Cytogam

Live Vaccines

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 vaccine (MMRV);1 36 no evidence that immune globulin preparations interfere with immune responses to rotavirus vaccine live oral, influenza virus vaccine live intranasal, yellow fever virus vaccine live, typhoid vaccine live oral, or zoster vaccine live.36 (See Specific Drugs under Interactions.)

Inactivated Vaccines and Toxoids

Immune globulin preparations are not expected to have a clinically important effect on immune responses to inactivated vaccines or toxoids; 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 CMV-IGIV.36

Specific Drugs

Absorption

Bioavailability

Pharmacokinetics not fully elucidated.1

Elimination

Half-life

Renal transplant patients receiving 50-mg/kg doses once daily for first 3 days posttransplant followed by once every 21 days for 4 months: 5–13 days during first 2 months posttransplant and 13–45 days during third to fifth month posttransplant.4 CMV antibody detectable for up to 2 months following last dose.4

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Talk with your doctor before getting any vaccines. Use with CytoGam may either raise the chance of an infection or make the vaccine not work as well.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Very bad and sometimes deadly kidney problems have happened with this medicine. The chance may be higher if you have kidney problems, high blood sugar (diabetes), fluid loss (dehydrated) or low blood volume, a blood infection, or proteins in the blood that are not normal. The chance may also be higher if you are 65 or older, or if you take other drugs that may harm the kidneys. Talk with your doctor.
• This medicine is made from human plasma (part of the blood) and may have viruses that may cause disease. This medicine is screened, tested, and treated to lower the chance that it carries an infection. Talk with the doctor.
• If you are 65 or older, use CytoGam with care. You could have more side effects.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Use CytoGam as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as an infusion into a vein over a period of time.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Flushing.
• Fever or chills.
• Joint pain.
• Back pain.
• Muscle pain or cramping.
• Upset stomach or throwing up.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

General

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

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

Renal Function

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

Aseptic Meningitis Syndrome

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

Hemolysis

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

Transfusion-Related Acute Lung Injury (TRALI)

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

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

Thrombotic Events

Thrombotic events have been reported in association with IGIV35-37 (see ADVERSE REACTIONS). Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity. The potential risks and benefits of IGIV should be weighed against those of alternative therapies for all patients for whom IGIV administration is being considered. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies [see PRECAUTIONS: Laboratory Tests].

Laboratory Tests

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

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

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

Drug Interactions

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

Pregnancy Category C

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

Information for Patients

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

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

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

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

Postmarketing

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

Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion-Related Acute Lung Injury (TRALI), cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm
Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension
Neurological: Coma, loss of consciousness, seizures, tremor
Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis
Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs) test
General/Body as a Whole: Pyrexia, Rigors
Musculoskeletal: Back pain
Gastrointestinal: Hepatic dysfunction, abdominal pain

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

Although few data are available, clinical experience with other immunoglobulin preparations suggests that the major manifestations would be those related to volume overload.

Cytogam, Cytomegalovirus Immune Globulin Intravenous (Human), is supplied in one single-dose vial form:

STORAGE

Cytogam should be stored between 2-8°C (36-46°F), and used within 6 hours after entering the vial.

1. Snydman DR, McIver J, Leszczynski J, et al. A pilot trial of a novel cytomegalovirus immune globulin in renal transplant recipients. Transplantation 1984;38:553-557.
2. Horowitz B, Wiebe ME, Lippin A, et al. Inactivation of viruses in labile blood derivatives. Transfusion 1985;25:516-522.
3. Snydman DR, Werner BG, Heinze-Lacey BH, et al. Use of cytomegalovirus immune globulin to prevent cytomegalovirus disease in renal transplant recipients. N Engl J Med 1987;317:1049-1054.
4. Snydman DR, Werner BG, Dougherty NN, et al. Cytomegalovirus Immune Globulin prophylaxis in liver transplantation. A randomized, double-blind, placebo-controlled trial. Ann Int Med 1993;119:984-991.
5. Falagas ME, Snydman DR, Ruthazer R, et al. Cytomegalovirus Immune Globulin (CMVIG) prophylaxis is associated with increased survival after orthotopic liver transplantation. Clin Transplant 1997;11:432-437.
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14. Wells MA, Wittek AE, Epstein JS, et al. Inactivation and partition of human T-cell lymphotropic virus type III, during ethanol fractionation of plasma. Transfusion 1986;26:210-213.
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For additional information concerning Cytomegalovirus Immune Globulin Intravenous (Human) contact:
CSL Behring Medical Affairs
CSL Behring LLC
King of Prussia, PA 19406 USA
1-800-504-5434

Manufactured by:
CSL Behring AG
Bern, Switzerland
US License No. 1766

Distributed by:
CSL Behring LLC
Kankakee, IL 60901 USA

Revised November 2010

A8304/852