HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use Vivaglobin
`safely and effectively. See full prescribing information for Vivaglobin.
`
`Vivaglobin®
`Immune Globulin Subcutaneous (Human)
`16% Liquid
`Initial U.S. Approval: 2006
`
`----------------------------------RECENT MAJOR CHANGES-----------------------------------
`Dosage and Administration (2.3) 04/2010
`Warnings and Precautions (5.1, 5.2, 5.3) 04/2010
`
`---------------------------------INDICATIONS AND USAGE-------------------------------------
`Vivaglobin is an Immune Globulin Subcutaneous (Human) (IGSC), 16% Liquid indicated for
`the treatment of primary humoral immunodeficiency (PI) (1).
`
`----------------------------DOSAGE AND ADMINISTRATION----------------------------------
`For subcutaneous infusion only. DO NOT INJECT INTO A BLOOD VESSEL.
`Start patients on treatment with Vivaglobin 1 week after having received Immune Globulin
`Intravenous (Human) (IGIV) infusions at regular intervals for a period of at least 3 months.
`Initial Weekly Dose (2.3)
`The initial weekly dose of Vivaglobin is calculated to achieve a systemic serum IgG exposure
`(area under the concentration-time curve [AUC]) not inferior to the AUC of the previous
`IGIV treatment.
`• Vivaglobin weekly dose (in grams [g]) = 1.37 x previous IGIV dose (g)
`
` No. of weeks between IGIV doses
`• Divide by 0.16 to convert the dose in g to milliliters (mL).
`Dose Adjustment (2.3, Table 1)
`• Doses may need to be adjusted over time based on the patient’s clinical response and
`serum immunoglobulin G (IgG) trough levels.
`• To determine if a dose adjustment should be considered, measure the serum IgG trough
`level during IGIV therapy prior to switching to Vivaglobin and again after 2 to 3 months
`of treatment with Vivaglobin. Adjust the Vivaglobin dose to achieve a serum IgG trough
`level that is equal to the last trough level during prior IGIV therapy plus 180 mg/dL.
`Administration (2.4)
`• Infuse subcutaneously, preferably in the abdomen, thigh, upper arm, and/or lateral hip.
`• Divide doses >15 mL and infuse into multiple sites that are at least two inches apart.
`
` o Adults – Up to six simultaneous sites
`
` o Children <45 kg (99 pounds) – Up to three simultaneous sites
` o Patients ≥65 years – Up to four simultaneous sites
`
`If necessary, additional sites can be used consecutively during an infusion.
`• Administer at a rate of ≤20 mL/hour per site. The maximum infusion rate should not
`exceed a total of 3 mg/kg/minute (1.13 mL/kg/hour) for all simultaneous infusion sites
`combined.
`• Ensure that patients are not volume depleted.
`
`------------------------------DOSAGE FORMS AND STRENGTHS-----------------------------
`16% IgG (160 mg/mL) for subcutaneous infusion (3)
`
`---------------------------------------CONTRAINDICATIONS -----------------------------------
`• Anaphylactic or severe systemic reaction to Immune Globulin (Human) (4)
`• IgA-deficient patients with antibodies against IgA or a history of hypersensitivity (4)
`
`-----------------------------------WARNINGS AND PRECAUTIONS----------------------------
`• IgA-deficient patients with antibodies against IgA are at greater risk of developing
`severe hypersensitivity and anaphylactic reactions. Discontinue use if a hypersensitivity
`reaction occurs. Epinephrine should be immediately available to treat any acute severe
`hypersensitivity reactions (5.1).
`• Aseptic meningitis syndrome has been reported to occur infrequently with IGIV treatment
`and with Vivaglobin treatment (5.2).
`• Monitor patients for reactions reported to occur with IGIV treatment that may occur
`with Vivaglobin, including renal dysfunction/failure, thrombotic events, hemolysis, and
`transfusion-related acute lung injury (TRALI) (5.3).
`• Vivaglobin is made from human plasma and may contain infectious agents, e.g., viruses
`and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent (5.4).
`
`-------------------------------------ADVERSE REACTIONS--------------------------------------
`The most common adverse reactions (observed in ≥5% of study subjects) were local
`injection-site reactions (swelling, redness, and itching), headache, nausea, rash, asthenia,
`and gastrointestinal disorder (6.1).
`
`To report SUSPECTED ADVERSE REACTIONS, contact the CSL Behring
`Pharmacovigilance Department at 1-866-915-6958 or FDA at
`1-800-FDA-1088 or www.fda.gov/medwatch.
`
`-------------------------------------DRUG INTERACTIONS--------------------------------------
`• The passive transfer of antibodies may interfere with the response to live virus vaccines
`(7.1).
`• The passive transfer of antibodies may lead to misinterpretation of the results of
`serological testing (7.2).
`
`------------------------------USE IN SPECIFIC POPULATIONS---------------------------------
`• Pregnancy: No human or animal data. Use only if clearly needed (8.1).
`
`See 17 for PATIENT COUNSELING INFORMATION and the accompanying FDA-
`approved patient labeling.
`
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` Revised: April 2010
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`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`INDICATIONS AND USAGE
`1
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Self-Administration
`
`2.2 Preparation and Handling
`
`2.3 Dosage
`
`2.4 Administration
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Hypersensitivity Reactions
`
`5.2 Aseptic Meningitis Syndrome
`
`5.3 Reactions Reported With IGIV Treatment
`
`5.4 Transmissible Infectious Agents
`
`5.5
`Laboratory Tests
`6 ADVERSE REACTIONS
`
`6.1 Clinical Studies Experience
`
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`
`7.1
`Live Virus Vaccines
`
`7.2 Serological Testing
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.3 Pharmacokinetics
`14 CLINICAL STUDIES
`
`14.1 US-Canada Study
`
`14.2 Europe-Brazil Study
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`16.1 How Supplied
`
`16.2 Storage and Handling
`17 PATIENT COUNSELING INFORMATION
`
`17.1 Self-Administration
`
`17.2 Additional Information for Patients
`
`*
`
`Sections or subsections omitted from the full prescribing information are not listed.
`
`CSL EXHIBIT 1064
`CSL v. Shire
`
`Page 1 of 8
`
`

`

`CSL Behring
`FULL PRESCRIBING INFORMATION
`Vivaglobin®
`Immune Globulin Subcutaneous
`(Human)
`16% Liquid
`
`1 INDICATIONS AND USAGE
`Vivaglobin is an Immune Globulin Subcutaneous (Human) (IGSC), 16% Liquid indicated
`as replacement therapy for primary humoral immunodeficiency (PI). This includes, but
`is not limited to, the primary immunodeficiency in common variable immunodeficiency
`(CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich
`syndrome, and severe combined immunodeficiencies.
`2 DOSAGE AND ADMINISTRATION
`For subcutaneous infusion only. DO NOT INJECT INTO A BLOOD VESSEL.
`2.1 Self-Administration
`Self-administration is appropriate for some patients. If self-administration is planned,
`the healthcare professional should provide the patient with instructions and training for
`subcutaneous infusion in the home or other appropriate setting (see Patient Counseling
`Information [17.1] and the FDA-Approved Patient Labeling).
`2.2 Preparation and Handling
`Vivaglobin is a colorless to light brown solution. Do not use if the solution is cloudy (turbid)
`or contains particulates.
`• Prior to administration, bring the Vivaglobin vial(s) to room temperature. Then, visually
`inspect each vial for particulate matter by gently swirling the vial, and check for
`discoloration by holding it up to the light.
`• Check the product expiration date on the vial label. Do not use beyond the expiration
`date.
`• Do not mix Vivaglobin with other products.
`• Do not shake the Vivaglobin vial.
`• Use aseptic technique when preparing and administering Vivaglobin.
`• The Vivaglobin vial is for single-use only. Discard all administration equipment and any
`unused product immediately after each infusion in accordance with local requirements.
`2.3 Dosage
`The dose should be individualized based on the patient’s clinical response to Vivaglobin
`therapy and serum immunoglobulin (IgG) trough levels.
`Begin treatment with Vivaglobin one week after the patient has received a regularly
`scheduled Immune Globulin Intravenous (Human) (IGIV) infusion. Prior to receiving
`treatment with Vivaglobin, patients need to have been receiving IGIV treatment for at least
`3 months at dosing intervals of either every 3 weeks or every 4 weeks.
`The initial weekly dose of Vivaglobin is established by converting the monthly IGIV dose
`into a weekly equivalent and increasing it using a dose adjustment factor (see Initial
`Weekly Dose). The goal is to achieve a systemic serum IgG exposure (area under the
`concentration-time curve [AUC]) not inferior to the AUC of the previous IGIV treatment
`(see Pharmacokinetics [12.3]).
`Prior to switching treatment from IGIV to Vivaglobin, obtain the patient’s serum IgG
`trough level to guide subsequent dose adjustment (see Dose Adjustment). After 2 to
`3 months, weekly administration of Vivaglobin will lead to stable steady-state serum IgG
`levels with lower IgG peak levels and higher IgG trough levels compared with monthly
`IGIV treatment.
`Initial Weekly Dose
`To calculate the initial weekly dose of Vivaglobin, multiply the previous IGIV dose in grams
`(g) by the dose adjustment factor of 1.37, then divide this dose by the number of weeks
`between doses during the patient’s previous IGIV treatment (i.e., 3 or 4).
`
`
`
`IGSC weekly dose (g) = 1.37 x previous IGIV dose (g)
`
`
` Number of weeks between IGIV doses
`To convert the Vivaglobin dose (g) to milliliters (mL), divide the dose in grams (g) by 0.16.
`Dose Adjustment
`Over time, the dose may need to be adjusted to achieve the desired clinical response and
`serum IgG trough level. To determine if a dose adjustment should be considered, measure
`the patient’s serum IgG trough level on IGIV prior to switching to Vivaglobin and every 2 to
`3 months after switching from IGIV to Vivaglobin.
`To achieve the same AUC with Vivaglobin as with the previous IGIV treatment, follow
`these steps:
`1. Estimate the target serum IgG trough level on weekly Vivaglobin treatment, which is
`derived as follows:
`
`Target concentration (mg/dL) during Vivaglobin treatment =
`
`the last trough level during prior IGIV treatment + 180 mg/dL
`
`Body Weight (kg)
`
`10 15 20
`
`30
`
`40
`
`50
`
`60
`
`70
`
`80
`
`90 100 110 120
`
`2. In Table 1, find the additional Vivaglobin dose to be administered, based on the patient’s
`body weight, and the difference between the target IgG concentration (mg/dL) and the
`observed trough level during Vivaglobin treatment.
`Additional dosage increments may be indicated based on the patient’s clinical
`response (infection frequency and severity).
`Table 1: Adjustment (±mL) of the Weekly Vivaglobin Dose Based on the
`Difference (±mg/dL) From the Target Serum IgG Trough Level*
`Difference
`From
`Target
`IgG
`Trough
`Level*
`(mg/dL)
`100
`12
`11
`10
`9
`8
`7
`6
`5
`4
`3
`2
`2
`1
`150
`18
`17
`15
`14
`12
`11
`9
`8
`6
`5
`3
`2
`2
`200
`25
`23
`20
`18
`16
`14
`12
`10
`8
`6
`4
`3
`2
`250
`31
`28
`26
`23
`20
`18
`15
`13
`10
`8
`5
`4
`3
`300
`37
`34
`31
`28
`25
`22
`18
`15
`12
`9
`6
`5
`3
`350
`43
`39
`36
`32
`29
`25
`22
`18
`14
`11
`7
`5
`4
`400
`49
`45
`41
`37
`33
`29
`25
`20
`16
`12
`8
`6
`4
`450
`55
`51
`46
`41
`37
`32
`28
`23
`18
`14
`9
`7
`5
`500
`61
`56
`51
`46
`41
`36
`31
`26
`20
`15
`10
`8
`5
`* Target IgG concentration (mg/dL) during Vivaglobin treatment equals the last observed trough level during prior IGIV
`treatment plus 180 mg/dL.
`† Dose adjustment in mL is based on the slope of the serum IgG trough level response to Vivaglobin dose increments
`(6.1 mg/dL per increment of 1 mg/kg per week).
`For example, if a patient with a body weight of 70 kg has an actual IgG trough level of 900
`mg/dL and the target trough level is 1000 mg/dL, this results in a difference of 100 mg/dL.
`Therefore, increase the weekly dose of Vivaglobin by 7 mL.
`Monitor the patient’s clinical response, and repeat the dose adjustment process as
`needed.
`2.4 Administration
`Vivaglobin is for subcutaneous infusion only. DO NOT INJECT INTO A BLOOD
`VESSEL.
`Vivaglobin is for subcutaneous infusion, preferably in the abdomen, thigh, upper arm, and/
`or lateral hip. Multiple injection sites should be at least two inches apart, and the actual
`point of injection should be changed with each weekly administration.
`• Infusion volume – Do not exceed 15 mL per site. Divide doses greater than 15 mL
`and infuse into a maximum of three simultaneous sites for children weighing less
`than 45 kg (99 pounds), a maximum of six simultaneous sites for adults up to age 65,
`and a maximum of four simultaneous sites for patients 65 years of age and older. If
`necessary, additional sites can be used consecutively during an infusion.
`• Infusion rate – The maximum recommended infusion rate is 20 mL per hour per site and
`should not exceed a total of 3.0 mg/kg/minute (1.13 mL/kg/hour) for all simultaneous
`injection sites combined.
`Ensure that patients are not volume depleted.
`Follow the steps below and use aseptic technique to administer Vivaglobin. For information
`about subcutaneous infusion in the home or other appropriate setting, see Patient
`Counseling Information (17.1).
`1. Assemble supplies – Place the Vivaglobin vial(s) and all supplies needed for the
`infusion on a clean, flat surface.
`2. Thoroughly wash and dry hands – The use of gloves when preparing and
`administering Vivaglobin is optional.
`3. Clean the vial stopper – Remove the protective cap from the vial to expose the
`central portion of the rubber stopper. Clean the stopper with alcohol and allow it to dry.
`4. Prepare and fill the syringe(s) – Using a sterile
`syringe and needle, pull back on the plunger to draw
`air into the syringe that is equal to the amount of
`Vivaglobin to be withdrawn. Then, insert the needle
`into the vial stopper and inject the air into the vial.
`Finally, withdraw the desired volume of Vivaglobin.
`If multiple vials are required to achieve the desired
`dose, repeat this step with another syringe.
`5. Fill and prime the infusion pump – Follow the manufacturer’s instructions for
`filling the pump reservoir and for preparing the pump, administration tubing, and Y-site
`connection tubing, if needed. Be sure to prime the administration tubing to ensure that no
`air is left in the tubing or needle by filling the tubing/needle with Vivaglobin.
`
`Dose Adjustment (mL per Week)†
`
`

`
`Page 2 of 8
`
`

`

`6. Select the injection site(s) – The number and
`location of injection sites depends on the volume of
`the total dose. Doses greater than 15 mL should be
`divided and infused into multiple sites that are at
`least two inches apart. The recommended number
`of simultaneous injection sites is up to six for adults,
`up to three for children who weigh less than 45 kg
`(99 pounds) and up to four for patients ages 65 and
`over. If necessary, additional injection sites can be
`used consecutively.
`7. Clean the injection site(s) – Using an antiseptic solution, clean each site beginning
`at the center and working outward in a circular motion. Allow each site to dry before
`proceeding.
`8. Insert the needle – Based on the patient’s body
`mass, grasp or spread the skin; then insert the needle
`into the subcutaneous tissue.
`
`

`
`

`9. Check for proper placement of the needle. Vivaglobin must not be injected
`

`into a blood vessel – After inserting each needle into the subcutaneous tissue and
`before starting the infusion, test to make sure that a blood vessel has not been accessed
`accidentally. To do this, attach a sterile syringe to the end of the primed administration
`tubing, gently pull back on the plunger, and see if any blood is flowing back into the tubing.
`If blood is present, remove and discard the needle and administration tubing. Repeat steps
`5 and 8 (priming and needle insertion) using a new needle, new administration tubing, and
`a different injection site.
`10. Secure the needle to the skin – Apply sterile
`gauze or transparent dressing over each site to hold
`the needle in place. If using multiple, simultaneous
`injection sites, secure the Y-site connection tubing to
`the administration tubing.
`
`

`
`11. Infuse Vivaglobin – Follow the manufacturer’s instructions to turn on the pump.
`12. Record the infusion – Remove the peel-off portion of the label from each vial used,
`and affix it to the patient record.
`After administration, immediately discard any unused product and administration
`equipment in accordance with local procedures.
`3 DOSAGE FORMS AND STRENGTHS
`Vivaglobin is a solution containing 16% IgG (160 mg/mL) for subcutaneous infusion.
`4 CONTRAINDICATIONS
`Vivaglobin is contraindicated in patients who have had an anaphylactic or severe systemic
`reaction to the administration of Immune Globulin (Human).
`Vivaglobin is contraindicated in IgA-deficient patients with antibodies against IgA or a
`history of hypersensitivity (see Description [11]).
`5 WARNINGS AND PRECAUTIONS
`5.1 Hypersensitivity Reactions
`Severe hypersensitivity reactions may occur (see Patient Counseling Information
`[17.2]). In case of hypersensitivity, discontinue the Vivaglobin infusion immediately and
`institute appropriate treatment. Epinephrine should be immediately available to treat any
`acute severe hypersensitivity reactions.
`Individuals with IgA deficiency can develop anti-IgA antibodies and anaphylactic reactions
`(including anaphylaxis and shock) after administration of blood components containing
`IgA. Patients with known antibodies to IgA may have a greater risk of developing
`potentially severe hypersensitivity and anaphylactic reactions. Vivaglobin contains
`≤1.7 mg/mL IgA (see Description [11]). The minimum concentration of IgA that will
`provoke a hypersensitivity reaction is not known; therefore all IgG preparations carry the
`risk of inducing an anaphylactic reaction to IgA.
`5.2 Aseptic Meningitis Syndrome (AMS)
`AMS has been reported to occur infrequently with IGIV treatment5 and with Vivaglobin
`treatment. The syndrome usually begins within several hours to 2 days following IGIV
`treatment. AMS is characterized by signs and symptoms including severe headache, nuchal
`rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting.
`Cerebrospinal fluid (CSF) studies frequently show pleocytosis up to several thousand cells
`per cubic millimeter, predominantly from the granulocytic series, and with elevated protein
`levels up to several hundred mg/dL. AMS may occur more frequently in association with
`high doses (2 g/kg) and/or rapid infusion of IGIV.
`Patients exhibiting such signs and symptoms should receive a thorough neurological
`examination, including CSF studies, to rule out other causes of meningitis. Discontinuation
`
`of IGIV treatment has resulted in remission of AMS within several days without sequelae.
`5.3 Reactions Reported with IGIV Treatment
`The following reactions have been reported to occur with IGIV treatment and may occur
`with IGSC treatment.
`Renal Dysfunction/Failure
`Renal dysfunction/failure, osmotic nephropathy, and death may occur with use of human
`immune globulin products. Ensure that patients are not volume depleted and assess renal
`function, including measurement of blood urea nitrogen (BUN) and serum creatinine,
`before the initial infusion of Vivaglobin and at appropriate intervals thereafter.
`Periodic monitoring of renal function and urine output is particularly important in patients
`judged to have a potential increased risk of developing acute renal failure.1 If renal
`function deteriorates, consider discontinuing Vivaglobin. For patients judged to be at risk
`of developing renal dysfunction because of pre-existing renal insufficiency or predisposition
`to acute renal failure (such as those with diabetes mellitus or hypovolemia, those who are
`overweight or use concomitant nephrotoxic medicinal products, or those who are over 65
`years of age), administer Vivaglobin at the minimum rate practicable.
`Thrombotic Events
`Thrombotic events may occur with use of human immune globulin products.2-4 Patients at
`risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors,
`advanced age, impaired cardiac output, hypercoagulable disorders, prolonged periods of
`immobilization, and/or known or suspected hyperviscosity. Because of the potentially
`increased risk of thrombosis, consider baseline assessment of blood viscosity in patients
`at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/
`markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients
`judged to be at risk of developing thrombotic events, administer Vivaglobin at the minimum
`rate practicable.
`Hemolysis
`Vivaglobin may 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 (Coombs’) test result and hemolysis.6-8 Delayed hemolytic anemia can develop
`subsequent to immune globulin therapy due to enhanced RBC sequestration, and acute
`hemolysis, consistent with intravascular hemoylysis, has been reported.9
`Monitor recipients of Vivaglobin for clinical signs and symptoms of hemolysis. If these are
`present after Vivaglobin infusion, perform appropriate confirmatory laboratory testing. If
`transfusion is indicated for patients who develop hemolysis with clinically compromising
`anemia after receiving Vivaglobin, perform adequate cross-matching to avoid exacerbating
`on-going hemolysis.
`Transfusion-Related Acute Lung Injury (TRALI)
`Noncardiogenic pulmonary edema may occur in patients administered human immune
`globulin products.10 TRALI is characterized by severe respiratory distress, pulmonary
`edema, hypoxemia, normal left ventricular function, and fever. Typically, it occurs within
`1 to 6 hours following transfusion. Patients with TRALI may be managed using oxygen
`therapy with adequate ventilatory support.
`Monitor recipients of Vivaglobin for pulmonary adverse reactions. If TRALI is suspected,
`perform appropriate tests for the presence of anti-neutrophil antibodies in both the product
`and patient’s serum.
`5.4 Transmissible Infectious Agents
`Because Vivaglobin is made from human plasma, it may carry a risk of transmitting infectious
`agents, e.g., viruses and, theoretically, the Creutzfeldt-Jakob (CJD) agent. No cases of
`transmission of viral diseases or CJD have been associated with the use of Vivaglobin.
`Report all infections thought possibly to have been transmitted by Vivaglobin to the CSL
`Behring Pharmacovigilance Department at 1-866-915-6958 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch. The physician should discuss the risks and benefits of this
`product with the patient before prescribing or administering it to the patient (see Patient
`Counseling Information [17.2]).
`5.5 Laboratory Tests
`After infusion of IgG, the transitory rise of the various passively transferred antibodies in
`the patient’s blood may yield positive serological testing results, with the potential for
`misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g.,
`A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs’) test.
`6 ADVERSE REACTIONS
`The most common adverse reactions (those AEs considered by the investigator to be at least
`possibly related to Vivaglobin administration) observed in ≥5% of study subjects receiving
`Vivaglobin were local injection-site reactions (swelling, redness, and itching), headache,
`nausea, rash, asthenia, and gastrointestinal disorder.
`6.1 Clinical Studies Experience
`Because clinical studies are conducted under widely varying conditions,
`adverse reaction rates observed in the clinical trials of a drug cannot be
`directly compared to rates in the clinical trials of another drug and may not
`reflect the rates observed in practice.
`US-Canada Study
`The safety of Vivaglobin was evaluated in a clinical study in the US and Canada for 12
`
`Page 3 of 8
`
`

`

`months in 65 subjects with PI who had been previously treated with IGIV every 3 or 4
`weeks (see Clinical Studies [14.1]). After 3 months, subjects were switched from IGIV
`to weekly subcutaneous administration of Vivaglobin for 12 months. Subjects were treated
`weekly with Vivaglobin at a mean dose of 158 mg/kg body weight (range: 34 to 352 mg/
`kg). The 65 subjects received a total of 3,656 infusions of Vivaglobin.
`Table 2 shows the number of subjects who withdrew from the US-Canada study due to
`adverse events (AEs) and the AEs leading to discontinuation.
`Table 2:
`Subjects with Adverse Events (AEs) Leading to Discontinuation, US-
`Canada Study
`
`AEs
`
`Subjects with at
`least 1 AE leading to
`discontinuation
`
`Injection-site reaction
`
`Intestinal obstruction
`
`Hyperventilation
`
`Tachycardia
`
`Subjects with
`AEs At Least
`Possibly Related
`
`Subjects with AEs
`Irrespective of
`Causality
`
`Total Number
`(%) of Subjects
`
`4
`
`3
`
`–
`
`1*
`
`1*
`
`1
`
`–
`
`1
`
`–
`
`–
`
`5 (8%)
`
`3 (5%)
`
`1 (2%)
`
`1 (2%)
`
`1 (2%)
`
`* One subject experienced hyperventilation and tachycardia.
`Table 3 summarizes the most frequent AEs (experienced by more than 5% of subjects),
`irrespective of causality. It includes all AEs and those considered temporally associated
`with the Vivaglobin infusion, i.e., occurring during the infusion or within 72 hours after the
`end of the infusion.
`Table 3:
`Incidence of Subjects With Adverse Events (AEs)* (Experienced by
`>5% of Subjects) and Rate† per Infusion, Irrespective of Causality, in the
`US-Canada Study
`
`All AEs
`
`AEs Occurring During
`or Within 72 Hours of
`Infusion
`
`AEs*
`(>5% of Subjects)
`
`Number
`(%) of
`Subjects
`(n=65)
`
`Number
`(Rate†) of
`AEs per
`Infusion
`(n=3656)
`
`Number
`(%) of
`Subjects
`(n=65)
`
`AEs at the injection site‡
`
`60 (92%)
`
`1789 (0.49) 60 (92%)
`
`Other AEs
`Headache
`Gastrointestinal disorder
`Fever
`Nausea
`Rash
`Sore throat
`Allergic reaction
`Pain
`Diarrhea
`Cough increased
`Gastrointestinal pain
`Migraine
`Skin disorder
`Asthma
`Arthralgia
`Asthenia
`Malaise
`
`
`31 (48%)
`24 (37%)
`16 (25%)
`12 (18%)
`11 (17%)
`10 (15%)
`7 (11%)
` 6 (9%)
` 6 (9%)
` 6 (9%)
`5 (8%)
`5 (8%)
`5 (8%)
`5 (8%)
`4 (6%)
`4 (6%)
`4 (6%)
`
`
`159 (0.04)
`35 (0.01)
`28 (0.008)
`18 (0.005)
`22 (0.006)
`17 (0.005)
`8 (0.002)
`8 (0.002)
`6 (0.002)
`6 (0.002)
`6 (0.002)
`5 (0.001)
`7 (0.002)
`8 (0.002)
`4 (0.001)
`4 (0.001)
`5 (0.001)
`
`
`30 (46%)
`18 (28%)
`12 (8%)
`11 (17%)
`10 (15%)
`8 (12%)
`5 (8%)
`4 (6%)
`5 (8%)
`5 (8%)
`4 (6%)
`2 (3%)
`3 (5%)
`3 (5%)
`3 (5%)
`2 (3%)
`2 (3%)
`
`Number
`(Rate†) of
`AEs Per
`Infusion
`(n=3656)
`
`1767
`(0.4848)
`
`
`104 (0.033)
`24 (0.007)
`20 (0.005)
`15 (0.004)
`16 (0.004)
`11 (0.003)
`5 (0.001)
`4 (0.001)
`5 (0.001)
`5 (0.001)
`5 (0.001)
`2 (0.001)
`5 (0.001)
`4 (0.001)
`3 (0.001)
`2 (0.001)
`2 (0.001)
`
`* Excluding infections.
`† Rate, number of AEs per infusion.
`‡ Includes injection-site inflammation.
`The total number of AEs, irrespective of causality, including injection-site reactions, that
`began during or within 72 hours after the end of an infusion was 2262 (a rate of 0.62 AEs
`per infusion); excluding injection-site reactions, the rate of AEs per infusion was 0.14.
`Table 4 summarizes the severity of local AEs by infusion, irrespective of causality.
`
`Severity of Local Adverse Events (AEs) by Infusion, Irrespective of
`Table 4:
`Causality, in the US-Canada Study
`
`AEs
`(Number of infusions: 3656)
`
`Number (Rate*)
`of AEs
`
`Number (Rate*) of AEs
`Occurring During or
`Within 72 Hours of
`Infusion
`
`AEs at the injection site
`Mild†
`Moderate‡
`Severe§
`Unknown severity
`
`1789 (0.49)
`1112 (0.30)
`601 (0.16)
`65 (0.02)
`11 (<0.01)
`
`1767 (0.48)
`1100 (0.30)
`593 (0.16)
`64 (0.02)
`10 (<0.01)
`
`Discontinuations due to AEs at the
`injection site
`
`3 subjects
`
`* Rate, number of AEs per infusion.
`† Defined as those reactions that did not interfere with routine activities.
`‡ Defined as those reactions that interfered with routine activities.
`§ Defined as those reactions that made it impossible to perform routine activities.
`Of the three subjects who discontinued the study due to injection-site reactions, one
`withdrew on Day 1 (Infusion 1) of the wash-in/wash-out period after a moderate injection-
`site reaction and a mild headache; one withdrew on Day 22 (Infusion 4) of the wash-in/
`wash-out period following severe injection-site reactions for two weeks; and one withdrew
`on Day 78 following a mild injection-site reaction.
`Local reactions decreased substantially after repeated use.
`Table 5 summarizes the most frequent adverse reactions (experienced by at least 3% of
`subjects) and considered by the investigator to be at least possibly related to Vivaglobin
`administration.
`Incidence of Subjects With Adverse Reactions (Experienced in ≥3%
`Table 5:
`of Subjects) and Rate* Per Infusion in the US-Canada Study
`Number (Rate*) of
`Adverse Reactions
`per Infusion
`(n=3656)
`
`Related Adverse Reactions
`(≥3% Subjects)
`
`Number (%) of
`Subjects
`(n=65)
`
`Adverse reactions at the injection site†
`
`60 (92%)
`
`1787 (0.49)
`
`Other Adverse reactions
`Headache
`Nausea
`Rash
`Asthenia
`Gastrointestinal disorder
`Fever
`Skin disorder
`Tachycardia
`Urine abnormality
`
`21 (32%)
`7 (11%)
`4 (6%)
`3 (5%)
`3 (5%)
`2 (3%)
`2 (3%)
`2 (3%)
`2 (3%)
`
`59 (0.016)
`9 (0.002)
`9 (0.002)
`3 (0.001)
`3 (0.001)
`2 (0.001)
`3 (0.001)
`2 (0.001)
`3 (0.001)
`
`* Rate, number of adverse reactions per infusion.
`† Includes injection-site inflammation.
`Europe-Brazil Study
`In a clinical study conducted in Europe and Brazil, the efficacy and safety of Vivaglobin
`were evaluated for 10 months in 60 subjects with PI. Subjects were treated weekly with
`Vivaglobin at a mean dose of 89 mg/kg body weight (range: 51 to 147 mg/kg), which was
`101% of their previous weekly IGIV or IGSC dose (see Clinical Studies [14.2]). Study
`subjects received a total of 2,297 infusions of Vivaglobin.
`The AEs and their rates reported in this study were similar to those reported in the US-
`Canada study, with two exceptions: no episodes of headache were reported; and 18 (a rate
`of 0.008 per infusion) episodes of fever were judged to be related to the administration
`of Vivaglobin. One subject discontinued due to repeated local reactions of moderate
`severity.
`6.2 Postmarketing Experience
`Because postmarketing reporting of adverse reactions is voluntary and from
`a population of uncertain size, it is not always possible to reliably estimate
`the frequency of these reactions or establish a causal relationship to product
`exposure.
`Vivaglobin
`Adverse reactions identified during worldwide postmarketing use of Vivaglobin for
`treatment of PI are allergic-anaphylactic reactions (including dyspnea, pruritus, urticaria,
`rash, edema and other cutaneous reactions, wheezing, syncope, hypotension, and
`throat swelling), generalized reactions (including flu-like symptoms, myalgia, chills, fever,
`tachycardia, arthralgia, nausea and vomiting, diarrhea, gastrointestinal cramping, stomach
`pain, back pain, headache, headache possibly caused by increased blood pressure, and
`chest tightness), migraine, and injection-site reactions.
`
`Page 4 of 8
`
`

`

`General
`The following adverse reactions have been identified and reported during the postmarketing
`use of IGIV products11:
`• Renal: Acute renal dysfunction/failure, osmotic nephropathy
`• Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis,
`hypoxemia, pulmonary edema, dyspnea, bronchospasm
`• Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension
`• Neurological: Coma, loss of consciousness, seizures, tremor, aseptic meningitis
`syndrome
`• 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
`7 DRUG INTERACTIONS
`7.1 Live Virus Vaccines
`The passive transfer of antibodies with immunoglobulin administration may interfere with
`the response to live virus vaccines such as measles/mumps/rubella and varicella (see
`Patient Counseling Information [17.2]).
`7.2 Serological Testing
`Various passively transferred antibodies in immunoglobulin preparations may lead to
`misinterpretation of the results of serological testing.
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Pregnancy Category C. Animal reproduction studies have not been conducted with
`Vivaglobin. It is also not known whether Vivaglobin can cause fetal harm when administered
`to a pregnant woman or can