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Description for HyperRAB

Rabies Immune Globulin (Human)

HyperRAB® S/D treated with solvent/detergent is a colorless to pale yellow or pink sterile solution of antirabies immune globulin for intramuscular administration; it is preservative-free and latex-free. HyperRAB S/D is prepared by cold ethanol fractionation from the plasma of donors hyperimmunized with rabies vaccine. The immune globulin is isolated from solubilized Cohn Fraction II. The Fraction II solution is adjusted to a final concentration of 0.3% tri-n-butyl phosphate (TNBP) and 0.2% sodium cholate. After the addition of solvent (TNBP) and detergent (sodium cholate), the solution is heated to 30°C and maintained at that temperature for not less than 6 hours. After the viral inactivation step, the reactants are removed by precipitation, filtration and finally ultrafiltration and diafiltration. HyperRAB S/D is formulated as a 15–18% protein solution at a pH of 6.4–7.2 in 0.21–0.32 M glycine. HyperRAB S/D is then incubated in the final container for 21–28 days at 20–27°C. The product is standardized against the U.S. Standard Rabies Immune Globulin to contain an average potency value of 150 IU/mL. The U.S. unit of potency is equivalent to the international unit (IU) for rabies antibody.

The removal and inactivation of spiked model enveloped and non-enveloped viruses during the manufacturing process for HyperRAB S/D has been validated in laboratory studies. Human Immunodeficiency Virus, Type 1 (HIV-1), was chosen as the relevant virus for blood products; Bovine Viral Diarrhea Virus (BVDV) was chosen to model Hepatitis C virus; Pseudorabies virus (PRV) was chosen to model Human Herpes viruses and other large enveloped DNA viruses; and Reo virus type 3 (Reo) was chosen to model non-enveloped viruses and for its resistance to physical and chemical inactivation. Significant removal of model enveloped and non-enveloped viruses is achieved at two steps in the Cohn fractionation process leading to the collection of Cohn Fraction II: the precipitation and removal of Fraction III in the processing of Fraction II + IIIW suspension to Effluent III and the filtration step in the processing of Effluent III to Filtrate III. Significant inactivation of enveloped viruses is achieved at the time of treatment of solubilized Cohn Fraction II with TNBP/sodium cholate.

Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents.27-30

Studies of the HyperRAB S/D manufacturing process demonstrate that TSE clearance is achieved during the Pooled Plasma to Effluent III Fractionation Process (6.7 log10). These studies provide reasonable assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed.

REFERENCES

27. Stenland CJ, Lee DC, Brown P, et al. Partitioning of human and sheep forms of the pathogenic prion protein during the purification of therapeutic proteins from human plasma. Transfusion 2002. 42(11):1497-500.

28. Lee DC, Stenland CJ, Miller JL, et al. A direct relationship between the partitioning of the pathogenic prion protein and transmissible spongiform encephalopathy infectivity during the purification of plasma proteins. Transfusion 2001. 41(4):449-55.

29. Lee DC, Stenland CJ, Hartwell RC, et al. Monitoring plasma processing steps with a sensitive Western blot assay for the detection of the prion protein. J Virol Methods 2000. 84(1):77-89.

30. Cai K, Miller JL, Stenland CJ, et al. Solvent-dependent precipitation of prion protein. Biochim Biophys Acta 2002. 1597(1):28-35.

Uses for HyperRAB

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.1-3

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.1-3

Beyond 7 days (after the first vaccine dose), HYPERRAB is not indicated since an antibody response to vaccine is presumed to have occurred.

Dosage for HyperRAB

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.

Rabies Postexposure Prophylaxis Schedule*

Vaccination Status	Treatment	Regimen†
Not previously vaccinated	Wound cleansing	Cleanse all wounds immediately and thoroughly with soap and water. Irrigate the wounds with a virucidal agent such as a povidone-iodine solution, if available.
	HYPERRAB 20 lU/kg body weight OR 0.0665 mL/kg body weight Single-dose	Administer HYPERRAB as soon as possible after exposure, preferably at the time of the first vaccine dose. Infiltrate the full dose of HYPERRAB thoroughly in the area around and into the wound(s), if anatomically feasible. [see DOSAGE AND ADMINISTRATION] Inject the remainder, if any, intramuscularly at an anatomical site distant from the site of vaccine administration. [see DOSAGE AND ADMINISTRATION] Do not exceed the recommended dose of HYPERRAB, otherwise the active production of rabies antibody may be partially suppressed. [see DRUG INTERACTIONS] Use separate syringes, needles, and anatomical injection sites for HYPERRAB and for rabies vaccine.
	Rabies Vaccine	Administer rabies vaccine on day 0‡. Complete a rabies vaccination series for previously unvaccinated persons.†
Previously vaccinated§	Wound cleansing	Cleanse all wounds immediately and thoroughly with soap and water. Irrigate the wounds with a virucidal agent such as a povidone-iodine solution, if available.
	HYPERRAB	Do not administer HYPERRAB. [see INDICATIONS AND USAGE]
	Rabies Vaccine	Administer rabies vaccine on day 0‡. Complete a rabies vaccination series for previously vaccinated persons.†
* Adapted from reference 1. † These regimens are applicable for all age groups, including children. ‡ Day 0 is the day the first dose of vaccine is administered. Refer to vaccine manufacturer’s instructions or to the recommendations of the Advisory Committee on Immunization Practices (ACIP)1,3 for appropriate rabies vaccine formulations, schedules and dosages. § Any person with a history of rabies vaccination and a documented history of antibody response to the prior vaccination.

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.
• Discard unused portion.

Administration

• Administer HYPERRAB at the time of the first vaccine dose (day 0), but no later than day 7.1-3
• 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.

HOW SUPPLIED

Dosage Forms And Strengths

HYPERRAB is a sterile, 300 IU/mL solution for injection supplied in 1 mL, 3 mL and 5 mL single-dose vials. The 1 mL vial is sufficient for a child weighing 15 kg. The 3 mL vial is sufficient for a person weighing 45 kg. The 5 mL vial is sufficient for an adult weighing 75 kg.

HYPERRAB is standardized against the U.S. Standard Rabies Immune Globulin to contain a potency of ≥300 IU/mL. The U.S. unit of potency is equivalent to the international unit (IU) for rabies antibody.

Storage And Handling

HYPERRAB is supplied in 1 mL, 3 mL and 5 mL single-dose vials of ready-to-use solution with a potency value of not less than 300 IU/mL.

HYPERRAB contains no preservative and is not made with natural rubber latex.

NDC Number	Size
13533-318-01	1 mL
13533-318-03	3 mL
13533-318-05	5 mL

• Store HYPERRAB at 2 to 8°C (36 to 46°F). Do not freeze.
  • HYPERRAB may be stored at room temperatures not to exceed 25°C (77°F) 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.
• Do not use after expiration date printed on the label.
• Discard unused portion.

REFERENCES

1. Centers for Disease Control and Prevention. Human rabies prevention — United States, 2008: Recommendations of the Advisory Committee on Immunization Practices. MMWR. 2008;57(RR03):1-26, 28.

2. World Health Organization. WHO Expert Consultation on Rabies: Second report. 2013. WHO technical report series, No. 982.

3. Centers for Disease Control and Prevention. Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies. Recommendations of the Advisory Committee on Immunization Practices. MMWR. 2010;59(RR02):1-9. Erratum in: MMWR 2010;59(16):493.

Grifols Therapeutics LLC Research Triangle Park, NC 27709 USA U.S. License Number 1871. Revised: Jan 2021

Side Effects for 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

Drug Interactions for HyperRAB

• Do not administer repeated doses of HYPERRAB® [rabies immune globulin (human)] once vaccine treatment has been initiated as this could prevent the full expression of active immunity expected from the rabies vaccine.1
• 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.5

REFERENCES

1. Centers for Disease Control and Prevention. Human rabies prevention — United States, 2008: Recommendations of the Advisory Committee on Immunization Practices. MMWR. 2008;57(RR03):1-26, 28.

5. Centers for Disease Control and Prevention. General recommendations on immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2011;60(RR02):1-61. Erratum in: MMWR 2011;60(29):993.

Warnings for HyperRAB

Included as part of the PRECAUTIONS section.

Precautions for HyperRAB

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.4

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 Specific Populations

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.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established.

Geriatric Use

Safety and effectiveness in geriatric population have not been established.

REFERENCES

4. Fudenberg HH. Sensitization to immunoglobulins and hazards of gamma globulin therapy. In: Merler E (editor). Immunoglobulins: biologic aspects and clinical uses. Washington, DC: National Academy of Science; 1970, p. 211-20.

Overdose Information for HyperRAB

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).1

Contraindications for HyperRAB

None.

REFERENCES

1. Centers for Disease Control and Prevention. Human rabies prevention — United States, 2008: Recommendations of the Advisory Committee on Immunization Practices. MMWR. 2008;57(RR03):1-26, 28.

Clinical Pharmacology for HyperRAB

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.1

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.7,8 Similarly, beneficial results were later reported from the U.S.S.R.9 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.10-13 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.14 In carefully controlled clinical studies, this globulin was used in conjunction with rabies vaccine of duck-embryo origin (DEV).14,15 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.14-22 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.21

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).23-24

Figure 1: Mean (Standard Deviation) Rabies Virus Neutralizing Antibody Levels (IU/mL) versus Time following a Single 20 IU/kg Dose of HYPERRAB® (300 IU/mL) by Intramuscular Injection

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 (Figure 2).

Figure 2: Reciprocal of Anti-Rabies Virus Neutralizing Antibody Titer Following a Single 20 IU/kg Dose of HYPERRAB® (300 IU/mL; RIG-C) or HYPERRAB® S/D (150 IU/mL; RIG-S/D) Product (mean [standard deviation])

Clinical Studies

HYPERRAB was administered to a total of 20 healthy adult subjects in two clinical trials. [see CLINICAL PHARMACOLOGY] 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).

REFERENCES

1. Centers for Disease Control and Prevention. Human rabies prevention — United States, 2008: Recommendations of the Advisory Committee on Immunization Practices. MMWR. 2008;57(RR03):1-26, 28.

7. Baltazard M, Bahmanyar M, Ghodssi M, et al. Essai pratique du sérum antirabique chez les mordus par loups enragés. [Practical test of anti-rabies serum in bites by rabid wolves]. Bull WHO. 1955;13:747-72.

8. Habel K, Koprowski H. Laboratory data supporting the clinical trial of antirabies serum in persons bitten by a rabid wolf. Bull WHO. 1955;13:773-9.

9. Selimov M, Boltucij L, Semenova E, et al. [The use of antirabies gamma globulin in subjects severely bitten by rabid wolves or other animals.] J Hyg Epidemiol Microbiol Immunol (Praha). 1959;3:168-80.

10. Atanasiu P, Bahmanyar M, Baltazard M, et al. Rabies neutralizing antibody response to different schedules of serum and vaccine inoculations in non-exposed persons. Bull WHO. 1956;14:593-611.

11. Atanasiu P, Bahmanyar M, Baltazard M, et al. Rabies neutralizing antibody response to different schedules of serum and vaccine inoculations in non-exposed persons: Part II. Bull WHO. 1957;17:911-32.

12. Atanasiu P, Cannon DA, Dean DJ, et al. Rabies neutralizing antibody response to different schedules of serum and vaccine inoculations in non-exposed persons: Part 3. Bull WHO. 1961;25:103-14.

13. Atanasiu P, Dean DJ, Habel K, et al. Rabies neutralizing antibody response to different schedules of serum and vaccine inoculations in non-exposed persons: Part 4. Bull WHO. 1967;36:361-5.

14. Cabasso VJ, Loofbourow JC, Roby RE, et al. Rabies immune globulin of human origin: preparation and dosage determination in non-exposed volunteer subjects. Bull WHO. 1971;45:303-15.

15. Loofbourow JC, Cabasso VJ, Roby RE, et al. Rabies immune globin (human): clinical trials and dose determination. JAMA. 1971;217(13):1825-31.

16. Plotkin SA. New rabies vaccine halts disease — without severe reactions. Mod Med. 1977;45(20):45-8.

17. Plotkin SA, Wiktor TJ, Koprowski H, et al. Immunization schedules for the new human diploid cell vaccine against rabies. Am J Epidemiol. 1976;103(1):75-80.

18. Hafkin B, Hattwick MA, Smith JS, et al. A comparison of a WI-38 vaccine and duck embryo vaccine for preexposure rabies prophylaxis. Am J Epidemiol. 1978;107(5):439-43.

19. Kuwert EK, Marcus I, Höher PG. Neutralizing and complement-fixing antibody responses in pre- and post-exposure vaccinees to a rabies vaccine produced in human diploid cells. J Biol Stand. 1976;4(4):249-62.

20. Grandien M. Evaluation of tests for rabies antibody and analysis of serum responses after administration of three different types of rabies vaccines. J Clin Microbiol. 1977;5(3):263-7.

21. Kuwert EK, Marcus I, Werner J, et al. Postexpositionelle Schutzimpfung des Menschen gegen Tollwut mit einer neu-entwickelten Gewebekulturvakzine (HDCS-Impfstoff). [Post exposure use of human diploid cell culture rabies vaccine (author’s transl)]. Zentralbl Bakteriol [A]. 1977;239(4):437-58.

22. Bahmanyar M, Fayaz A, Nour-Salehi S, et al. Successful protection of humans exposed to rabies infection: postexposure treatment with the new human diploid cell rabies vaccine and antirabies serum. JAMA. 1976;236(24):2751-4.

23. Helmick CG, Johnstone C, Sumner J, et al. A clinical study of Merieux human rabies immune globulin. J Biol Stand. 1982;10:357-67.

24. Lang J, Gravenstein S, Briggs D, et al. Evaluation of the safety and immunogenicity of a new, heat-treated human rabies immune globulin using a sham, post-exposure prophylaxis of rabies. Biologicals. 1998;26:7-15.

Patient Information for HyperRAB

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 WARNINGS AND PRECAUTIONS]

Inform the patient who is deficient in IgA the potential for developing anti-IgA antibodies and severe potentially life-threatening allergic reactions. [see WARNINGS AND 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 WARNINGS AND PRECAUTIONS]