2.1 Preparation and Handling

• Inspect the drug product visually for particulate matter and discoloration prior to administration. CUVITRU is a clear and colorless or pale yellow or light brown solution and clear of particulate matter. Do not use if the solution is cloudy, turbid, or if it contains particulates.
• Do not mix CUVITRU with other products.
• Do not shake.
• Do not dilute.
• CUVITRU comes in a single-dose vial. Any vial that has been entered should be used promptly. Partially used vials should be discarded. CUVITRU contains no preservative.
• Record the name and lot number of the product in the recipient's records.

2.2 Dose

• CUVITRU can be administered at regular intervals from daily up to every two weeks (biweekly).
• Individualize the dose based on the patient's pharmacokinetic and clinical response.
• Monitor serum IgG trough levels regularly to guide subsequent dose adjustments and dosing intervals as needed (see Dose Adjustment).

For patients switching from Immune Globulin Intravenous (Human) treatment (IGIV) or adult patients switching from HYQVIA [Immune Globulin Infusion 10% (Human) with Recombinant Human Hyaluronidase]:

• Begin treatment with CUVITRU one week after the patient's last IGIV or HYQVIA infusion.
• Establish the initial weekly dose by converting the monthly IGIV or HYQVIA dose into an equivalent weekly dose and increasing it using a dose adjustment factor.
• To calculate the initial weekly dose, divide the previous IGIV or HYQVIA dose in grams by the number of weeks between intravenous doses; then multiply this dose by the dose adjustment factor of 1.30.

  Initial Weekly dose =	Previous IGIV or HYQVIA dose (in grams)	× 1.30
  	Number of weeks between IGIV or HYQVIA doses

• To convert the dose (in grams) to milliliters (mL), multiply the calculated dose (in grams) by 5.
• Doses divided over the course of a week, or once weekly, or biweekly, achieve similar exposure when administered regularly at steady-state.
• To determine the dose for alternative regular dosing intervals:

  ‒

  Frequent dosing (2-7 times per week): Divide the calculated weekly dose by the desired number of times per week.

  ‒

  Biweekly dosing: Multiply the calculated weekly dose by 2.

To guide dose adjustments, see section Dose Adjustments (Table 1).

For patients switching from Immune Globulin Subcutaneous (Human) treatment (IGSC):

• The weekly dose of CUVITRU (in grams) is recommended to be the same as the weekly dose of prior IGSC treatment (in grams).
• Doses divided over the course of a week, once weekly, or biweekly, achieve similar exposure when administered regularly at steady-state.
• To determine the dose for alternative regular dosing intervals:

  ‒

  Frequent dosing (2-7 times per week): Divide the calculated weekly dose by the desired number of times per week.

  ‒

  Biweekly dosing: Multiply the calculated weekly dose by 2.

• To convert the dose (in grams) to milliliters (mL), multiply the calculated dose (in grams) by 5.

To guide dose adjustments, see section Dose Adjustments (Table 1).

For patients at risk for 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 CUVITRU of less than 230 mg/kg subcutaneously per week, the dose should be increased to at least 230 mg/kg per week, or the weekly equivalent of 230 mg/kg for dosing intervals other than weekly.

2.3 Administration

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 sucrose3,4. 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 occur7-11.

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 group7, 11. Underlying inflammatory state in an individual patient may increase the risk of hemolysis7 but its role is uncertain10,12.

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-TAKEDA-7 (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 thrombosis3,5.
• 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.

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 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.

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.

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: Aseptic meningitis

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

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.

8.5 Geriatric Use

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), Dosage and Administration (2.3)].

12.1 Mechanism of Action

CUVITRU supplies a broad spectrum of opsonizing and neutralizing IgG antibodies against a wide variety of bacterial and viral agents. CUVITRU also contains a spectrum of antibodies capable of interacting with and altering the activity of cells of the immune system as well as antibodies capable of reacting with cells such as erythrocytes. The role of these antibodies and the mechanisms of action of IgG in CUVITRU have not been fully elucidated.

12.2 Pharmacodynamics

Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against infectious agents. Human normal immunoglobulin contains the IgG antibodies present in the normal population. It has a distribution of immunoglobulin G subclasses closely proportional to that in native human plasma.

Adequate doses of CUVITRU may restore abnormally low immunoglobulin G levels to the normal range.

12.3 Pharmacokinetics

Pharmacokinetic (PK) parameters of subcutaneously administered CUVITRU were evaluated in 60 subjects with primary immunodeficiency (PI) during a clinical study in North America [see Clinical Studies (14)]. Subjects were treated intravenously for 13 weeks with a comparator product [GAMMAGARD LIQUID, Immune Globulin (Human), 10%] and then switched to weekly subcutaneous CUVITRU infusions. Initially, subjects were treated for up to 12 to 16 weeks at a subcutaneous dose that was 145% of the intravenous dose. A comparison of the area under the curve (AUC) for subcutaneous versus intravenous infusions was performed on 15 subjects aged 12 years and older. Subsequently, all subjects were treated with this dose for 12 weeks after which the dose was individualized for all subjects using the trough IgG levels, as described below. After approximately 4 months treatment at this subcutaneous dose, a PK evaluation was conducted on all subjects.

At this dose adjustment, the geometric mean ratio of the AUC for subcutaneous CUVITRU versus intravenous administration immune globulin 10% was 109%. The peak IgG level occurred at a geometric mean of 79 hours after subcutaneous CUVITRU administration.

In part 4 of the study, pharmacokinetic parameters for CUVITRU were assessed for 60 subjects aged 2 years and older. The pharmacokinetic parameters of CUVITRU administered subcutaneously are shown in Table 8. The median peak IgG levels were lower (1809 mg/dL) during subcutaneous treatment with CUVITRU compared to IGIV 10% administration (2602 mg/dL for 3 week intervals and 2521 mg/dL for 4 week intervals), consistent with the lower weekly dose compared with the dose administered every 3 or 4 weeks intravenously. In contrast, the geometric mean trough levels were higher with CUVITRU (1474 mg/dL), compared with those when given intravenously (1158 mg/dL for 3 week intervals and 1019 mg/dL for 4 week intervals), a result of both higher monthly dose and more frequent dosing. Weekly subcutaneous administration resulted in relatively stable steady-state serum IgG levels compared with IGIV administered at 3 to 4 week intervals. Pharmacokinetic parameters for CUVITRU did not significantly differ between age groups. The pharmacokinetic parameters of CUVITRU for the different age groups are shown in Table 9.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies were conducted to evaluate the carcinogenic or mutagenic effects of CUVITRU or its effects on fertility.

13.2 Animal Toxicology and/or Pharmacology

Animal studies were conducted to evaluate possible toxicity of CUVITRU.

In a local tolerance study in mini-pigs, 50 mL of CUVITRU were administered subcutaneously to anesthetized mini-pigs. Subcutaneous administration of CUVITRU was well tolerated in this study.

In local tolerance studies in rabbits, mild to moderate inflammatory reactions were observed locally after subcutaneous administration of 2.5 mL/kg of CUVITRU. These reactions are considered to be a consequence of the animals' immune response to the human IgG preparation and thus model specific and of minor relevance for the assessment of clinical local tolerability.

North America Study

A prospective, open-label, non-controlled, multi-center clinical study was conducted in North America to determine the efficacy, tolerability and PK of CUVITRU in 77 adult and pediatric subjects with PI. Efficacy was determined in 53 adults aged 16 years or older, 6 adolescents aged 12 to <16 years, and 15 children aged 2 to <12 years. CUVITRU was administered to 74 subjects with a mean dose of 222 mg/kg/week ± 71 mg/kg/week for a median treatment duration of 380.5 days (range: 30 - 629 days) and a mean (± SD) of 413.1 ± 116.5 days. The median duration of treatment did not vary significantly between age groups. The total exposure to CUVITRU was 83.70 subject-years and 4327 infusions.

Initially subjects received immune globulin 10% intravenously (IGIV) every 3 or 4 weeks at a monthly dose equivalent to that received prior to the study for 13 weeks. The objective of part 1 of the study was to determine AUCIV of total IgG following IGIV administration. In part 2 of the study, subjects received CUVITRU subcutaneously at an adjusted dose of 145% of the IGIV dose. The objective of part 2 was to determine AUCSC of total IgG following weekly CUVITRU administration and to calculate an adjusted dose to be used in part 3. The dose adjustment factor was assesed to be 145% of the IGIV 10% dose by comparing the AUCSC with the AUCIV, 0-τ (standardized to 1 week) of part 1 for the first 15 subjects that completed part 2. Subjects who completed part 1 after this assessment was available, went directly into part 3. In part 3 of the study, subjects were treated weekly for 12 weeks at the adjusted dose. The ratio of serum IgG trough levels for part 1 and 3 were compared to the expected trough level determined in part 2 to establish the individually adapted dose for part 4 for each subject. In part 4 of the study, subjects were infused weekly with CUVITRU at the individually adapted dose for 40 weeks. During part 4, an additional pharmacokinetic assessment was performed. Follow-up with the subject either by diary system or by investigator occurred 3-5 days after every infusion in each study part to document adverse events. Adverse events were assessed using the subject's eDiary – all subjects received eDiary tablet to continuously record home treatments, adverse events, and additional information as they occurred.

One acute serious bacterial infection (ASBI) of pneumonia was reported in a 78-year old subject who had specific antibody deficiency and allergic bronchopulmonary aspergillosis while receiving CUVITRU. The point estimate of the annualized rate of ASBIs was 0.012 (upper limit of 99% CI: 0.024) during CUVITRU treatment. This annual rate of ASBIs was lower than 1.0 ASBIs /year (p<0.0001), the threshold specified as providing substantial evidence of efficacy.

The summary of infections and associated events for subjects during subcutaneous treatment with CUVITRU is summarized in Table 10.

In the clinical study, across all age groups, the median maximum infusion rate was 60 mL/hr/site. This infusion rate was achieved in 57.3% (2480/4327) of completed CUVITRU infusions. CUVITRU infusion rate of 60 mL/h/site was achieved in 28.6% (6/21) of pediatric subjects (2 years to <16 years of age), in 88.7% (47/53) of adults (16 years of age and older) and in 71.6% (53/74) of all subject. For more than half of CUVITRU infusions (2393/4327), a volume of 30 to 39 mL (1096/4327 infusions) or 40 to 49 mL (1297/4327 infusions) was infused per site. For 320/4327of CUVITRU infusions, a volume of 60 mL/site or more was infused. Infusion paramenters resulted in a median of 2 infusion sites (range: 1 to 4) per CUVITRU administration. During CUVITRU treatment, 84.9% (3662/4314) of infusions were administered using 1 infusion site (18.5%; 798/4314) or 2 infusion sites (66.4%; 2864/4314) across all ages. The median duration of infusions was less than 1 hour (0.95 h; range: 0.2-6.4 hours). During all treatment periods, 99.8% of infusions were completed without a reduction, interruption, or discontinuation for tolerability reasons. Infusion characteristics did not significantly differ between adult and pediatric subjects.

Throughout the study, health-related quality of life was assessed using the Pediatric Quality of Life Inventory™ (PEDS-QL) questionnaire14 (pediatric subjects) or the self-administered SF-36 survey15(adult subjects). Quality of life was analyzed separately for the age groups 2 to 4 and 5 to 7 years (PEDS-QL, observer: parent), 8 to 12 and 13 years (PEDS-QL, observer: subject) and 14 years and older (SF-36, observer: subject). Treatment satisfaction was measured using the Life Quality Index questionnaire (LQI)16,17 and the Treatment Satisfaction Questionnaire for Medication (TSQM-9)18. The LQI was assessed for the age group 2 years to 12 years (observer: parent) and the age group 13 years and older (observer: subject) in three domains: Treatment Interference, Therapy-related Problems and Therapy Settings. The TSQM-9 was assessed in subjects aged 2 to 12 years (observer: parent) and 13 years and older (observer: subject) in 3 domains: Effectiveness, Convenience and Global Satisfaction. Differences between scores during the intravenous study part and subcutaneous 20% study part were calculated for selected domains of the instruments, see Table 11.

European Study

A prospective, open-label, non-controlled, multi-center study conducted in 16 sites in Europe to evaluate the efficacy, safety, tolerability, and PK parameters of CUVITRU in subjects with PI aged 2 years and older at time of screening. The study consisted of 2 parts. In study part 1, subjects were treated with IGSC 16% for 12 weeks or with IGIV 10% for 13 weeks. Administration, dosage frequency, and dose were dependent on the pre-study treatment. However, the dose range had to be within 0.3-1.0 g/kg BW/4 weeks.

During study part 2, subjects received weekly CUVITRU infusions for 51 weeks at the dose used during study part 1, adjusted to a weekly equivalent dose if necessary. PK assessments were performed before the end of study part 1 and after approximately 5 months in study part 2 in subjects aged ≥12 years. For younger subjects (aged 2 to <12 years) only IgG trough levels were assessed to avoid multiple blood draws. The geometric mean of CUVITRU trough levels was 827 mg/dL [95% CI: 748-913]. Human and population PK parameters for CUVITRU were calculated from levels of Immunoglobulin G (IgG) measured during each part of the study.

CUVITRU was administered at the same weekly-equivalent dose as with the previously used IG product (mean (± SD) dose: 0.125 ± 0.042 g/kg/week). CUVITRU administered at this dose was shown to be effective in PI subjects aged ≥2 years.

One acute serious bacterial infection (ASBI) of pneumonia was reported in a 12-year old subject with a more severe form of hypogammaglobulinemia (XLA) while receiving CUVITRU. The point estimate of the annualized rate of ASBIs was 0.022 (upper limit of 99% CI: 0.049) during CUVITRU treatment. This annual rate of ASBIs was lower than 1.0 ASBIs /year, (p<0.0001), the threshold specified as providing substantial evidence of efficacy.

The summary of infections and associated events for subjects in the EU study during subcutaneous treatment with CUVITRU are summarized in Table 12.

How Supplied

CUVITRU is supplied in single-dose vials containing the labeled amount of functionally active IgG. The components used in the packaging for CUVITRU are not made with natural rubber latex.

The following presentations of CUVITRU are available:

Storage and Handling

• Store at refrigeration temperature: 2°C to 8°C [36°F to 46°F] for up to 36 months or
• Room temperature: not to exceed 25°C [77°F]) for up to 24 months.
• Do not return CUVITRU to the refrigerator if you take it out to room temperature.
• Do not freeze.
• Do not shake.
• Keep the vials in the carton in order to protect from light.
• Discard any unused product.
• Do not use past the expiration date.

Self-administration – If self-administration is deemed to be appropriate by the physician, clear instructions and training on subcutaneous infusion should be given to the patient/caregiver, and the demonstration of their ability to independently administer subcutaneous infusions should be documented.

• Ensure the patient understands the importance of consistent subcutaneous infusions to maintain appropriate steady IgG levels.
• Inform the patient to start the infusion promptly after drawing CUVITRU into the syringe. Ensure the patient understands that it is suggested to complete the administration within 2 hours due to the potential formation of particles caused by siliconized syringes.
• Instruct the patient to keep a treatment diary/log book. This diary/log book should include information about each infusion such as, the time, date, dose, lot number(s), infusion sites, and any reactions.
• Inform the patient that mild to moderate local infusion-site reactions (e.g., pain, redness and itching) are a common side effect of subcutaneous treatment, but to contact their healthcare professional if a local reaction increases in severity or persists for more than a few days.