2.1 Dosage

Post-exposure prophylaxis consists of a single 20 IU/kg body weight dose of KEDRAB and a full course of rabies vaccine (See Table 1).

2.2 Administration

Infiltrate as much of the KEDRAB dose as possible into and around any detectable bite wounds if infiltration at the bite site is feasible. Administer any remaining KEDRAB intramuscularly into anatomical site(s) distant from the site of the rabies vaccine.

• When the bite site is unknown or indeterminate (undetectable) or if infiltration is difficult at the bite site (e.g., lips, fingers, knee), administer the full KEDRAB dose by the intramuscular route at a site distant from the site of rabies vaccination.
• If a large intramuscular volume is required (>2 mL for children or >5 mL for adults), administer the total volume in divided doses at different sites.
• Do not mix KEDRAB with the rabies vaccine or administer in the same syringe with the rabies vaccine.
• Discard unused portion of the product in the vial.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if either of these conditions exists, and contact Kedrion Biopharma Inc. at 1-855-353-7466. Do not discard the vial.

5.1 Previous Rabies Vaccination

Patients who can document previous complete rabies pre-exposure prophylaxis or complete post-exposure prophylaxis should only receive a booster rabies vaccine without KEDRAB because KEDRAB may interfere with the anamnestic response to the vaccine (ACIP)1.

5.2 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, may occur with KEDRAB. History of prior systemic allergic reactions to human immunoglobulin preparations places patients at greater risk. Have epinephrine available for treatment of acute allergic symptoms. Patients with isolated immunoglobulin A (IgA) deficiency may develop severe hypersensitivity reactions to KEDRAB or, subsequently, to the administration of blood products that contain IgA.

5.5 Live Attenuated Virus Vaccines

KEDRAB administration may interfere with the development of an immune response to live attenuated virus vaccines. If feasible, delay immunization with measles vaccine for 4 months, and other live attenuated virus vaccines for 3 months, after KEDRAB administration.

5.6 Interference with Serologic Testing

• A transient rise of the various passively transferred antibodies in the patient's blood may result in misleading positive results of serologic tests after KEDRAB administration.
• Passive transmission of antibodies to erythrocyte antigens, e.g., A, B, and D, may interfere with serologic tests for red cell antibodies such as the antiglobulin test (Coombs' test).

5.7 Transmissible Infectious Agents

Because KEDRAB is made from human plasma donors hyper-immunized with rabies vaccine, 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 (CJD) agent. All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Kedrion Biopharma Inc. at 1-855-353-7466.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates of adverse reactions in clinical trials of another drug and may not reflect the rates observed in clinical practice.

KEDRAB was evaluated in three single-center, controlled clinical trials in adults. Subjects in these clinical studies of KEDRAB were healthy adults, primarily white, and ranged in age from 18 to 72 years. A total of 160 adult subjects were treated in these three studies, including 91 subjects who received single intramuscular doses of KEDRAB (20 IU/kg) with or without rabies vaccine.

Table 2 summarizes adverse reactions occurring in >3% of adult subjects in the clinical trials of KEDRAB. (Table 2).

Less frequent adverse reactions (≤3%) in adult subjects were diarrhea, vomiting, decreased appetite, musculoskeletal stiffness, malaise, weakness (asthenia), fainting (syncope), itching (pruritis), tingling sensation (paresthesia), rash, sunburn and elevation in liver function.

KEDRAB was also evaluated in a two-center, open-label clinical trial in 30 pediatric patients exposed or possibly exposed to rabies virus. They ranged in age from 0.5 to 14.9 years. Study treatment included a single dose of KEDRAB (20 IU/kg) and active rabies vaccine on Days 0, 3, 7 and 14 administered as per ACIP1 recommendations for rabies post-exposure prophylaxis.

Twelve pediatric patients (40%) experienced adverse reactions within 14 days of receipt of KEDRAB and first dose of rabies vaccine. There were no serious adverse reactions. Table 3 summarizes the adverse reactions that occurred in >5% of patients in the pediatric clinical trial within 14 days of receipt of KEDRAB and the first dose of the rabies vaccine.

Less common adverse reactions (≤5%) in pediatric patients were injection site redness (erythema), injection site swelling (edema), muscle pain, oral pain, and wound complication.

Insomnia was reported as a less common adverse reactions (<5%) in pediatric patients occurring after 14 days of administration.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness have been established in children. In a pediatric study of 30 patients ranging in age from 0.5 to 14.9 years, KEDRAB presented no serious adverse reactions through day 84. Of the 30 patients, 28 (93.3%) achieved a Day-14 RVNA titer ≥0.5 IU/mL, the WHO recommended level. None of the patients who were followed until the end of the study (28/30 patients) developed rabies infection through day 84. [see Clinical Trials (14)]

Adverse reactions that occurred in ≥3.3% of patients within the first 14 days of KEDRAB and the first rabies vaccination administration are listed in Section 6.1.

The clinical trial conducted in the pediatric population is described in Section 14.

Additional evidence to support the use of KEDRAB in children comes from Real World Evidence. Based on claims data, 172 U.S. children (≤17 years) were treated with KEDRAB between 2018-2020. Based on Center for Disease Control data, no children in the U.S. treated with post-exposure prophylaxis have been reported to have had rabies between 2018-April 2021.

8.5 Geriatric Use

Clinical studies of KEDRAB did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Clinical experience with HRIG products has not identified differences in effectiveness between elderly and younger patients (ACIP)1.

12.1 Mechanism of Action

Rabies is a zoonotic disease caused by RNA viruses in the family Rhabdoviridae, genus Lyssavirus. Virus is typically present in the saliva of rabid mammals and is transmitted primarily through a bite. KEDRAB is infiltrated into the inoculation site(s) in previously unvaccinated persons, to provide immediate passive rabies virus neutralizing antibody protection until the patient's immune system responds to vaccination by actively producing antibodies.

12.2 Pharmacodynamics

A protective threshold for rabies virus neutralizing activity (RVNA) has never been established. However, the WHO has generally accepted a RVNA of at least 0.5 IU/mL measured 14 days after initiation of post-exposure prophylaxis as protective.

12.3 Pharmacokinetics

A randomized, single-dose, two-period, two-treatment, two-sequence, double-blind, crossover study assessed the pharmacokinetics of KEDRAB. Twenty-six healthy volunteer subjects were randomized to receive a single IM injection of 20 IU/kg HRIG on two separate occasions (KEDRAB or Comparator HRIG). Subjects received the second treatment (A or B) following the 42-day test period and a 21-day washout period. Single dose IM injection of KEDRAB resulted in maximum plasma RVNA levels of 0.25 IU/mL. The median Tmax was 7 days (range: 3-14 days). The elimination half-life was approximately 17.9 days. A statistical analysis of the pharmacokinetic parameters showed that KEDRAB was not bioequivalent to the Comparator HRIG (Table 5).

A plot of plasma rabies virus neutralizing antibody titer concentration versus time (Figure 1) demonstrated that, in both treatment groups, plasma rabies virus neutralizing antibody concentrations declined in a biphasic manner after the absorption phase was complete.

Figure 1: Plasma HRIG Concentrations [Mean (±SD)] at Scheduled PK Sampling Days (Semi-log Scale), Phase 2/3 Study, Pharmacokinetic Analysis

Additionally, a prospective, randomized, double-blind, non-inferiority, study evaluated the pharmacokinetics, safety, and effectiveness of simulated post-exposure prophylaxis with KEDRAB with co-administration of active rabies vaccine in 118 healthy subjects. Subjects were randomized into two treatment groups (59 per treatment group) to receive intramuscular KEDRAB or comparator HRIG at a dose of 20 IU/kg on Day 0, and rabies vaccine on Days 0, 3, 7, 14 and 28. The peak plasma RVNA was 71.9 IU/mL and 53.9 IU/mL for KEDRAB and comparator HRIG respectively. For both treatment groups, the median Tmax was 14 days (range: 14-49 days). The half-lives were 48.6 hours and 52.7 hours for KEDRAB and comparator HRIG respectively.

Bioequivalent assessment showed that KEDRAB was not bioequivalent to the comparator HRIG when co-administered with a five-dose rabies vaccine regimen (Table 6). Furthermore, the RVNA on Day 3 was lower in the KEDRAB with rabies vaccine group relative to the comparator HRIG with vaccine group (0.188+0.051 vs 0.229+0.054, P=0.0005). However, these pharmacokinetic differences are not expected to affect clinical outcomes.

Please see Clinical Studies (14) section for clinical efficacy.

13.2 Animal Toxicology and/or Pharmacology

Intramuscular administration of a single dose of KEDRAB to rats at 60 and 120 IU/kg (3-fold and 6-fold higher than the recommended human dose of 20 IU/kg) did not result in any signs of toxicity.