation. Transplantation . 1994; 57:876-84. [PubMed 8154035]
53. Kathawalla SA, Stillwell PC, Gordon S et al. Cytomegalovirus infection in seromismatched lung transplant recipients with and without prophylaxis with CMV immunoglobulin. Transplant Proc . 1996; 28(Suppl 2):16. [PubMed 9037272]
54. Ham J, Shelen SL, Godkin RR et al. Cytomegalovirus prophylaxis with ganciclovir, acyclovir, and CMV hyperimmune globulin in liver transplant patients receiving OKT3 induction. Transplant Proc . 1995; 27(Suppl 1):31-3. [PubMed 7482814]
55. Valantine HA. Prevention and treatment of cytomegalovirus disease in thoracic organ transplant patients: evidence for a beneficial effect of hyperimmune globulin. Transplant Proc . 1995; 27(Suppl 1):49-57. [PubMed 7482821]
56. Reusser P. The challenge of cytomegalovirus infection after bone arrow transplantation: epidemiology, prophylaxis, and therapy. Bone Marrow Transplant . 1996; 18:107-9. [PubMed 8932809]
57. Badas A, Stoukides CA. Guidelines for prophylaxis of cytomegalovirus disease in bone marrow transplant patients. Ann Pharmacother . 1996; 30:1483-6. [PubMed 8968462]
58. Paya CV. Defining an optimal regimen for cytomegalovirus prophylaxis in organ transplant recipients. Transplant Proc . 1996; 28(Suppl 2):9-11. [PubMed 9037269]
59. Wittes JT, Kelly A, Plante KM. Meta-analysis of CMVIG studies for the prevention an treatment of CMV infection in transplant patients. Transplant Proc . 1996; 28(Suppl 2):17-24. [PubMed 9037273]
60. Trulock EP. Lung transplantation. Am J Respir Crit Care Med . 1997; 155:789-818. [PubMed 9117010]
61. Wood DE, Raghu G. Lung transplantation. Part II. Postoperative management and results. West J Med . 1997; 166:45-55. [PubMedCentral][PubMed 9074338]
62. Guglielmo BJ, Wong-Beringer A, Linker CA. Immune globulin therapy in allogeneic bone marrow transplant: a critical review. Bone Marrow Transplant . 1994; 13:499-510. [PubMed 8054903]
63. Bass EB, Powe NR, Goodman SN et al. Efficacy of immune globulin in preventing complications of bone marrow transplantation: a meta-analysis. Bone Marrow Transplant . 1993; 12:273-82. [PubMed 8241987]
64. So S, Mayo C, McCullough C et al. Cytomegalovirus prophylaxis in pediatric renal transplant recipients. Transplant Proceed . 993; 25:1414-5.
65. Meyers JD. Prevention of cytomegalovirus infection after marrow transplantation. Rev Infect Dis . 1989; 11(Suppl 7):S1691-705. [PubMed 2557664]
66. Winston DJ, Ho WG, Champlin RE. Cytomegalovirus infections after allogeneic bone marrow transplantation. Clin Infect Dis . 1990; 12(Suppl 7):S776-87.
67. Hirsch MS. Cytomegalovirus and human herpesvirus types 6, 7, and 8. In: Fauci AS, Braunwald E, Isselbacher KJ et al, eds. Harrison's principles of internal medicine. 14th ed. New York: McGraw-Hill Company; 1998:1092-5.
68. Kaplan JE, Benson C, Holmes KH et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep . 2009; 58(RR-4):1-207; quiz CE1-4. [Fulltext MMWR][PubMedCentral]
69. Griffiths PD. Prophylaxis against CMV infection in transplant patients. J Antimicrob Chemother . 1997; 39:299-301. [PubMed 9096177]
70. Conti DJ, Shen G, Singh T et al. Ganciclovir prophylaxis of cytomegalovirus disease. Transplant Proc . 1997; 29:804-6. [PubMed 9123534]
71. Prentice HG, Kho P. Clinical strategies for the management of cytomegalovirus infection and disease in allogeneic bone marrow transplant. Bone Marrow Transplant . 1997; 19:135-42. [PubMed 9116610]
72. Winston DJ. Prevention of cytomegalovirus disease in transplant recipients. Lancet . 1995; 346:1380-1. [PubMed 7475816]
73. Winston DJ, Wirin D, Shaked A et al. Randomised comparison of ganciclovir and high-dose acyclovir for long-term cytomegalovirus prophylaxis in liver-transplant recipients. Lancet . 1995; 346:69-74. [PubMed 7603215]
74. Verdonck LF, Dekker AW, Rozenberg-Arska M et al. A risk-adapted approach with a short course of ganciclovir to prevent cytomegalovirus (CMV) pneumonia in CMV-seropositive recipients of allogeneic bone marrow transplants. Clin Infect Dis . 1997; 24:901-7. [PubMed 9142790]
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