2.1 Dose

• Individualize the dose based on the patient’s pharmacokinetic and clinical response. Monitor serum IgG trough levels regularly to guide subsequent dose adjustments as needed (see Dose Adjustment ).
• Start CUTAQUIG treatment one week after the last Immune Globulin Intravenous (IGIV)/ Immune Globulin Subcutaneous (IGSC) infusion.

Dose for patients switching to CUTAQUIG from IGIV:

• Establish the initial weekly dose of CUTAQUIG by converting the monthly IGIV dose into an equivalent weekly dose and increasing it using a dose adjustment factor.
• To calculate the initial weekly dose of CUTAQUIG, divide the monthly IGIV dose in grams by the number of weeks between IGIV infusions and then multiply this value with a Dose Adjustment Factor of 1.30.

• To convert the dose (in grams) to milliliters (mL), multiply the calculated dose (in grams) by 6.
• Provided the total weekly dose is maintained, any dosing interval from daily up to weekly can be used and will result in systemic IgG exposure that is comparable to the previous IGIV treatment.
• For every other week dosing, multiply the calculated weekly CUTAQUIG dose by 2.
• For more frequent than weekly dosing (2-7 times a week) divide the calculated weekly CUTAQUIG dose by the desired number of infusions per week (e.g.: if you want to infuse CUTAQUIG 2 times per week, divide the weekly dose by 2).
• On average, serum IgG trough levels were approximately 23% higher during CUTAQUIG administration compared to those obtained during prior IGIV therapy.
• To guide dose adjustments, see Table 1 under Dose Adjustment .

Dose for patients switching to CUTAQUIG from IGSC:

• It is recommended to maintain the same weekly dosing (in grams) of CUTAQUIG that was used for the previous Immune Globulin Subcutaneous (Human) (IGSC) therapy (in grams).
• For every other week dosing, multiply the weekly dose by 2.
• For more frequent than weekly dosing (2-7 times a week) divide the weekly dose by the desired number of infusions per week (e.g.: if you want to infusion CUTAQUIG 2 times per week, divide the weekly dose by 2).
• To convert the dose (in grams) to milliliters (mL), multiply the calculated dose (in grams) by 6.
• Obtain a trough IgG level before switching, monitor clinical response and check the trough IgG level 2 to 3 months after initiating CUTAQUIG.
• To guide dose adjustments, see Table 1 under Dose Adjustment , if the trough IgG level during CUTAQUIG administration differs from the trough IgG level obtained during treatment with the previously administered IGSC product or target trough level.

Dose Adjustment:

Over time the dose may need to be individualized for each patient, depending on the pharmacokinetic and clinical response and on the desired IgG trough level. Measure the patient’s serum IgG trough level 2-3 months after switching to CUTAQUIG or after the last CUTAQUIG dose adjustment, in order to determine if a dose adjustment is necessary.

Calculate the difference between the patient’s target serum IgG trough level (in mg/dL) and the IgG trough level obtained during subcutaneous treatment with CUTAQUIG. Find this difference in column 1 of Table 1 and according to frequency of administration (weekly or every other week) locate the corresponding adjustment amount of CUTAQUIG in mL/administration according to the body weight of the patient.

For more frequent dosing than weekly or every other week, add the weekly increment from Table 1 to the weekly equivalent dose of the patient and then divide by the desired number of administrations per week.

Use the patient’s clinical response as the primary point to consider for any dose adjustment. Additional dose increments may be indicated based on the patient's clinical response (i.e., infection frequency and severity).

Table 1 Incremental adjustment (mL) of weekly or every other week CUTAQUIG dosing based on the calculated difference between actual IgG trough level and the target trough level for the patient*

* Derived from a linear regression model of trough levels and weekly dose per kg body weight.

For example: a patient with body weight of 70 kg is treated weekly and has a trough level of 600 mg/dL, but the target trough level is 900 mg/dL. The difference between the actual trough level (600) and the targeted trough level (900) is plus 300 mg/dL. Therefore, the recommended increase in the weekly dose would be approximately 49 mL.

A patient with a body weight of 50 kg, on an every other week dosing schedule and with an actual trough level of 900 mg/dL has a target trough level of 700 mg/dL. The difference between actual trough level (900) and targeted trough level (700) is minus 200 mg/dL, therefore the patient needs a decrease in his every other week dose of approximately 47 mL.

Monitor the patient’s clinical response and periodically check trough IgG levels, and repeat dose adjustment as needed.

Measles Exposure

If a patient has been exposed to measles, it may be prudent to administer a dose of Immune Globulin Intravenous as soon as possible and within 6 days of exposure. A dose of 400 mg/kg should provide a serum level > 240 mIU/mL of measles antibodies for at least two weeks.

If a patient is at risk of future measles exposure and receives a dose of less than 245 mg/kg subcutaneously per week, increase the dose to 245 mg/kg.

2.2 Preparation

CUTAQUIG is a clear and colorless solution that may turn to slightly opalescent and pale yellow during storage. Do not use the solution if it appears cloudy or contains particulates.

• Use aseptic technique when preparing and administering CUTAQUIG.
• Prior to administration visually inspect each vial of CUTAQUIG for particulate matter, whenever the solution and container permit.
• Do not mix CUTAQUIG with other products.
• Do not dilute CUTAQUIG.
• Do not shake the solution.
• Check the labeling for the expiration date and do not use beyond this date.
• CUTAQUIG vials are for single use only. Discard any unused product after each infusion in accordance with local requirements.
• Do not freeze. Do not use frozen product.
• Record lot number in patient’s medical history.

2.3 Administration

CUTAQUIG is for subcutaneous use only.

Administer CUTAQUIG by a healthcare provider, or by caregiver or self-administered by the patient after appropriate training.

Infuse CUTAQUIG in the following areas: abdomen, thigh, upper arm, and/or upper leg/hip area.

CUTAQUIG is intended for subcutaneous use using an infusion pump and compatible syringe(s).

Infuse CUTAQUIG simultaneously into up to 6 different sites. Infusion sites should be at least 2 inches (5 cm) apart. Rotate infusion sites between subsequent administrations.

Volume:

For patients not already on IGSC therapy, do not exceed the maximum initial volume per injection site of 25 mL/site for adults (≥17 years), 15 mL/site (for ages 7-16 years) and 10 mL/site (for ages 2-6 years) for the first 2 infusions.

For subsequent infusions, if tolerated, you may gradually increase infusion volume/site by approximately 10 mL per infusion site in adults (≥17 years) and by approximately 5-10 mL per infusion site in children (2-16 years) every 2-4 weeks.

The maximum infusion volume is 40 mL/site (for adults ≥17 years), 29 mL/site (for ages 7-16 years) and 15.5 mL/site (for ages 2-6 years).

Rate:

For patients not already on IGSC therapy, do not exceed the maximum recommended flow rates per hour per infusion site of 20 mL per hour per site for adults (≥17 years) and 15 mL per hour per site for children (2-16 years) for the first 2 infusions.

For subsequent infusions, if tolerated, you may gradually increase the infusion rate by approximately 10mL/hr/site in adults (≥17 years) and by approximately 5-10 mL/hr/site in children (2-16 years) every 2-4 weeks.

The maximum infusion rate is 52 mL per hour per site for adults (≥17 years) and 25 mL per hour per site for children (2-16 years).

Table 2 Infusion Volumes and Infusion Rates (Infusion rate and infusion volume per site may gradually be increased every 2-4 weeks as tolerated by patients)

* As tolerated

Administration/Handling instructions

CUTAQUIG is for subcutaneous use only.

Follow the administration guidance below and use aseptic technique when administrating CUTAQUIG.

Figure 1	1. Getting ready for infusion - Choose and prepare a clean work area. - Gather your infusion equipment: Infusion pump and compatible syringe(s). Needle or needleless transfer device (for drawing up product from the vial). Infusion set (varies according to manufacturer’s instructions). Infusion tubing and Y-connector (if required). Ancillary supplies: disinfectant wipes, gauze or transparent dressing, tape and sharps container. Patient’s treatment diary/log book. - Wash your hands thoroughly and let them dry ( Figure 1 ).
Figure 2	2. Checking and opening the vials - If taken out of the refrigerator, allow products to reach room temperature (≤ 25°C / 77°F). - Inspect each vial carefully: Check that labelled dose is correct and based on prescription. Check that the expiration date has not been passed. Check the appearance of the solution: do not use the solution if it is cloudy or contains particles. Make sure the protective cap is not broken or missing. - Remove the protective cap. - Disinfect the rubber stopper by using a sterile wipe and allow it to dry ( Figure 2).
Figure 3	3. Preparing and filling the syringe - Open sterile syringe and needle or needleless transfer device. - If a needleless transfer device is used, follow the instructions of the device manufacturer. - If the transfer is done using needle and syringe follow the instructions below: Attach the needle to the syringe with a screw action. Draw back on the plunger to fill the syringe with air which should be roughly equal to the amount of solution needed from the vial. Insert the needle into the center of the vial stopper and turn the vial upside down. To avoid foaming, ensure that the tip of the needle is not in the solution, and then inject the air. Next, move the needle so that the tip is in the solution, and then slowly draw up the desired volume of CUTAQUIG ( Figure 3 ). Withdraw the needle from the vial. This procedure might be repeated if you need to use more than one vial. When finished, remove the needle and dispose of it into the sharps bin and proceed to the next step.
Figure 4	4. Preparing the infusion pump and tubing - Follow the manufacturer’s instructions for preparing the infusion pump. - Prime the administration tubing according to manufacturer’s instruction to eliminate all remaining air ( Figure 4 ). - Stop priming before fluid reaches the needle tip.
Figure 5	5. Preparing the infusion site(s) and inserting the infusion needle(s) - CUTAQUIG can be infused in the following areas: abdomen, thigh, upper arm, and/or upper leg/hip area ( Figure 5 ). - The number and location of injection sites depends on the volume of the total dose. The infusion sites should be at least 2 inches apart. A maximum of 6 infusion sites can be used simultaneously. - Rotate sites between infusions. - Avoid inserting the needle into scars, tattoos or injured/inflamed skin areas and inspect skin for signs of infection. - Clean your skin at your selected infusion site(s) with an antiseptic skin wipe starting at the center and working outward in a circular motion, and allow each site to dry before proceeding.
Figure 6	- Pinch the skin between your thumb and forefinger around the injection site ( Figure 6 ) and insert the needle into the subcutaneous tissue ( Figure 7 ). The angle of the needle will depend on the type of infusion set being used.
Figure 7
Figure 8	- Secure the needle in place by applying sterile gauze and tape or transparent dressing ( Figure 8 ).

6. Checking the infusion

- Check needle placement by pulling back on the syringe plunger. There should not be any blood return in the tubing.

- If blood return is seen, remove needle and restart from step 5 with new tubing at a different location.

7. Starting the infusion

- Start the infusion. Follow infusion pump manufacturer’s instructions.

8. Recording the infusion

- On each vial of CUTAQUIG, you will find a peel-off portion of the label with the batch number details. Stick this label in your patient’s treatment diary or infusion log book. Record details of the dose, date, time, infusion site location and any infections, side effects or other comments.

9. After infusion is complete

- Gently remove the needle(s) and immediately place into the sharps bin.

- If necessary, press a small piece of gauze on the needle site and apply a dressing.

- Discard all used disposable supplies as well as any unused product and the empty vial(s) as recommended by your healthcare provider and according to local requirements.

- Clean and store the infusion pump according to the manufacturer’s instructions.

For self-administration, provide the patient and caregiver with instructions and appropriate training for infusion at home or other appropriate setting. Verify that the patient or caregiver is capable of self-administration or administration, respectively, using appropriate technique.

5.1 Hypersensitivity

Severe hypersensitivity reactions may occur with CUTAQUIG, even in patients who tolerated previous treatment with human immune globulin. If a hypersensitivity reaction occurs, discontinue the CUTAQUIG infusion immediately and initiate appropriate treatment. Have epinephrine immediately available to treat any severe acute hypersensitivity reaction.

IgA-deficient patients with known anti-IgA antibodies have a higher risk of developing potentially severe hypersensitivity and/or anaphylactic reactions (including anaphylaxis and shock) with administration of CUTAQUIG. CUTAQUIG contains on average 0.206 mg of IgA /mL.

5.2 Thrombosis

Thrombosis may occur following treatment with immune globulin products, including CUTAQUIG. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in absence of known risk factors.

Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, such as those with cryoglobulins, fasting chylomicronemia/markedly high triglycerides, or monoclonal gammopathies. For patients at risk of thrombosis, administer CUTAQUIG at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. [see WARNING , Patient Counseling Information ( 17 )]

5.3 Falsely Elevated Glucose Readings

Blood Glucose Testing: Some types of blood glucose testing systems (for example, those based on the glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase methods) falsely interpret the maltose contained in CUTAQUIG as glucose. This may potentially result in falsely elevated glucose readings and, consequently, in the inappropriate administration of insulin, resulting in life-threatening hypoglycemia. Also, cases of true hypoglycemia may go untreated if the hypoglycemic state is masked by falsely elevated glucose readings. Accordingly, when administering CUTAQUIG, measure blood glucose with a glucose-specific method. The product information of the blood glucose testing system, including that of the test strips, should be carefully reviewed to determine if the system is appropriate for use with maltose-containing parenteral products. If any uncertainty exists, contact the manufacturer of the testing system to determine if the system is appropriate for use with maltose-containing parenteral products.

5.4 Aseptic Meningitis Syndrome (AMS)

Aseptic Meningitis Syndrome can occur with CUTAQUIG. AMS has been reported after the use of human immune globulin administered intravenously and subcutaneously. It usually begins a few hours to 2 days following treatment and occurs more frequently in females than in males.

AMS is characterized by the following signs and symptoms: 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 mm 3 , predominantly from the granulocytic series, and elevated protein levels up to several hundred milligram/dL, but negative culture results. To rule out other causes of meningitis, conduct a thorough neurological examination on patients showing such symptoms and signs, including CSF studies. Discontinuation of immunoglobulin treatment has resulted in remission of AMS within several days without sequelae.

5.5 Renal Dysfunction/Failure

Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis and death may occur with use of human immune globulin, especially those containing sucrose. CUTAQUIG does not contain sucrose. Ensure that patients are not volume-depleted before administration of CUTAQUIG.

In patients at risk of developing renal dysfunction because of any degree of preexisting renal insufficiency or predisposition to acute renal failure (such as diabetes mellitus, age greater than 65 years, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs) monitor renal function and consider lower, more frequent dosing [see Dosage and Administration ( 2 ), Patient Counseling Information ( 17 )].

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. Assess renal function, including measurements of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of CUTAQUIG and again at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing CUTAQUIG.

5.6 Hemolysis

IgG products, including CUTAQUIG, can contain blood group antibodies that may act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin (Coombs’) test result. Delayed hemolytic anemia can develop subsequent to immune globulin therapy due to enhanced RBC sequestration, and acute hemolysis, consistent with intravascular hemolysis, has been reported.

Monitor CUTAQUIG recipients for clinical signs and symptoms of hemolysis, particularly patients with risk factors (such as non-O blood group, administration of high IgG doses (≥ 2g/kg BW)). Underlying inflammatory state in a patient may increase the risk of hemolysis but its role is uncertain. Consider appropriate confirmatory laboratory testing if signs and symptoms of hemolysis are present after CUTAQUIG infusion.

5.7 Transfusion-related Acute Lung Injury (TRALI)

Non-cardiogenic pulmonary edema may occur in patients administered human immune globulin products. 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.

Monitor patients 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. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support.

5.8 Transmittable Infectious Agents

Because CUTAQUIG is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. This also applies to unknown or emerging viruses and other pathogens. No cases of transmission of viral diseases or CJD have been associated with the use of CUTAQUIG. All infections suspected by a physician to have possibly been transmitted by CUTAQUIG should be reported to Octapharma USA Inc. at 1-866-766-4860.

5.9 Interference with Laboratory Tests

After infusion of CUTAQUIG, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield false positive serological test 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.

6.1 Clinical Trials Experience

Because clinical trials 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.

Clinical safety data are based on one pivotal open-label, single arm, prospective, multicenter major effectiveness study of CUTAQUIG in subjects with primary humoral immunodeficiency (PI), previously treated with Immune Globulin Intravenous (Human) (IGIV) for at least 6 months and its extension study. The pivotal study was conducted in Europe and North America and was followed by an extension safety study (prospective, open-label, single-arm, multicenter phase 3). 21 patients were initially treated in the pivotal study and 6 patients from Canada were newly treated. Total number of patients in both studies combined was 81.

In the pivotal study, the 75 subjects in the Safety Analysis Set received 4462 infusions, with a mean of 59 infusions administered per subject. The average dose of CUTAQUIG used per subject was 0.187 g/kg in adult subjects, 0.150 g/kg in young children, 0.164 g/kg in older children and 0.170 g/kg in adolescents.

In the extension study, the 27 subjects in the Safety Analysis Set received 2777 infusions. The average dose of CUTAQUIG used per subject was 0.166 g/kg in adult subjects, 0.127 g/kg in young children, 0.210 g/kg in older children and 0.160 g/kg in adolescents.

Excluding infections, a total of 74 out of 81 subjects (91%) experienced 1527 adverse reactions (ARs, defined as adverse events occurring during or within 72 hours of infusion or any adverse events otherwise causally related) in both studies. Of the 1527 ARs 1088 were infusion site reactions. The proportion of infusions with adverse reactions was 0.21. Sixty-one subjects (75%) had at least one systemic AR.

Local reactions were the most common ARs and were experienced by 59 subjects (73%). The rate of infusion site reaction per infusion was 0.15. Most local ARs were either mild (transient AR causing discomfort but not interfering with routine activities [87.5%]) or moderate (AR sufficiently discomforting to interfere with routine activities [10.3%]) in intensity.

Table 3 and Table 4 summarize adverse reactions occurring in ≥ 5% of adult subjects and pediatric subjects in both the pivotal and the extension study.

Table 3 Adverse reactions* in ≥ 5% of adult subjects and rate per infusion in adult subjects (pivotal and extension study)

* Excluding infections.

** Rate = total number of adverse reactions divided by total number of infusions.

Table 4 Adverse reactions* in ≥ 5% pediatric subjects and rate per infusion in pediatric subjects (pivotal and extension study)

* Excluding infections.

** Rate = total number of adverse reactions divided by total number of infusions.

The most frequent infusion site reactions were redness, swelling, and itching. During the pivotal study period the incidence of local reactions decreased over time from 37% of infusions triggering an infusion site reaction during the first 4 infusions to around 16% of infusions with an infusion site reaction during the last 4 infusions.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of immune globulin products administered subcutaneously. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Table 5 summarizes adverse reactions that have been reported during post-marketing use of immune globulin products:

Table 5 Adverse reactions reported during post-marketing use of immune globulin products

The following adverse reactions have been identified during post-approval use of CUTAQUIG: dizziness, nausea, pruritus and fatigue. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

To report SUSPECTED ADVERSE REACTIONS, contact Octapharma USA Inc. at 1-866-766-4860 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7.1 Serological Testing

Various passively transferred antibodies in immunoglobulin preparations may lead to misinterpretation of results of serological testing.

7.2 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. Inform the immunizing medical practitioner of recent therapy with CUTAQUIG so that appropriate precautions can be taken. [See Patient Counselling Information ( 17 )]

8.1 Pregnancy

Risk Summary

No human data are available to indicate the presence or absence of drug-associated risk. Animal reproduction studies have not been conducted with CUTAQUIG. It is not known whether CUTAQUIG can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Immune globulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation

Risk summary

No human data are available to indicate the presence or absence of drug associated risk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CUTAQUIG and any potential adverse effects on the breastfed infant from CUTAQUIG or from the underlying maternal condition.

8.4 Pediatric Use

The safety and efficacy of CUTAQUIG have been established for primary humoral immunodeficiency in the pediatric age group 2 to 16 years CUTAQUIG was evaluated in 38 pediatric subjects with primary humoral immunodeficiency (26 children and 12 adolescents) in the pivotal and extension studies. [see Clinical Studies ( 14 )]

Overall safety and efficacy findings in pediatric age group were comparable to those seen in adults. However, infusion site reactions were more commonly observed in adults compared to the pediatric population.

PK parameters are comparable between pediatric and adult patients. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels.

Safety and effectiveness of CUTAQUIG in pediatric patients below the age of 2 have not been established.

8.5 Geriatric Use

Clinical studies of CUTAQUIG did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Three study subjects enrolled in the clinical trial were 65 years and over. In general, dose selection for an elderly patient should be cautious. Medical practitioners should start at the low end of the dosing range to reduce the risk of hyperviscosity and precipitation of cardiac, renal, or hepatic adverse reaction and of concomitant disease or other drug therapy.

12.1 Mechanism of Action

CUTAQUIG supplies a broad spectrum of opsonizing and neutralizing Immunoglobulin G (IgG) antibodies against a wide variety of bacterial and viral agents. It has a distribution of immune globulin subclasses closely proportional to that in native human plasma. The mechanism of action in primary humoral immunodeficiency (PI) has not been fully elucidated; however adequate doses may restore abnormally low immune globulin G levels to the normal range and thus help in preventing infections.

12.2 Pharmacodynamics

CUTAQUIG contains mainly IgG with a broad spectrum of antibodies against various infectious agents reflecting the IgG activity found in the donor population. CUTAQUIG which is prepared from pooled material from not less than 1000 donors, has an IgG subclass distribution similar to that of native human plasma. Adequate doses of Immune Globulin Subcutaneous (Human) (IGSC) can restore an abnormally low IgG level to the normal range. Standard pharmacodynamic studies were not performed.

12.3 Pharmacokinetics

A pharmacokinetic (PK) sub-study was conducted in 37 subjects (18 adults and 19 pediatric subjects) who were enrolled in the pivotal safety and efficacy study. Blood samples for PK study were collected prior to switching to CUTAQUIG (IGIV profile: PK IV ), after the 11 th infusion of CUTAQUIG (first SC profile: PK SC1 ) and after the 28th infusion of CUTAQUIG (second SC profile: PK SC2 ). The objective of the PK sub-study was to compare the AUCs following the IV and SC administration. At steady state, the ratio of geometric least square means (SC2:IV) was 1.06, (90% CI: 1.03, 1.10), indicating comparable exposure between IGSC and IGIV treatment (standardized to a 7-day period). The actual dose converting factor was 1.41 (1.21, 1.89). Using a Population PK model calculation, the DCF was determined in a statistically more advanced manner at 1.33 for a median patient.

Serum IgG and IgG subclass trough levels were nearly constant during the IGSC phase of the study, with higher mean levels after SC treatment compared with those following IGIV. At the end of the IGIV period, trough levels ranged from 5.0 g/L to 15.1 g/L. Over the entire IGSC treatment period individual trough levels of total IgG ranged between 4.4 g/L to 24.0 g/L.

Table 7 summarizes the Key PK parameters for CUTAQUIG. PK parameters are comparable between pediatric and adult patients.

Table 7 Key Pharmacokinetic Parameters for CUTAQUIG and IGIV

# T max is presented as Median (range)

* standardized to a 7-day period

+ apparent clearance (CL/F) for CUTAQUIG (F = bioavailability)

Compared with weekly administration, administration of CUTAQUIG on a every other week basis at double the weekly dose is expected to result in comparable IgG exposure [equivalent AUCs, with a slightly higher IgG peak (Cmax) and slightly lower trough (Cmin)] in both adult and pediatric subjects. In addition, for the same total weekly dose, CUTAQUIG infusions given 2, 3, 5, or 7 times per week (frequent dosing) are expected to produce IgG exposures comparable to weekly dosing in both adult and pediatric subjects.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies were conducted with CUTAQUIG to assess carcinogenesis, mutagenesis or impairment of fertility.

13.2 Animal Toxicology and/or Pharmacology

Safety of CUTAQUIG has been demonstrated in several standard nonclinical toxicology studies (local tolerance in rabbits, cardiovascular and respiratory effects in dogs, thrombogenic potential in rabbits).

The product given subcutaneously to CD1 mice inoculated with Streptococcus pneumoniae showed a dose related improvement in survival.

TNBP and Octoxynol may be found in CUTAQUIG in trace amounts. In animals and in vitro studies, these compounds were not genotoxic and did not have mutagenic properties. They did not show teratogenic effects when administered to pregnant rabbits and rats during organogenesis.