INDICATIONS AND USAGE
Cytomegalovirus Immune Globulin Intravenous (Human) is indicated for the prophylaxis of cytomegalovirus disease associated with transplantation of kidney, lung, liver, pancreas and heart. In transplants of these organs other than kidney from CMV seropositive donors into seronegative recipients, prophylactic CMV-IGIV should be considered in combination with ganciclovir.
CLINICAL STUDIES
Clinical studies have shown a 50% reduction in primary CMV disease in renal transplant patients given CMV-IGIV (3) and a 56% reduction in serious CMV disease (4) in liver transplant patients given CMV-IGIV. CMV-IGIV prophylaxis was associated with increased survival in liver transplant recipients (5).
In two separate clinical trials, CytoGam® was shown to provide effective prophylaxis in renal transplant recipients at risk for primary CMV disease. In the first randomized trial, (3) the incidence of virologically confirmed CMV-associated syndromes was reduced from 60% in controls (n=35) to 21% in recipients of CMV immune globulin (n=24) (P < 0.01); marked leukopenia was reduced from 37% in controls to 4% in globulin recipients (P < 0.01); and fungal or parasitic superinfections were not seen in globulin recipients but occurred in 20% of controls (P = 0.05). Serious CMV disease was reduced from 46% to 13%. There was a concomitant but not statistically significant reduction in the incidence of CMV pneumonia (17% of controls as compared with 4% of globulin recipients). There was no effect on rates of viral isolation or seroconversion although the rate of viremia was less in CytoGam® recipients. In a subsequent non-randomized trial in renal transplant recipients (n=36), (6) the incidence of
virologically confirmed CMV-associated syndrome was reduced to 36% in the globulin recipients in comparison to a 60% incidence in control patients (n=35) in the randomized trial. The rates of serious CMV disease, and concomitant fungal and parasitic superinfection were similar to patients receiving CMV-IGIV in the first trial.
In a randomized, double-blind, placebo-controlled trial in liver transplant recipients (4), the incidence of serious CMV-associated disease was reduced from 26% in the 72 control patients to 12% in the 69 CMV-IGIV recipients (p=0.02); serious CMV-associated disease included CMV disease in 2 or more organs, CMV pneumonia, or CMV-associated invasive fungal infection, the incidence of which was 18% in controls and 7% in CMV-IGIV recipients (p=0.04). In follow-up (5) of the liver transplant patients studied in this randomized controlled trial and a subsequent open-label trial (7), the one year survival of the 72 control patients was 72% versus 86% in the 90 recipients of CMV-IGIV (p=0.03). In the randomized control trial, the reduction in serious CMV-associated disease in CMV seronegative recipients of livers from a CMV seropositive donor (7/19 in the CMV-IGIV group vs. 9/19 in control) was less than in transplants with other donor and recipient serologic status (1/50 in the CMV-IGIV group vs. 10/53 in the
control group). This finding was similar to that of Merigan et al. (8) in a study of ganciclovir prophylaxis after heart transplantation. In this study, patients received ganciclovir IV at 5 mg/kg bid for the initial 14 days post-transplant, then at 6 mg/kg each day for 5 days per week through day 28.
Recent studies of combined prophylaxis with CMV-IGIV and ganciclovir have shown reductions in the incidence of serious CMV associated disease in CMV seronegative recipients of CMV seropositive organs below that expected from one drug alone (9-12).
Ham et al. (9) used CMV-IGIV with a dosage schedule of 150 mg/kg CMV-IGIV within 72 hours of transplant; 100 mg/kg at two, four, six and eight weeks following liver transplant and then 50 mg/kg at 12 and 16 weeks post-transplant in combination with ganciclovir (10 mg/kg/day for 14 days). The incidence of CMV disease was reduced from an expected 60-80% rate to 7% in 15 seronegative recipients of a seropositive organ.
Snydman (10) using the CMV-IGIV dosage schedule listed under DOSAGE AND ADMINISTRATION section in combination with ganciclovir (10 mg/kg/day for 14 days) reduced the incidence of serious CMV disease in D+R- liver transplant recipients receiving placebo or one drug from 16/47 (34%) to 3/41 (7%) in patients receiving both drugs for prophylaxis.
Martin (11) using CMV-IGIV 100 mg/kg every two weeks for six weeks followed by 50 mg/kg every two weeks with a final dose at week 16, in combination with ganciclovir 10 mg/kg/day for 14 days after transplantation, observed severe CMV disease in 1/74 (1%) of CMV seronegative recipients of a kidney from a CMV seropositive donor, in 0/14 (0%) of CMV seronegative recipients of a kidney-pancreas transplant from a CMV seropositive donor and in 1/12 (8%) of CMV seronegative recipients of a liver from a CMV seropositive donor. The incidence of serious CMV disease with combined CMV-IGIV and ganciclovir prophylaxis was lower than previous experience with single drug prophylaxis.
Valantine and Luikart (12) compared prophylaxis with CMV-IGIV (biweekly for three months) in combination with ganciclovir prophylaxis (IV at 5 mg/kg bid for the initial 14 days post-transplant, then at 6 mg/kg through day 28) in 16 CMV seronegative recipients of hearts from CMV seropositive donors with 16 matched controls receiving ganciclovir alone. The actuarial incidence of CMV disease was reduced from 55% in the ganciclovir group to 46% in the combined group (p</=0.06) and survival was increased from 61% to 94% (p</=0.001). In heart-lung or lung transplant patients in whom either the donor or recipient was CMV seropositive, the actuarial incidence of CMV disease in patients receiving ganciclovir alone (n=25) was 85% as compared to 36% of the 33 patients receiving both CMV-IGIV and ganciclovir (p</=0.05). Survival was 60% in the ganciclovir group and 80% in patients receiving CMV-IGIV and ganciclovir (p</=0.01).
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DOSAGE AND ADMINISTRATION
The maximum recommended total dosage per infusion is 150 mg Ig/kg, administered according to the following schedule:
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Type of Transplant
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Kidney
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Liver, Pancreas
Lung, Heart
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Within
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72 hours of transplant:
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150 mg/kg
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150 mg/kg
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2 weeks post transplant:
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100 mg/kg
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150 mg/kg
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4 weeks post transplant:
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100 mg/kg
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150 mg/kg
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6 weeks post transplant:
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100 mg/kg
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150 mg/kg
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8 weeks post transplant:
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100 mg/kg
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150 mg/kg
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12 weeks post transplant:
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50 mg/kg
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100 mg/kg
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16 weeks post transplant:
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50 mg/kg
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100 mg/kg
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Preparation for Administration . Remove the tab portion of the vial cap and clean the rubber stopper with 70% alcohol or equivalent. DO NOT SHAKE VIAL; AVOID FOAMING.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Infuse the solution only if it is colorless, free of particulate matter and not turbid.
Infusion . Infusion should begin within 6 hours after entering the vial and should be complete within 12 hours of entering the vial. Vital signs should be taken preinfusion, mid-way and post-infusion as well as before any rate increase. CytoGam® should be administered through an intravenous line using an administration set that contains an in-line filter (pore size 15µ) and a constant infusion pump (i.e., IVAC pump or equivalent). A smaller in-line filter (0.2µ) is also acceptable. Pre-dilution of CytoGam® before infusion is not recommended. CytoGam® should be administered through a separate intravenous line. If this is not possible, CytoGam® may be "piggybacked" into a pre-existing line if that line contains either Sodium Chloride, Injection, USP, or one of the following dextrose solutions (with or without NaCl added): 2.5% dextrose in water, 5% dextrose in water, 10% dextrose in water, 20% dextrose in water. If a pre-existing line must be used, the CytoGam® should not be diluted more than
1:2 with any of the above-named solutions. Admixtures of CytoGam® with any other solutions have not been evaluated. Initial Dose. Administer intravenously at 15 mg Ig per kg body weight per hour. If no adverse reactions occur after 30 minutes, the rate may be increased to 30 mg Ig/kg/hr; if no adverse reactions occur after a subsequent 30 minutes, then the infusion may be increased to 60 mg Ig/kg/hr (volume not to exceed 75 ml/hour). DO NOT EXCEED THIS RATE OF ADMINISTRATION. The patient should be monitored closely during and after each rate change.
Subsequent Doses. Administer at 15 mg Ig/kg/hr for 15 minutes. If no adverse reactions occur, increase to 30 mg Ig/kg/hr for 15 minutes and then increase to a maximum rate of 60 mg Ig/kg/hr (volume not to exceed 75 ml/hour). DO NOT EXCEED THIS RATE OF ADMINISTRATION. The patient should be monitored closely during each rate change.
CytoGam® should be used with caution in patients with pre-existing renal insufficiency and in patients judged to be at increased risk of developing renal insufficiency (including, but not limited to those with diabetes mellitus, age greater than 65, volume depletion, paraproteinemia, sepsis and patients receiving known nephrotoxic drugs). In these cases especially, it is important to assure that patients are not volume depleted prior to CytoGam® infusion. While most cases of renal insufficiency have occurred in patients receiving total doses of 350 mg Ig/kg or greater, no prospective data are presently available to identify a maximum safe dose, concentration or rate of infusion in patients determined to be at increased risk of acute renal failure. In the absence of prospective data, recommended doses should not be exceeded and the concentration and infusion rate selected should be the minimum practicable.
Potential adverse reactions are: flushing, chills, muscle cramps, back pain, fever, nausea, vomiting, wheezing, drop in blood pressure. Minor adverse reactions have been infusion rate related - if the patient develops a minor side effect (i.e., nausea, back pain, flushing), slow the rate or temporarily interrupt the infusion. If anaphylaxis or drop in blood pressure occurs, discontinue infusion and use antidote such as diphenhydramine and adrenalin.
To prevent the transmission of hepatitis viruses or other infectious agents from one person to another, sterile disposable syringes and needles should be used. The syringes and needles should not be reused.
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