CUVITRU Solution for injection Ref.[27466] Active ingredients: Human normal immunoglobulin G

5.1 Hypersensitivity

Severe hypersensitivity reactions may occur, even in patients who had tolerated previous treatment with human immune globulin. If a hypersensitivity reaction occurs, discontinue CUVITRU infusion immediately and institute appropriate treatment.

CUVITRU contains trace amounts of IgA (average concentration of 80 mcg/mL). Patients with known antibodies to IgA have a greater risk of developing potentially severe hypersensitivity reactions, including anaphylaxis, with administration of CUVITRU.

5.2 Renal Dysfunction/Failure

Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis, and death may occur upon use of immune globulin treatment, especially those containing sucrose^3,4. CUVITRU does not contain sucrose. Ensure that patients are not volume depleted prior to the initiation of infusion of CUVITRU. In patients who are at risk of developing renal dysfunction because of pre-existing renal insufficiency or predisposition to acute renal failure (such as diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs), monitor renal function and consider lower, more frequent dosing [See Dosage and Administration (2.1)].

Periodic monitoring of renal function and urine output is particularly important in patients predisposed to be at increased risk for developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of CUVITRU and again at appropriate intervals thereafter. If renal function deteriorates, consider discontinuation of CUVITRU [See Dosage and Administration (2.3)].

5.3 Thrombosis

Thrombosis may occur following treatment with immune globulin products^5,6. 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 the absence of known risk factors.

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 at risk of thrombosis, administer CUVITRU 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 Boxed Warning, Dosage and Administration (2.1), Patient Counseling Information (17)].

5.4 Aseptic Meningitis Syndrome (AMS)

AMS has been reported with the use of immune globulin, including CUVITRU [See Postmarketing Experience (6.2)]. The syndrome usually begins within several hours to two days following immune globulin treatment. AMS may occur more frequently in female patients.

AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea and vomiting [See Patient Counseling Information (17)] Cerebrospinal fluid (CSF) studies frequently reveal 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. Conduct a thorough neurological examination, including CSF studies, on patients exhibiting such signs and symptoms, to rule out other causes of meningitis. Discontinuation of treatment has resulted in remission of AMS within several days without sequelae.

5.5 Hemolysis

CUVITRU can contain blood group antibodies that may act as hemolysins and induce in vivo coating of red blood cells (RBC) with immune globulin. This may cause a positive direct antiglobulin test [DAT (Coomb’s test)]^7,8. Delayed hemolytic anemia can develop subsequent to CUVITRU therapy due to enhanced RBC sequestration; acute hemolysis, consistent with intravascular hemolysis, can occur^7-11.

The following risk factors may be related to the development of hemolysis: high doses (e.g., ≥2 grams/kg, single administration or divided over several days) and non-O blood group^7,11. Underlying inflammatory state in an individual patient may increase the risk of hemolysis⁷ but its role is uncertain ^10,12.

Monitor patients for clinical signs and symptoms of hemolysis, particularly patients with risk factors noted above. Consider appropriate laboratory testing in higher risk patients, including measurement of hemoglobin or hematocrit prior to infusion and within approximately 36 to 96 hours post infusion.

5.6 Transfusion-Related Acute Lung Injury (TRALI)

Non-cardiogenic pulmonary edema (TRALI) has been reported in patients following treatment with immune globulin products. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically occur within 1 to 6 hours after treatment.

Monitor patients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil and anti-HLA antibodies in both the product and patient serum. TRALI may be managed using oxygen therapy with adequate ventilatory support.

5.7 Transmissible Infectious Agents

Because CUVITRU is made from human blood, 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 agent. This also applies to unknown or emerging viruses and other pathogens. No confirmed cases of viral transmission or vCJD have been associated with CUVITRU.

All infections thought by a physician to possibly have been transmitted by this product should be reported by the physician or other healthcare provider to Takeda Pharmaceuticals U.S.A., Inc., at 1-877-TAKEDA7 (1-877-825-3327).

5.8 Monitoring: Laboratory Tests

• Periodic monitoring of renal function and urine output is particularly important in patients predisposed to be at increased risk of developing acute renal failure. Assess renal function, including measurement of BUN and serum creatinine, before the initial infusion of CUVITRU and at appropriate intervals thereafter.
• 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, because of the potentially increased risk of thrombosis^3,5.
• If signs and/or symptoms of hemolysis are present after an infusion of CUVITRU, perform appropriate laboratory testing for confirmation.
• If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies and anti-HLA antibodies in both the product and patient’s serum.

5.9 Interference with Laboratory Tests

• After infusion of IgG, 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.
• Administration of CUVITRU can lead to false positive readings in assays that depend on detection of beta-D-glucans for diagnosis of fungal infections; this may persist during the weeks following infusion of the product.

The most common adverse reactions observed in ≥5% of subjects were: local adverse reactions, systemic adverse reactions including headache, nausea, fatigue, diarrhea, and vomiting.

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 clinical practice.

CUVITRU was administered subcutaneously in two prospective, open-label, non-controlled, multi-center studies to evaluate efficacy, safety, tolerability, and pharmacokinetics in subjects with primary immunodeficiency (PI). One study was performed in North America and the other was performed in Europe.

North American Study

In a clinical study conducted in North America, 67 out of 74 subjects treated with CUVITRU completed the study including 20/21 subjects aged 2 to <16 years old. Of the 7 subjects that discontinued treatment with CUVITRU, one subject withdrew due to fatigue (assessed as not related), 1 subject withdrew because of non-compliance, and 5 subjects withdrew for personal reasons.

A total of 4327 CUVITRU infusions were administered during the clinical study. No serious adverse reactions occurred during treatment with CUVITRU; 278 non-serious adverse reactions occurred at a rate per infusion of 0.06. Among the 4327 CUVITRU infusions, 99.3% (276/278) of adverse reactions were mild or moderate and transient in nature. Of the 278 non-serious adverse reactions (excluding infections), 83% (231/278) were rated as mild, 16% (45/278) were rated as moderate, and 1% (2/278, hemoptysis and abdominal pain) were severe.

Adverse reactions occurring in ≥5% of subjects (defined as adverse events occurring during or within 72 hours of infusion or any causally related event occurring within the study period) are shown in Table 3. No subject discontinued treatment due to local adverse reactions.

Table 3. Adverse Reactions* in ≥5% of Subjects Associated with Infusions of CUVITRU:

^* Excluding infections
^† Number and percentages of affected subjects
^‡ Rate = Total number of adverse reactions divided by the total number of infusions under treatment

Systemic adverse reactions to immune globulin intravenous in part 1 of the study occurred at a rate of 0.302 relative to a rate of 0.042 during treatment with CUVITRU. The CUVITRU systemic adverse reaction rate was approximately 7-fold lower than the immune globulin intravenous rate.

Local Adverse Reactions

The most frequent local adverse reactions are listed by frequency in Table 4. Of the total 96 local adverse reactions, 100% were either mild (92.5%) or moderate (7.5%) in severity. No severe local adverse reactions were reported. During the clinical study, no local adverse reactions were observed in 68.9% (51/74) of subjects and in 98.2% (4247/4327) of infusions. The overall rate of local adverse reactions (excluding infections) during the clinical study was 0.022 (0.021 mild and 0.002 moderate). The rate of local adverse reactions was not associated with increased rate of infusion or volume per site.

Table 4. Most Frequent Local Adverse Reactions Reported in ≥5% of Subjects:

^* Number and percentages of affected subjects
^† Rate= Total number of adverse reactions divided by the total number of infusions under treatment

European Study

Efficacy and safety during treatment with CUVITRU were evaluated in 48 subjects in a clinical trial in Europe. CUVITRU was administered for a median treatment duration of 358 days (range: 127.0-399 days) and a mean (± SD) of 347.4 ± 47.9 days. CUVITRU treatment: 45/48 subjects treated with CUVITRU completed the study, including 23/25 subjects aged 2 to <18 years old.

A total of 2349 CUVITRU infusions were administered during this clinical study. No serious adverse reactions occurred during treatment with CUVITRU. In total, 176 local adverse reactions and 205 systemic adverse reactions were reported (adverse reaction defined as adverse events occurring during or within 72 hours of infusion or any causally related event occurring within the study period), excluding infections. Of the 205 systemic reactions, the majority (134) were mild, 70 were moderate and one event was severe (headache, assessed as temporally associated, not causally related). The rate of systemic adverse reactions (excluding infections) during treatment with CUVITRU was 0.087, and the rate of related systemic AEs (excluding infections) per infusion was 0.032. During treatment with IGIV 10% in study part 1, the rate of related systemic AEs (excluding infections) was 0.173 events per infusion. The CUVITRU related systemic adverse event rate was approximately 5-fold lower than the immune globulin intravenous rate.

Table 5. EU Study: Adverse Reactions* in ≥5% of Subjects Associated with Infusions of CUVITRU:

^* Causally Related and/or Temporally Associated (Within 72 Hour) AEs (Excluding Infections)
^† Total number of affected subjects divided by the total number of subjects under treatment
^‡ Total number of AEs divided by the total number of infusions under treatment

Local Adverse Reactions

Among the 176 local adverse reactions in total (adverse reaction defined as adverse events occurring during or within 72 hours of infusion or any causally related event occurring within the study period), none was severe. In total, 175 adverse reactions (99.4%) were mild, and 1 adverse reaction (0.6%) was moderate. The overall rate of local adverse reactions was 0.075 per infusion. The most common reactions (by subject) were infusion site pain, infusion site erythema and infusion site pruritus.

Table 6. EU Study: Most Frequent Local Adverse Reactions Reported in ≥5% of Subjects:

^* Number and percentages of affected subjects
^† Rate= Total number of adverse reactions divided by the total number of infusions under treatment

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.

In addition to the adverse reactions listed above in clinical trials, the following adverse reactions have been reported in the post-marketing experience:

Infections and Infestations: Meningitis aseptic

Postmarketing Experience of Immune Globulin Products

The following adverse reactions have been identified and reported during the postmarketing use of immune globulin products administered subcutaneously:

Immune system disorders: Anaphylactic reaction

Cardiac disorders: Tachycardia

Nervous system disorders: Tremor and paresthesia

Respiratory, Thoracic and Mediastinal disorders: Dyspnea and laryngospasm

General disorders and administration site conditions: Injection site reaction (such as induration and warmth) and chest discomfort

Passive transfer of antibodies may transiently impair the immune responses to live attenuated virus vaccines such as mumps, rubella and varicella for up to 6 months and for a year or more to measles (rubeola). Inform the immunizing physician of recent therapy with CUVITRU so that appropriate precautions can be taken [See Patient Counseling 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 CUVITRU. It is also not known whether CUVITRU can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Immune globulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation. CUVITRU should be given to a pregnant woman only if clearly indicated. 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 CUVITRU and any potential adverse effects on the breastfed infant from CUVITRU or from the underlying maternal condition.

CUVITRU was evaluated in 21 pediatric subjects with PI (2 to 16 years of age) in a multicenter clinical study. The safety and efficacy profiles were similar to adult subjects. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels.

Safety and effectiveness of CUVITRU has not been evaluated in neonates or infants <2 years old.

CUVITRU was evaluated in 9 subjects over the age of 65 years in a multicenter clinical study. No differences in safety or efficacy were observed for this group, when compared to the rest of the study population.

Monitor patients who are at an increased risk for developing renal failure or thrombotic events. Do not exceed the recommended dose, and infuse at the minimum infusion rate practicable [See Boxed Warning, Warnings and Precautions (5.2, 5.4) and Dosage and Administration (2.3)].