CUTAQUIG Solution for infusion Ref.[10790] Active ingredients: Human normal immunoglobulin G

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 ≤0.6 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 mm³, 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 Pfizer Inc. at 1-800-438-1985.

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.

The most common adverse reactions (AR) observed in ≥ 5% of study subjects were local infusion site adverse reactions (such as redness, swelling, and itching), and, as systemic adverse reactions, headache, fever, diarrhea, dermatitis, asthma, and skin abrasion.

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 an 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. This study was conducted in Europe and North America.

Overall, the 61 subjects in the Safety Analysis Set received 3497 infusions in the study, with a mean of 57 infusions administered per subject. The average dose of CUTAQUIG used per subject was 0.185 g/kg in adult subjects, 0.135 g/kg in young children, 0.160 g/kg in older children and 0.172 g/kg in adolescents.

Excluding infections, a total of 50 subjects (82%) experienced 950 adverse reactions (ARs, defined as adverse events occurring during or within 72 hours of infusion or any adverse events otherwise causally related). Of the 950 ARs 814 were infusion site reactions. Forty-three subjects (70.5%) had at least one systemic AR. The proportion of infusions with adverse reactions was 0.27.

Local reactions were the most common ARs and were experienced by 46 subjects (75.4%). The rate of infusion site reaction per infusion was 0.23. Most local ARs were either mild (transient AR causing discomfort but not interfering with routine activities [89.4%]) or moderate (AR sufficiently discomforting to interfere with routine activities [10.3%]) in intensity.

Table 3 summarizes adverse reactions occurring in ≥5% of subjects (defined as adverse events occurring during or within 72 hours of infusion or any adverse events otherwise considered causally related event occurring within the study period).

Table 3. Adverse reactions* in ≥5% of subjects and rate per infusion:

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

In the study, the most frequent infusion site reactions were redness, swelling, and itching. During the study period the incidence of local reactions decreased over time from 38% of infusions triggering an infusion site reaction during the first 4 infusions to around 15% of infusions with an infusion site reaction during the last 4 infusions.

There is no post-marketing experience with CUTAQUIG. The following adverse reactions have been identified during post-approval use of immune globulins. 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 4 summarizes adverse reactions that have been reported during post-marketing use of immune globulin products and may also occur after CUTAQUIG administration.

Table 4. Adverse reactions reported during post-marketing use of immune globulin products:

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 physician of recent therapy with CUTAQUIG so that appropriate precautions can be taken [See Patient Counselling Information (17)].

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.

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.

The safety and efficacy of CUTAQUIG have not been established in patients under 17 years of age. There are only limited data available on the safety and efficacy of CUTAQUIG administration in pediatric patients. CUTAQUIG was evaluated in 23 pediatric subjects (15 children, 8 adolescents) with primary humoral immunodeficiency (PI).

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, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.