ASCENIV (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. The following adverse reactions have been identified and reported during the post-approval use of IGIV products:

  • Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), cyanosis, dyspnea, bronchospasm.
  • Cardiovascular: Cardiac arrest, vascular collapse, hypotension.
  • Neurological: Coma, loss of consciousness, seizures, tremor.
  • Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis.
  • Hematologic: Pancytopenia, leukopenia.
  • General/Body as a Whole: Pyrexia, rigors.
  • Gastrointestinal: Hepatic dysfunction, abdominal pain.

7 DRUG INTERACTIONS

Immunoglobulin administration may transiently impair the efficacy of live attenuated virus vaccines such as measles, mumps, rubella, and varicella because the continued presence of high levels of passively acquired antibody may interfere with an active antibody response. 15,16 The immunizing physician should be informed of recent therapy with ASCENIV so that appropriate measures may 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 ASCENIV. It is not known whether ASCENIV 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. ASCENIV should be given to pregnant women only if clearly needed. 17,18

8.2 Lactation

Risk Summary

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

8.4 Pediatric Use

ASCENIV was evaluated in 11 pediatric subjects (6 children less than 12 years and 5 adolescents age 12 – 16 years) with primary humoral immunodeficiency (PI). The pharmacokinetic (PK), safety, and effectiveness profile of ASCENIV in adolescent subjects appeared to be comparable to that demonstrated in adult subjects. There are insufficient PK, safety, and effectiveness data from pediatric subjects younger than 12 years. Safety and effectiveness has not been studied in pediatric patients with PI who are under the age of 3 years ( see Clinical Studies [14]).

8.5 Geriatric Use

Clinical studies of ASCENIV did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. 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.

10 OVERDOSAGE

With intravenous administration, overdose may lead to fluid overload and hyperviscosity. Patients at risk of complications of fluid overload and hyperviscosity include elderly patients and those with cardiac or renal impairment.

11 DESCRIPTION

ASCENIV is a purified, sterile, ready-to-use preparation of concentrated human immunoglobulin G (IgG) antibodies. The product is a clear to opalescent liquid, which is colorless to pale yellow. The distribution of IgG subclasses is similar to that of normal plasma. The active ingredient is human immunoglobulin purified from source human plasma and processed using a modified classical Cohn Method 6 / Oncley Method 9 fractionation procedure. ASCENIV contains 100 ± 10 mg/mL protein, of which not less than 96% is human immunoglobulin obtained from source human plasma. It is formulated in water for injection containing 0.100-0.140 M sodium chloride, 0.20-0.29 M glycine, 0.15–0.25% polysorbate 80, with pH 4.0–4.6. ASCENIV contains ≤ 200 µg/mL of IgA.

Each plasma donation used for the manufacture of ASCENIV is collected from FDA-licensed facilities. Plasma donations must test negative for hepatitis B virus (HBV) surface antigen (HBsAg), antibodies to human immunodeficiency virus (HIV) strains 1 and 2 (anti-HIV-1/2), and antibodies to the hepatitis C virus (anti-HCV) as determined by enzyme immunoassay (EIA). In addition, each plasma unit must test negative and/or non-reactive for HIV RNA, HCV RNA, HBV DNA, Hepatitis A Virus (HAV) RNA, and Parvovirus B19 (B19 virus) DNA as determined by Nucleic Acid Amplification Testing (NAT) of plasma minipools. NATs for HIV, HAV, HBV, HCV and B19 virus DNA are also performed on a sample of the manufacturing pool. The limit for B19 virus DNA in a manufacturing pool is set not to exceed 10 4 IU/mL and all other NAT results must be negative.

The manufacturing process of ASCENIV employs three steps to remove/inactivate adventitious viruses to minimize the risk of virus transmission. The steps are “Precipitation and removal of fraction III” during cold ethanol fractionation, classical “solvent/detergent treatment” and “35 nm virus filtration.” In compliance with current guidelines, the steps have been separately validated in a series of in vitro experiments for their capacity to inactivate or remove both enveloped and nonenveloped viruses.

Precipitation and removal of fraction III removes both enveloped and non-enveloped viruses, solvent/detergent treatment represents a virus inactivation step for enveloped viruses, and 35 nm virus filtration removes both enveloped and non-enveloped viruses by size exclusion. In addition to the steps above, low pH during several steps of the production process contributes to virus inactivation. The results of virus validation studies for ASCENIV are shown in Table 3, expressed as log 10 reduction factors.

Table 3: Virus Validation Data for ASCENIV
* without depth filtration — not done values below 1 log 10 are considered as insignificant and are not used for total clearance; HIV , human immunodeficiency virus; BVDV , Bovine viral diarrhea virus, model virus for HCV; SinV , Sindbis virus, model virus for HCV; WNV , West Nile virus; PRV , Pseudorabies virus, model virus for herpes viruses and Hepatitis B virus; MEV , Murine encephalomyelitis virus, model virus for hepatitis A virus; BPV , Bovine parvovirus, model virus for human B19 virus; PPV , Porcine parvovirus, model virus for human B19 virus; SV40, Simian virus 40, model virus for highly resistant non- enveloped viruses.
Virus Reduction (log 10 )
Virus Type Family Enveloped Viruses Non-enveloped Viruses
Retro Flavi Herpes Parvo Picorna Polyoma
Step / Test Virus HIV BVDV SinV WNV PRV PPV BPV MEV SV40
Precipitation and Removal of Fraction III and Depth Filtration 1.87 * 4.00 5.29 2.00 *
TnBP/Triton X-100 Treatment > 4.43 > 5.04 > 7.11 > 4.96 > 4.01
35 nm Virus Filtration > 5.19 > 4.88 > 4.64 < 1.0 6.18 < 1.0 > 5.02
Total Clearance > 9.62 > 11.79 > 7.11 > 4.96 > 8.65 4.00 6.18 5.29 > 7.02

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