CUVITRU: Package Insert and Label Information (Page 3 of 6)

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

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

7 DRUG INTERACTIONS

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)].

8 USE IN SPECIFIC POPULATIONS

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 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.

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 CUVITRU and any potential adverse effects on the breastfed infant from CUVITRU or from the underlying maternal condition.

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)].

11 DESCRIPTION

CUVITRU is a ready-for-use, sterile, liquid preparation of highly purified and concentrated immunoglobulin G (IgG) antibodies. The distribution of the IgG subclasses is similar to that of normal plasma. The Fc and Fab functions are maintained in CUVITRU.

CUVITRU has a purity ≥98% IgG and a pH of 4.6 to 5.1. The osmolality is 280-292 milli-osmoles per kilogram. CUVITRU contains 200 milligram/mL protein. The average immunoglobulin A (IgA) concentration is 80 mcg/mL. CUVITRU contains a broad spectrum of IgG antibodies against bacterial and viral agents. Glycine (0.25M) serves as a stabilizing and buffering agent, and there are no added sugars, sodium or preservatives.

CUVITRU is manufactured from large pools of human plasma. IgG preparations are purified from plasma pools using a modified Cohn-Oncley cold ethanol fractionation process, as well as cation and anion exchange chromatography.

Screening against potentially infectious agents begins with the donor selection process and continues throughout plasma collection and plasma preparation. Each individual plasma donation used in the manufacture of CUVITRU is collected only at FDA approved blood establishments and is tested by FDA licensed serological tests for Hepatitis B Surface Antigen (HBsAg), and for antibodies to Human Immunodeficiency Virus (HIV-1/HIV-2) and Hepatitis C Virus (HCV) in accordance with U.S. regulatory requirements. As an additional safety measure, mini-pools of the plasma are tested for the presence of HIV-1 and HCV by FDA licensed Nucleic Acid Testing (NAT) and found to be negative.

To further improve the margin of safety, validated virus inactivation/removal steps have been integrated into the manufacturing and formulation processes, namely solvent/detergent (S/D) treatment13 , 35 nm nanofiltration, and a low pH incubation at elevated temperature (30°C to 32°C). The S/D process includes treatment with an organic mixture of tri-n-butyl phosphate, octoxynol 9 and polysorbate 80 at 18°C to 25°C for a minimum of 60 minutes. S/D treatment inactivates the lipid-enveloped viruses investigated to below detection limits within minutes13. The ethanol fractionation process provides an additional virus clearance capacity.

In vitro virus spiking studies have been used to validate the capability of the manufacturing process to inactivate and remove viruses. To establish the minimum applicable virus clearance capacity of the manufacturing process, these virus clearance studies were performed under extreme conditions (e.g., at minimum S/D concentrations, incubation time and temperature for the S/D treatment).

Virus clearance studies for CUVITRU performed in accordance with good laboratory practices are summarized in Table 7.

Table 7 Three Dedicated Independent Virus Inactivation/Removal Steps Mean Log10 Reduction Factors * (RFs) For Each Virus and Manufacturing Step
Virus type Enveloped RNA Enveloped DNA Non-enveloped RNA Non-enveloped DNA
Family Retroviridae Flaviviridae Herpesviridae Picornaviridae Parvoviridae
Virus HIV-1 BVDV WNV PRV HAV EMCV MMV
Abbreviations: HIV-1, Human Immunodeficiency Virus Type 1; BVDV, Bovine Viral Diarrhea Virus (model for Hepatitis C Virus and other lipid enveloped RNA viruses); WNV, West Nile Virus; PRV, Pseudorabies Virus (model for lipid enveloped DNA viruses, including Hepatitis B Virus); EMCV, Encephalomyocarditis Virus (model for non-lipid enveloped RNA viruses, including Hepatitis A virus [HAV]); MMV, Mice Minute Virus (model for non-lipid enveloped DNA viruses, including B19 virus [B19V]); n.d. (not done), n.a. (not applicable).
*
For the calculation of these RF data from virus clearance study reports, applicable manufacturing conditions were used. Log10 RFs on the order of 4 or more are considered effective for virus clearance in accordance with the Committee for Medicinal Products for Human Use (CHMP, formerly CPMP) guidelines.
No RF obtained due to immediate neutralization of HAV by the anti-HAV antibodies present in the product.
Fractionation >5.1 1.3 >6.1 >4.9 3.9 4.2 4.9
SD treatment >4.5 >6.2 n.a. >4.8 n.d. n.d. n.d
35 nm nanofiltration >4.5 >5.1 >6.2 >5.6 5.7 1.4 2.0
Low pH treatment >5.8 >5.5 >6.0 >6.5 n.d. >6.3 3.1
Overall log reduction factor (ORF) >19.9 >18.1 >18.3 >21.8 9.6 >11.9 10.1

12 CLINICAL PHARMACOLOGY

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.

Table 8 Pharmacokinetic Parameters
Parameter Median (95% Cl)N=60
AUC [g*days/L] 115 (110 to 121)
Apparent clearance [mL/kg/day] 1.86 (1.80 to 2.17)
Cmax [mg/dL] 1809 (1745 to 2068)
Cmin [mg/dL] 1477 (1323 to 1535)
Tmax [hours] 105 (71 to 119)
Table 9 Pharmacokinetic Parameters by Age Group
Parameter Age Groups
2 to <5(n=1)Median(95% CI) 5 to <12(n=10)Median(95% CI) 12 to <16(n=5)Median(95% CI) 16 to <65(n=37)Median(95% CI) ≥65(n=7)Median(95% CI)
AUC [g*days/L] 106(N/A) 110(87 to 121) 116(N/A) 114(103 to 127) 139(90 to 158)
Apparent clearance [mL/kg/day] 1.86(N/A) 1.85(1.31 to 2.37) 1.80(N/A) 1.98(1.81 to 2.23) 1.72(0.90 to 2.36)
Cmax [mg/dL] 1619(N/A) 1725(1518 to 1892) 1732(N/A) 1940(1778 to 2220) 2419(1480 to 3201)
Cmin [mg/dL] 1527(N/A) 1351(1130 to 1635) 1554(N/A) 1423(1231 to 1524) 1585(976 to 2000)
Tmax [hours] 70(N/A) 164(70 to 168) 68(N/A) 74(68 to 119) 119(24 to 164)

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