HyperRAB

Rabies immune globulin (human).

HYPERRAB is a clear or slightly opalescent, and colorless or pale yellow or light brown sterile solution of human antirabies immune globulin for infiltration and intramuscular administration. HYPERRAB contains no preservative. HYPERRAB is prepared from pools of human plasma collected from healthy donors (hyperimmunized with rabies vaccine) by a combination of cold ethanol fractionation, caprylate precipitation and filtration, caprylate incubation, anion-exchange chromatography, nano filtration and low pH incubation. HYPERRAB consists of 15 to 18% protein at pH 4.1 to 4.8 in 0.16 to 0.26 M glycine. The product is standardized against the U.S. Standard Rabies Immune Globulin to contain a potency value of not less than 300 IU/mL. The U.S. unit of potency is equivalent to the international unit (IU) for rabies antibody.
When medicinal biological products are administered, infectious diseases due to transmission of pathogens cannot be totally excluded. However, in the case of products prepared from human plasma, the risk of transmission of pathogens is reduced by epidemiological surveillance of the donor population and selection of individual donors by medical interview; testing of individual donations and plasma pools; and the presence in the manufacturing processes of steps with demonstrated capacity to inactivate/remove pathogens.
In the manufacturing process of HYPERRAB [rabies immune globulin (human)], there are several steps with the capacity for virus inactivation or removal. The main steps of the manufacturing process that contribute to the virus clearance capacity are as follows: Caprylate precipitation/depth filtration, Caprylate incubation, Depth filtration, Column chromatography, Nanofiltration, Low pH final container incubation.
To provide additional assurance of the pathogen safety of the final product, the capacity of the HYPERRAB manufacturing process to remove and/or inactivate viruses has been demonstrated by laboratory spiking studies on a scaled down process model using a wide range of viruses with diverse physicochemical properties.
The combination of all of the previously mentioned measures provides the final product with a high margin of safety from the potential risk of transmission of infectious viruses.
The caprylate/chromatography manufacturing process was also investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the variant Creutzfeldt-Jakob disease (vCJD), and Creutzfeldt-Jakob disease (CJD) agents. These studies provide reasonable assurance that low levels of vCJD/CJD agent infectivity, if present in the starting material, would be removed by the caprylate/chromatography manufacturing process.

Pharmacology: Mechanism of Action: HYPERRAB provides immediate, passive, rabies virus neutralizing antibody coverage until the previously unvaccinated patient responds to rabies vaccine by actively producing antibodies.
Pharmacodynamics: The usefulness of prophylactic rabies antibody in preventing rabies in humans when administered immediately after exposure was dramatically demonstrated in a group of persons bitten by a rabid wolf in Iran. Similarly, beneficial results were later reported from the U.S.S.R. Studies coordinated by WHO (World Health Organization) helped determine the optimal conditions under which antirabies serum of equine origin and rabies vaccine can be used in man. These studies showed that antirabies serum can interfere to a variable extent with the active immunity induced by the vaccine, but could be minimized by booster doses of vaccine after the end of the usual dosage series.
Preparation of rabies immune globulin of human origin with adequate potency was reported by Cabasso et al. In carefully controlled clinical studies, this globulin was used in conjunction with rabies vaccine of duck-embryo origin (DEV). These studies determined that a human globulin dose of 20 IU/kg of rabies antibody, given simultaneously with the first DEV dose, resulted in amply detectable levels of passive rabies antibody 24 hours after injection in all recipients. The injections produced minimal, if any, interference with the subject's endogenous antibody response to DEV.
Subsequently, human diploid cell rabies vaccines (HDCV) prepared from tissue culture fluids containing rabies virus have received substantial clinical evaluation in Europe and the United States. In a study in adult volunteers, the administration of rabies immune globulin (human) did not interfere with antibody formation induced by HDCV when given in a dose of 20 IU per kilogram body weight simultaneously with the first dose of vaccine.
CLINICAL STUDIES: HYPERRAB was administered to a total of 20 healthy adult subjects in two clinical trials [see Pharmacokinetics as follows]. A single intramuscular dose of 20 IU/kg HYPERRAB (12 subjects) or HYPERRAB S/D (8 subjects) was administered and rabies neutralizing antibody titers were monitored in serum for 21 days. Administration of both HYPERRAB formulations resulted in detectable titers of neutralizing antibodies to the rabies virus that persisted throughout the 21 day study period (Figure 2).
Pharmacokinetics: In a clinical study of 12 healthy human subjects receiving a 20 IU/kg intramuscular dose of HYPERRAB detectable passive rabies neutralizing antibody was present by 24 hours and persisted through the 21 day follow-up evaluation period. Figure 1 shows the mean levels of rabies virus antibodies in IU/mL across the 21 day evaluation period and indicates that the titer remains stable during this period. This level of passive rabies neutralizing antibody is similar to that reported in the literature for administration of human rabies immune globulin, and is clinically important because it provides interim protection until the host immune response to rabies vaccine produces definitive protective titers of neutralizing rabies antibody (therefore the rabies vaccine series is also essential). (See Figure 1.)

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The previous formulation, HYPERRAB S/D [rabies immune globulin (human)], was studied in 8 healthy subjects over 21 days. As with the new formulation, rabies neutralizing antibody was present by 24 hours and persisted through the 21 day follow up period (see Figure 2).

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HYPERRAB is a human rabies immune globulin indicated for postexposure prophylaxis, along with rabies vaccine, for all persons suspected of exposure to rabies.
Limitations of Use: Persons who have been previously immunized with rabies vaccine and have a confirmed adequate rabies antibody titer should receive only vaccine.
For unvaccinated persons, the combination of HYPERRAB and vaccine is recommended for both bite and nonbite exposures regardless of the time interval between exposure and initiation of postexposure prophylaxis.
Beyond 7 days (after the first vaccine dose), HYPERRAB is not indicated since an antibody response to vaccine is presumed to have occurred.

For infiltration and intramuscular use only.
The strength of HYPERRAB is 300 IU/mL.
Dose: Use HYPERRAB in combination with rabies vaccine series to be effective. Do not use HYPERRAB alone for prevention.
Administer HYPERRAB within 7 days after the first dose of rabies vaccine. (See table.)

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Preparation: Calculate the volume of HYPERRAB for the recommended dose of 20 IU/kg.
Ensure the correct strength is used for the calculation. HYPERRAB is formulated with a strength of 300 IU/mL. The predecessor product, HYPERRAB S/D [rabies immune globulin (human)] was formulated at 150 IU/mL. The volume required of HYPERRAB (300 IU/mL) to achieve the recommended dose of 20 IU/kg is approximately one half of that required for the previous HYPERRAB S/D (150 IU/mL).
Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. HYPERRAB is a clear or slightly opalescent, and colorless or pale yellow or light brown sterile solution.
Do not use HYPERRAB if the product shows any sign of tampering. Notify Grifols Therapeutics LLC immediately [1-800-520-2807].
Do not freeze. Do not use any solution that has been frozen.
Administration: Administer HYPERRAB at the time of the first vaccine dose (day 0), but no later than day 7.
Infiltrate the full dose of HYPERRAB in the area around the wound, if anatomically feasible. Dilute HYPERRAB with an equal volume of dextrose, 5% (D5W), if additional volume is needed to infiltrate the entire wound. Do not dilute with normal saline.
Inject the remainder, if any, of the HYPERRAB dose intramuscularly into the deltoid muscle of the upper arm or into the lateral thigh muscle, and distant from the site of vaccine administration.
Do not administer HYPERRAB in the same syringe or needle or in the same anatomic site as vaccine.

Because rabies immune globulin (human) may partially suppress active production of antibody in response to the rabies vaccine, do not give more than the recommended dose of rabies immune globulin (human).

None.

Hypersensitivity Reactions: Severe hypersensitivity reactions may occur with HYPERRAB. Patients with a history of prior systemic allergic reactions to human immunoglobulin preparations are at a greater risk of developing severe hypersensitivity and anaphylactic reactions. Have epinephrine available for treatment of acute allergic symptoms, should they occur.
Patients with isolated immunoglobulin A (IgA) deficiency may develop severe hypersensitivity reactions to HYPERRAB, or subsequently, to the administration of blood products that contain IgA.
Transmissible Infectious Agents: HYPERRAB is made from human blood and 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. HYPERRAB is purified from human plasma obtained from healthy donors. When medicinal biological products are administered, infectious diseases due to transmission of pathogens cannot be totally excluded. However, in the case of products prepared from human plasma, the risk of transmission of pathogens is reduced by: (1) epidemiological controls on the donor population and selection of individual donors by a medical interview and screening of individual donations and plasma pools for viral infection markers; (2) testing of plasma for hepatitis C virus (HCV), human immunodeficiency virus (HIV), hepatitis B virus (HBV), HAV and human parvovirus (B19V) genomic material; and (3) manufacturing procedures with demonstrated capacity to inactivate/remove pathogens.
ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Grifols Therapeutics LLC [1-800-520-2807].
Use in Children: Safety and effectiveness in the pediatric population have not been established.
Use in the Elderly: Safety and effectiveness in geriatric population have not been established.

Pregnancy: Risk Summary: There are no data with HYPERRAB use in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with HYPERRAB. It is not known whether HYPERRAB can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. HYPERRAB should be given to a pregnant woman only if clearly needed. In the U.S. general population, the estimated backgrounds risk of major birth defect and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Lactation: Risk Summary: There is no information regarding the presence of HYPERRAB in human milk, the effect on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for HYPERRAB and any potential adverse effects on the breastfed infant from HYPERRAB.

The most common adverse reactions in >5% of subjects during clinical trials were injection site pain, headache, injection site nodule, abdominal pain, diarrhea, flatulence, nasal congestion, and oropharyngeal pain.
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 practice.
The new formulation for HYPERRAB is manufactured using caprylate/chromatography purification and has a rabies antibody concentration of 300 IU/mL. The previous formulation, HYPERRAB S/D, was manufactured using a solvent detergent process and had a rabies antibody concentration of 150 IU/mL. These products were evaluated in 2 clinical trials in a total of 20 healthy subjects using a 20 IU/kg single-dose. The initial study evaluated the original 150 IU/mL HYPERRAB S/D in 8 subjects and the second study evaluated HYPERRAB in 12 subjects. The original study of HYPERRAB S/D reported headache (1/8; 13%).
In the study with HYPERRAB at 300 IU/mL, 5 subjects (5/12; 42%) experienced at least 1 adverse reaction. These were: injection site pain (4/12; 33%), injection site nodule (1/12; 8%), abdominal pain (1/12; 8%), diarrhea (1/12; 8%), flatulence (1/12; 8%), headache (1/12; 8%), nasal congestion (1/12; 8%), and oropharyngeal pain (1/12; 8%).
Postmarketing Experience: There are no data on the postmarketing use of HYPERRAB (300 IU/mL). The following adverse reactions have been identified during post approval use of the predecessor formulation, HYPERRAB S/D. Because these 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 drug exposure.
Among patients treated with HYPERRAB S/D, cases of allergic/hypersensitivity reactions including anaphylaxis have been reported. Soreness at the site of injection (injection site pain) may be observed following intramuscular injection of immune globulins. Sensitization to repeated injections has occurred occasionally in immunoglobulin-deficient patients.
The following have been identified as the most frequently reported post-marketing adverse reactions: Immune system disorder: Anaphylactic reaction*, hypersensitivity*.
Nervous system disorders: Hypoesthesia.
Gastrointestinal disorders: Nausea.
Musculoskeletal and connective tissue disorders: Arthralgia, myalgia, pain in extremity.
*These reactions have been manifested by dizziness, paresthesia, rash, flushing, dyspnea, tachypnea, oropharyngeal pain, hyperhidrosis, and erythema.

Do not administer repeated doses of HYPERRAB once vaccine treatment has been initiated as this could prevent the full expression of active immunity expected from the rabies vaccine.
Other antibodies in the HYPERRAB preparation may interfere with the response to live vaccines such as measles, mumps, polio or rubella. Defer immunization with live vaccines for 4 months after HYPERRAB administration.

HYPERRAB contains no preservative and is not made with natural rubber latex.
Store HYPERRAB at 2 to 8°C. Do not freeze.
HYPERRAB may be stored at room temperatures not to exceed 25°C for up to 6 months.
Use within 6 months after removal from refrigeration at any time prior to the expiration date, after which the product must be used or discarded. Do not return to refrigeration.

Discuss the risks and benefits of this product with the patient, before prescribing or administering it to the patient.
Inform the patient who is allergic to human immune globulin products that severe, potentially life-threatening allergic reactions could occur [see Hypersensitivity Reactions under Precautions].
Inform the patient who is deficient in IgA the potential for developing anti-IgA antibodies and severe potentially life-threatening allergic reactions [see Hypersensitivity Reactions under Precautions].
Inform the patient that HYPERRAB is made from human plasma and may carry a risk of transmitting infectious agents that can cause disease. While the risk that HYPERRAB can transmit an infectious agent has been reduced by screening plasma donors for prior exposure, testing donated plasma, and including manufacturing steps with the capacity to inactivate and/or remove pathogens, the patient should report any symptoms that concern them [see Transmissible Infectious Agents under Precautions].

Vaccines, Antisera & Immunologicals

J06BB05 - rabies immunoglobulin ; Belongs to the class of specific immunoglobulins. Used in passive immunizations.

POM