Cytogam Product Monograph

Recent Major Label Changes

Not applicable.

Table of Contents

Certain sections (as indicated in section 2.1. of the PM Guidance) or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes .................................................................................................... 2

Table of Contents .................................................................................................................... 2

Part 1: Healthcare Professional Information ............................................................................ 4

1. 1.

   Indications ........................................................................................................................ 4

   1.1. Pediatrics .................................................................................................................... 4

   1.2. Geriatrics ..................................................................................................................... 4

2. 2. Contraindications ............................................................................................................. 4
3. 3. Serious Warnings and Precautions Box ............................................................................. 4
4. 4.

   Dosage and Administration .............................................................................................. 5

   4.1. Dosing Considerations................................................................................................. 5

   4.2. Recommended Dose and Dosage Adjustment ............................................................ 5

   4.4. Administration ............................................................................................................ 5

5. 5. Overdose .......................................................................................................................... 6
6. 6. Dosage Forms, Strengths, Composition, and Packaging .................................................... 6
7. 7.

   Warnings and Precautions ................................................................................................ 6

   General .................................................................................................................................. 7

   Hematologic .......................................................................................................................... 7

   Monitoring and Laboratory Tests .......................................................................................... 8

   Neurologic ............................................................................................................................. 8

   Renal ...................................................................................................................................... 8

   Respiratory ............................................................................................................................ 9

   7.1. Special Populations ..................................................................................................... 9

   7.1.1. Pregnancy ........................................................................................................... 9

   7.1.2. Breastfeeding ..................................................................................................... 9

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7.1.3. Pediatrics ............................................................................................................ 9

7.1.4. Geriatrics ............................................................................................................ 9

1. 8.

   Adverse Reactions .......................................................................................................... 10

   8.1. Adverse Reaction Overview ...................................................................................... 10

   8.2. Clinical Trial Adverse Reactions ................................................................................. 10

   8.5. Post-Market Adverse Reactions ................................................................................ 10

2. 9.

   Drug Interactions ............................................................................................................ 11

   9.1. Serious Drug Interactions .......................................................................................... 11

   9.2. Drug Interactions Overview ...................................................................................... 11

   9.3. Drug-Behaviour Interactions ..................................................................................... 11

   9.4. Drug-Drug Interactions ............................................................................................. 11

   9.5. Drug-Food Interactions ............................................................................................. 11

   9.6. Drug-Herb Interactions ............................................................................................. 11

   9.7. Drug-Laboratory Test Interactions ............................................................................ 11

3. 10.

   Clinical Pharmacology .................................................................................................... 12

   10.1. Mechanism of Action ............................................................................................. 12

   10.3. Pharmacokinetics .................................................................................................. 12

4. 11. Storage, Stability, and Disposal ....................................................................................... 12
5. 12. Special Handling Instructions .......................................................................................... 12

Part 2: Scientific Information ................................................................................................. 13

1. 13. Pharmaceutical Information ........................................................................................... 13
2. 14.

   Clinical Trials ................................................................................................................... 13

   14.1. Clinical Trials by Indication .................................................................................... 13

3. 15. Microbiology .................................................................................................................. 14
4. 16. Non-Clinical Toxicology ................................................................................................... 14

Patient Medication Information ............................................................................................ 15

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Part 1: Healthcare Professional Information

1. Indications

Cytomegalovirus Immunoglobulin Intravenous (Human) is indicated for the attenuation of primary (1°) Cytomegalovirus disease associated with kidney transplantation. Specifically, the product is indicated for kidney transplant recipients who are seronegative for CMV and who receive a kidney from a CMV seropositive donor.

1.1. Pediatrics

Pediatrics (<18 years): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2. Geriatrics

Geriatrics (>65 years of age): Clinical studies of CYTOGAM did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

2. Contraindications

CYTOGAM, Cytomegalovirus Immunoglobulin Intravenous (Human), should not be used in individuals with a history of a prior severe reaction associated with the administration of this or other human immunoglobulin preparations. Persons with selective immunoglobulin A deficiency have the potential for developing antibodies to immunoglobulin A and could have anaphylactic reactions to subsequent administration of blood products that contain immunoglobulin A, including CYTOGAM.

3. Serious Warnings and Precautions Box

CYTOGAM is prepared from pools of human plasma which may contain the causative agents of hepatitis and other viral diseases, including, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses during manufacturing. Despite these measures, such products can still potentially transmit disease and should be given only if a benefit is expected.

There is also the possibility that unknown infectious agents may be present in such products.

True hypersensitivity reactions are rare. These reactions can occur in very rare cases of IgA deficiency or hypersensitivity to human globulin. In case of allergic or anaphylactic reaction, the infusion should be stopped immediately. In case of shock, the current medical standards for treatment of shock should be observed.

The physician should discuss the risks and benefits of this product with the patient before prescribing or administering to the patient (see 7. WARNINGS AND PRECAUTIONS, General).

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4. Dosage and Administration

4.1. Dosing Considerations

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.

4.2. Recommended Dose and Dosage Adjustment

The maximum recommended total dosage per infusion is 150 mg Ig/kg, administered according to the following schedule:

Within 72 hours of transplant: 150 mg/kg

2 weeks post transplant: 100 mg/kg

4 weeks post transplant: 100 mg/kg

6 weeks post transplant: 100 mg/kg

8 weeks post transplant: 100 mg/kg

12 weeks post transplant: 50 mg/kg

16 weeks post transplant: 50 mg/kg

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.

4.4. Administration

Preparation for Administration. Bring the product vial to room temperature. 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. CYTOGAM, Cytomegalovirus Immunoglobulin Intravenous (Human), does not contain a preservative. The vial should be entered only once for administration purposes.

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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 pre-infusion, 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.

5. Overdose

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

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

1. 6. Dosage Forms, Strengths, Composition, and Packaging

Table 1 – Dosage Forms, Strengths, and Composition

Each milliliter contains: 50 ± 10 mg of immunoglobulin, primarily IgG, and trace amounts of IgA and IgM; 50 mg of sucrose; 10 mg of Albumin (Human). The sodium content is 20-30 mEq per liter; i.e. 1.0-1.5 mEq per 50 mL. The solution should appear colorless and translucent. CYTOGAM is supplied in a single use vial and therefore, any product remaining after administration should be discarded.

To help ensure the traceability of biologic products, health professionals should recognise the importance of recording both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

7. Warnings and Precautions

This product is prepared from large pools of human plasma. Thus, there is a possibility it may contain causative agents of viral or other undetermined diseases.

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General

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

Although systemic allergic reactions are rare (see 8. 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.

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

All infections thought to have been possibly transmitted by this product should be reported by the physician or other health care provider to KI BioPharma LLC at 1-866-916-0077.

Hematologic

Hemolysis:

Immunoglobulin 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. Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration [See 8. ADVERSE REACTIONS]. IGIV recipients should be monitored for clinical signs and symptoms of hemolysis [See 7. Warning and Precautions: Monitoring and Laboratory Tests].

Thrombotic Events:

Thrombotic events have been reported in association with IGIVs (See 8. 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

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high triacylglycerols (triglycerides), or monoclonal gammopathies [See 7. WARNINGS AND PRECAUTIONS: Monitoring and Laboratory Tests].

Monitoring and Laboratory Tests

If signs and/or symptoms of hemolysis are present after IGIV infusion, appropriate confirmatory laboratory testing should be done [See 7. WARNINGS AND PRECAUTIONS, Hematologic].

If TRALI is suspected, appropriate tests should be performed for the presence of anti- neutrophil antibodies in both the product and patient serum [See 7. WARNINGS AND PRECAUTIONS, Respiratory].

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 7. WARNINGS AND PRECAUTIONS, Hematologic].

Neurologic

An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with Immunoglobulin Intravenous (Human) (IGIV) treatment. 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 studies are frequently positive with pleocytosis up to several thousand cells/mm³, 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.

Renal

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 with IGIV products 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.

Immunoglobulin Intravenous (Human) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis and death. Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia or patients receiving known nephrotoxic drugs. Especially in such patients, IGIV products should be administered at the minimum concentrations available and the minimum rate of infusion practical. While these reports of renal dysfunction and acute renal failure have been associated with the use of many IGIV products, those containing sucrose as a stabilizer (and given at

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daily doses of 350 mg/kg or greater) account for a disproportionate share of the total number. CYTOGAM contains sucrose as a stabilizer.

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) or 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. For patients judged to be at risk for developing renal dysfunction, it may be prudent to reduce the amount of product infused per unit time. The recommended rate of CYTOGAM infusion for prophylaxis of CMV disease in kidney transplant patients should NOT EXCEED 60 mg Ig/kg/hr (see 4.1 Dosing Considerations for important information intended to reduce the risk of acute renal failure).

Respiratory

There have been reports of noncardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] in patients administered IGIV. 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 7. WARNINGS and PRECAUTIONS: Monitoring and Laboratory Tests].

7.1. Special Populations

7.1.1. Pregnancy

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

Extent of exposure in pregnancy during clinical trials: No experience.

7.1.2. Breastfeeding

It is unknown if CYTOGAM is excreted in human milk. Precaution should be exercised because many drugs can be excreted in human milk.

7.1.3. Pediatrics

Pediatrics (<18 years): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4. Geriatrics

Geriatrics (>65 years of age): Clinical studies of CYTOGAM did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

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8. Adverse Reactions

8.1. Adverse Reaction Overview

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 Immunoglobulin Intravenous (Human). The incidence of these reactions during the clinical trials was less than 6.0% of all infusions and were most often related to infusion rates. If a patient develops a minor side effect, slow the rate immediately or temporarily interrupt the infusion.

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

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 immunoglobulin products. A reaction may be related to the rate of infusion; therefore, carefully adhere to the infusion rates as outlined under 4. DOSAGE AND ADMINISTRATION. If anaphylaxis or drop in blood pressure occurs, discontinue infusion and use antidote such as diphenhydramine and adrenalin.

8.5. Post-Market Adverse Reactions

In addition to adverse events reported during clinical trials, the following events have been reported during the post-approval use of CYTOGAM: Acute Respiratory Distress Syndrome (ARDS), cyanosis, pulmonary edema, dyspnea, cardiac arrest, circulatory collapse, hypotension, convulsions, bullous dermatitis, hemolysis, hepatic failure, and abdominal pain.

In addition to the adverse reactions seen with the use of CYTOGAM, the following adverse reactions have been identified and reported during the post-approval use of IGIV products:

Respiratory: Apnea, Transfusion Associated Lung Injury (TRALI), hypoxemia, bronchospasm

Cardiovascular: Thromboembolism

Neurological: Coma, loss of consciousness, tremor

Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme

Hematologic: Pancytopenia, leukopenia, positive direct antiglobulin (Coombs) test

Increase in serum creatinine and blood urea nitrogen (BUN): Increases in serum creatinine and 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.

Because post-marketing 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.

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9. Drug Interactions

9.1. Serious Drug Interactions

Live attenuated virus vaccines: immunoglobulin administration may impair the efficacy of live attenuated virus vaccines for a period of three months or more (see 9.2 Drug Interactions Overview).

9.2. Drug Interactions Overview

Antibodies present in immunoglobulin 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 4.4 Administration).

9.3. Drug-Behaviour Interactions

Interactions with behaviour have not been established.

9.4. Drug-Drug Interactions

Table 2 – Established or Potential Drug-Drug Interactions

T = Theoretical

9.5. Drug-Food Interactions

Interactions with food have not been established.

9.6. Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7. Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

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10. Clinical Pharmacology

10.1. Mechanism of Action

CYTOGAM, Cytomegalovirus Immunoglobulin Intravenous (Human) (CMV-IGIV), contains IgG antibodies representative of the large number of normal persons who contributed to the plasma pools from which the product was derived. The globulin contains a relatively high concentration of antibodies directed against Cytomegalovirus (CMV). In the case of persons who may be exposed to CMV, CYTOGAM can raise the relevant antibodies to levels sufficient to attenuate or reduce the incidence of serious CMV disease.

10.3. Pharmacokinetics

Duration of effect

Immunoglobulin administration may impair the efficacy of live attenuated virus vaccines for a period of three months or more (see 9.1 Serious Drug Interactions).

1. 11. Storage, Stability, and Disposal

CYTOGAM should be stored between 2-8°C (36-46°F) and used within 6 hours after entering the vial. The product is stable up to the expiration date which is stamped on the outer carton and vial label. It should not be used after that date.

12. Special Handling Instructions

CYTOGAM is supplied in a single use vial and therefore, any product remaining after administration should be discarded.

The product should be brought to room or body temperature before use. Do not shake. Avoid foaming.

The solution should appear colorless and translucent. Do not use solutions that are cloudy or have deposits.

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Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance(s): Cytomegalovirus Immunoglobulin Intravenous (Human)

Chemical name: Cytomegalovirus Immunoglobulin Intravenous (Human)

Molecular formula and molecular mass: Glycoprotein of approximately 160,000 Da

Physicochemical properties: IgG is a monomeric protein with a sedimentation coefficient of 7S and a molecular weight ranging from 146,000 to 170,000 Da. Carbohydrate content of IgG is approximately 2 to 3%.

Product Characteristics:

CYTOGAM, Cytomegalovirus Immunoglobulin Intravenous (Human), is an immunoglobulin G (IgG) product containing a standardized amount of antibody to Cytomegalovirus (CMV). CYTOGAM is formulated in final vial as a sterile liquid. The globulin is stabilized with 5% sucrose and 1% Albumin (Human). CYTOGAM contains no preservative. The purified immunoglobulin is derived from pooled adult human plasma selected for high titers of antibody for Cytomegalovirus (CMV). Source material for fractionation may be obtained from another U.S. licensed manufacturer. Pooled plasma was fractionated by ethanol precipitation of the proteins according to Cohn Methods 6 and 9, modified to yield a product suitable for intravenous administration.

14. Clinical Trials

14.1. Clinical Trials by Indication

Attenuation of primary (1°) Cytomegalovirus disease associated with kidney transplantation.

In a population of seronegative recipients of seropositive kidneys approximately 75% of the untreated recipients would be expected to develop CMV disease. Clinical studies have shown a 50% reduction in 1° CMV disease in renal transplant patients given Cytomegalovirus Immunoglobulin Intravenous (Human).

CYTOGAM was evaluated in one randomized clinical trial (n=59) and one non-randomized clinical trial in renal transplant recipients at risk for primary CMV disease (n=36).

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, the incidence of virologically confirmed CMV-associated syndromes was reduced from 60% in controls (n=35) to 21% in recipients of CMV immunoglobulin (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.

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In a subsequent non-randomized trial in renal transplant recipients (n=36), 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 CMV- associated pneumonia, CMV-associated hepatitis, and concomitant fungal and parasitic superinfection were similar to those in the first trial.

15. Microbiology

No microbiological information is required for this drug product.

16. Non-Clinical Toxicology

Toxicology studies have not been performed with Cytomegalovirus Immunoglobulin (Human).