WINRHO (Page 4 of 7)

6.2 Post-marketing Experience

The following adverse reactions listed by body system have been identified during the post-approval use of WinRho SDF. Because post-marketing adverse 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 product exposure.

Intravascular hemolysis (IVH) leading to death has been reported in patients treated with WinRho SDF for immune thrombocytopenic purpura (ITP).

Serious complications including severe anemia, acute renal insufficiency, renal failure and disseminated intravascular coagulation (DIC) have also been reported.

Blood and Lymphatic: Intravascular hemolysis, disseminated Intravascular coagulation, hemoglobinemia
Cardiac: Cardiac arrest, cardiac failure, myocardial infarction, tachycardia
Gastrointestinal: Nausea
General: Chest pain, fatigue, edema, pain
Hepatobilliary: Jaundice
Immune System: Anaphylactic reaction/shock, hypersensitivity, injection site reaction including induration, pruritus and/or swelling
Musculoskeletal: Myalgia, muscle spasm, pain in extremities
Renal: Renal failure, anuria, chromaturia, hematuria, hemoglobinuria
Respiratory: Acute respiratory distress syndrome, dyspnea, transfusion related acute lung injury
Skin: Hyperhidrosis, pruritus, rash

Healthcare professionals should report serious adverse reactions following the administration of WinRho SDF to Aptevo BioTherapeutics at 1-844-859-6675 or FDA’s MedWatch reporting system by phone (1-800-FDA-1088).

7 DRUG INTERACTIONS

7.1 Live Virus Vaccines

Administration of WinRho SDF concomitantly with other drugs has not been evaluated. Passive transfer of antibodies may transiently impair the immune response to live attenuated virus vaccines such as measles, mumps, rubella, and varicella (see Patient Counseling Information [17.1]). Do not give immunization with live vaccines within 3 months after WinRho SDF administration.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

For the treatment of ITP, there is no human data or animal data available to establish the presence or absence of drug-associated risk.

When administered to pregnant women in a clinical trial to evaluate WinRho for suppression of Rh isoimmunisation [see Clinical Studies (14.2)] following dosing regimens similar to Table 2 [see Dosing and Administration (2.1)], WinRho SDF was not shown to harm the fetus or newborn.12

8.2 Lactation

Risk Summary

There is no information regarding the presence of WinRho SDF in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for WinRho SDF and any potential adverse effects on the breastfed infant from WinRho SDF or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of WinRho has been evaluated for the treatment of chronic or acute ITP in children and in children (<16 years of age) with ITP secondary to HIV infection [see Adverse Reactions (6.2)]. The dosing recommendation in the treatment of children with ITP is the same as in adults [see Dosage and Administration (2.1)].

8.5 Geriatric Use

Clinical studies of WinRho did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Post marketing clinical experience suggests that patients of advanced age (age over 65) with co-morbid conditions including but not limited to cardio-respiratory decompensation, renal failure or insufficiency or prothrombotic conditions are at increased risk of developing serious complications from acute hemolytic reactions such as IVH. Patients receiving doses in excess of 300 IU/kg of WinRho SDF may also be at an increased risk of developing increased hemolysis. Fatal outcomes associated with IVH and its complications have occurred most frequently in patients of advanced age (age over 65) with co-morbid conditions.

Given the prevalence of co-morbid conditions and concomitant drug therapy in geriatric patients, consider starting at the low end of the dosing range when using WinRho SDF in this population.

10 OVERDOSAGE

Treatment of ITP and Suppression of Rh Isoimmunization

In post-marketing spontaneous reporting, there has been a limited number of medication error reports related to dosage calculations in which higher doses than that recommended for WinRho SDF were administered (doses > 60 µg/kg). Signs and laboratory findings of overdosage in Rh positive (ITP) patients have included hemoglobin decreases in excess of 1.2 g/dL. For the suppression of Rh isoimmunization, hemolytic reactions have been reported in cases of mis-matched blood transfusions where very large doses of WinRho SDF were administered.

In one ITP case report that involved an overdose due to confusion between mcg and international unit (IU), a patient with significant co-morbidities developed IVH and had a fatal outcome. In the event of overdose, monitor patients closely for signs and symptoms of hemolysis and initiate symptomatic and supportive treatment.

11 DESCRIPTION

WinRho SDF is a sterile, liquid gamma globulin (IgG) fraction containing antibodies to the Rho (D) antigen (D antigen). WinRho SDF is to be administered intravenously for the treatment of ITP and either intravenously or intramuscularly for the suppression of Rh isoimmunization.

WinRho SDF is prepared from human plasma by an anion-exchange column chromatography method. The manufacturing process includes two steps implemented specifically for viral clearance. The solvent detergent treatment step (using tri-n-butyl phosphate and octoxynol is effective in inactivating lipid enveloped viruses such as hepatitis B, hepatitis C, and HIV. Virus filtration, using a 20N virus filter, is effective in the removal of some non-lipid enveloped viruses. These two processes are designed to increase product safety by reducing the risk of transmission of enveloped and non-enveloped viruses, respectively. In addition to the two specific steps, the anion-exchange chromatography step contributes to the removal of small non-lipid enveloped viruses.

The inactivation and reduction of known enveloped and non-enveloped model viruses were validated in laboratory studies as summarized in Table 6.

Table 6 – Virus Reduction Values Obtained Through Validation Studies
* The PRV was retained by the 0.1 μm pre-filter during the virus validation. Since manufacturing employs a 0.1 μm pre-filter before the 20N filter, the claim of ≥5.6 reduction is considered applicable. Abbreviations: HIV-1: human immunodeficiency virus-1; relevant virus for human immunodeficiency virus-1 and model for HIV-2. BVDV: bovine viral diarrhea virus; model virus for hepatitis C virus (HCV) and West Nile virus (WNV) PRV: pseudorabies virus; model for large enveloped DNA viruses, including herpes HAV: human hepatitis A virus; relevant virus for HAV and model for small non-enveloped viruses in general EMC: encephalomyocarditis virus; model for HAV and for small non-enveloped viruses in general MMV: murine minute virus; model for human parvovirus B19 and for small non-enveloped viruses in general PPV: porcine parvovirus; model for human parvovirus B19 and for small non-enveloped viruses in general n.e.: not evaluated
Enveloped Non-Enveloped
Genome RNA DNA RNA DNA
Virus HIV-1 BVDV PRV HAV EMC MMV PPV
Family retro flavi herpes picorna parvo
Size (nm) 80-100 50-70 120-200 25-30 30 20-25 18-24
Anion Exchange Chromatography (partitioning) n.e. 2.3 n.e. 3.4 n.e.
20N Filtration (size exclusion) ≥ 4.7 ≥ 3.5 ≥ 5.6* n.e. 4.8 n.e. 4.1
Solvent/Detergent (inactivation) ≥ 4.7 ≥ 7.3 ≥ 5.5 n.e.
Total Reduction (log10 ) ≥ 9.4 ≥ 10.8 ≥ 11.1 2.3 4.8 3.4 4.1

The product potency is expressed in international units (IU) by comparison to the World Health Organization (WHO) standard. In the past, a full dose of Rho (D) Immune Globulin (Human) has traditionally been referred to as a “300 microgram (mcg)” dose. Potency and dosing recommendations are now expressed in IU by comparison to the WHO anti-Rho (D) standard. The conversion of mcg to IU is: 1 mcg = 5 IU. A 1,500 IU (300 mcg) vial contains sufficient anti-Rho (D) to effectively suppress the immunizing potential of approximately 17 mL of Rho (D) (D-positive) RBCs.

The liquid formulation is stabilized with 10% maltose and 0.03% polysorbate 80. There are no preservatives in the formulation. WinRho SDF does not contain mercury. This product contains ≤ 40 µg/mL IgA.

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