For Pre-Exposure Use Only

Pre-exposure immunization should be considered for persons in high risk groups, such as veterinarians, animal handlers, certain laboratory workers, and those whose vocational or avocational pursuits bring them into contact with potentially rabid dogs, cats, foxes, skunks, bats, or other species at risk of having rabies. (See Table 1 )

For persons traveling abroad into endemic areas, Human Diploid Cell Vaccine (HDCV) may be administered by the I.D. dose and route if the 3 dose series is completed 30 days or more before departure. If pre-exposure vaccination is performed for travelers at other times, a vaccine intended for intramuscular use should be used.

Vaccination is recommended for children living in or visiting countries where exposure to rabid animals is a constant threat. Worldwide statistics indicate children are more at risk than adults.

Pre-exposure prophylaxis is given for several reasons. First, it may provide protection to persons with inapparent exposure to rabies. Secondly, it may protect persons whose post-exposure therapy might be expected to be delayed. Finally, although it does not eliminate the need for additional therapy after a rabies exposure, it simplifies therapy by eliminating the need for globulin and decreasing the number of doses of vaccine needed. This is of particular importance for persons at high risk of being exposed in countries where the available rabies immunizing products may carry a higher risk of adverse reactions.

Pre-exposure immunization does not eliminate the need for prompt prophylaxis following an exposure. It only reduces the post-exposure treatment regimen.

Pre-Exposure Rabies Treatment Guide

Pre-exposure immunization consists of a total of three doses of HDCV given on Days 0, 7 and 21 or 28. Each dose is 0.1 given intradermally in the deltoid area of either arm. Administration of booster doses of vaccine following primary 3-dose immunization depends on exposure risk category as noted in Table 1. Pre-exposure immunization of immunosuppressed persons is not recommended. (9)

* Judgement of relative risk and extra monitoring of immunization status of laboratory workers is the responsibility of the laboratory supervisor (see U. S. Department of Health and Human Service's Biosafety in Microbiological and Biomedical Laboratories, 1984).

^† Pre-exposure booster immunization consists of one dose of HDCV, 0.1 ml l. D. or 1.0 ml l. M. (deltoid area). Acceptable antibody level is a titer of 1:5 (complete inhibition of infectious foci in RFFIT at 1:5 serum dilution). See CLINICAL PHARMACOLOGY. Boost if titer falls below 1:5.

PARENTERAL DRUG PRODUCTS SHOULD BE INSPECTED VISUALLY FOR PARTICULATE MATTER AND DISCOLORATION PRIOR TO ADMINISTRATION, WHENEVER SOLUTION AND CONTAINER PERMIT. THE FREEZEDRIED VACCINE IS CREAMY WHITE TO ORANGE. AFTER RECONSTITUTION IT IS PINK TO RED.

Primary Vaccination — Based upon studies in Europe (3,4) and the United States (8,9) the Immunization Practices Advisory Committee (ACIP) recommends three injections of 0.1 ml each; one injection on Day 0, one on Day 7, and one either on Day 21 or 28. (9,21) The ACIP, in making this recommendation, cites studies conducted in the United States and Europe in which more than 1500 persons received 0.1 ml of vaccine intradermally as the 2 or 3-dose pre-exposure vaccination. All subjects developed antibody as shown by the rapid fluorescent focus inhibition test (RFFIT). The ACIP suggests that routine serologic testing to confirm a satisfactory antibody response is not necessary. (22)

Booster Dose — Persons working with live rabies virus in research laboratories and in vaccine production facilities should have rabies antibody titers checked every six months and boosters given as needed to maintain an adequate titer. (For definition of adequate titer, see CLINICAL PHARMACOLOGY) Laboratory workers, such as those doing rabies diagnostic tests, spelunkers and veterinarians, animal control and wildlife officers in areas where rabies is epizootic should have boosters every 2 years or have their serum tested for rabies antibody every 2 years and if the titer is inadequate, have a booster dose. Veterinarians and animal control and wildlife officers working in areas of low rabies endemicity do not require routine doses of HDCV after completion of primary preexposure immunization (Table 1).

Persons who have experienced "immune complex-like" hypersensitivity reactions should receive no further doses of HDCV unless they are exposed to rabies or they are truly likely to be inapparently and or unavoidably exposed to rabies virus and have unsatisfactory antibody titers.

Instructions for Use — Please Read Carefully and Completely

This package contains.

- A single dose syringe of freeze dried Imovax Rabies l.D., Rabies Vaccine, which after reconstitution must be completely given by the intradermal route.

If the intradermal inoculation was not performed satisfactorily (vaccine injected subcutaneously) another dose should be given intradermally at a different site.

- One vial of diluent (Sterile Water for Injection USP). The quantity of diluent contained in the vial is in excess of the volume needed. The purpose of this excess is to permit withdrawal of diluent without introduction of air.

To Open Vial

1. Pull green metal flip top in direction of arrow. This will loosen outer seal enough to be removed.

2. Remove gray stopper.

3. Carefully slide syringe out of glass vial.

To Prepare Diluent

1. Remove center of green protective cover at perforation on diluent vial.

2. Disinfect pink stopper seal surface.

Reconstituting Vaccine

1. Remove protective rubber cap from needle.

2. Push plunger so that the leading edge of the black stopper is even with the broken blue line.

3. Insert needle into diluent bottle, keeping it upright. The needle must be in the liquid during withdrawal of the diluent to prevent air bubbles.

4. Withdraw diluent so that end of black stopper is at solid blue line.

5. Replace protective rubber cap on needle and wait for freezedried vaccine to dissolve. Make sure that the freeze dried vaccine is completely dissolved. Shake if necessary.

6. Remove protective cap and vaccine is ready to use.

- After reconstitution, eliminate the air bubbles and bring together the droplets of vaccine either by flicking the syringe or, if necessary, grasp the covered needle end of the syringe and use a strong downward motion. (as with a thermometer).

- THE RECONSTITUTED VACCINE SHOULD BE USED IMMEDIATELY.

- Remove the needle cover.

- Push in the plunger to eliminate the air.

- Disinfect the injection site.

- Inject intradermally.

- Destroy needle by clipping it off at the base of syringe.

Imovax Rabies I.D., Rabies Vaccine - for pre-exposure use only by the intradermal route is supplied in a tamperproof unit with:

• One disposable syringe with integral needle containing a single dose of freeze dried vaccine.
• One vial of Sterile Water for Injection USP for reconstitution.

Storage

The freeze-dried vaccine should be stored in the refrigerator between 2° C and 8° C (35° F to 47° F). Do not freeze.

REFERENCES

1. Aoki FY, Tyrell DA, Hill LE: Immunogenicity and acceptability of a human diploid cell rabies vaccine in volunteers. Lancet 1: 660- 62 (1975).

2. Turner GS, Aoki FY, Nicholson KG, Tyrrell DA, Hill LE: Human diploid cell strain rabies vaccine: Rapid prophylactic immunization of volunteers with small doses. Lancet 1: 1379- 81 (1976).

3. Cox JH, Schneider LG: Prophylactic immunization of humans against rabies by intradermal inoculation of human diploid cell culture vaccine. J. Clin. Microbial. 3: 96- 101 (1976).

4. Nicholson KG, Turner GS, Aoki FY: Immunization with a human diploid cell strain of rabies virus vaccine: Twoyear results, J. Infect. Dis. 137: 783- 88 (1978).

5. Nicholson KG, Turner GS: Studies with human diploid cell strain rabies vaccine and human antirabies globulin in man. Dev. Biol. Stand. 40: 115- 20 (1978).

6. Ajjan N, Soulebot JP, Triau R, Biron G: Intradermal Immunization with rabies vaccine: Inactivated Wistar strain cultivated in human diploid cells. JAMA 244: 2528- 31 (1980).

7. Bernard KW, Roberts MA, Sumner J, Winkler WG, Mallonee J, Baer GM, Chaney R: Human diploid cell rabies vaccine: Effectiveness of immunization with small intradermal or subcutaneous doses. JAMA 247: 1138- 42 (1982).

8. Dreesen DW, Brown WJ, Kemp DT, Brown J, Reid FL, Baer GM: Pre- exposure rabies prophylaxis: efficacy of a new packaging and delivery system for intradermal administration of human diploid cell vaccine. Vaccine 2: 185- 88 (1984).

9. C.C. Recommendations of the Immunization Practices Advisory Committee (ACIP). Rabies Prevention - United States, 1984. MMWR 33: 393- 402, 407- 8 (1984).

10. C.C. Systemic allergic reactions following immunization with human diploid cell rabies vaccine. MMWR 33: 185- 87 (1984).

11. Dreesen DW, Bernard KW, Parker RA, Deutsch AJ, Brown J: Immune complex like disease in 23 persons following a booster dose of rabies human diploid cell vaccine. Vaccine 4: 45- 49 (1986).

12. Baer H, Anderson HC, Bernard K, Quinnan G: Beta propiolactone treated human serum albumin (BPL- HSA) an allergen for humans receiving rabies vaccine. (Abstract). J. Allergy and Clin. Immunol. 75: (No. 1 Part 2 suppl) (1985).

13. Boe E, Nyand H: Guillain- Barré syndrome after vaccination with human diploid cell rabies vaccine. Scand. J. Infect. Dis. 12: 231- 32 (1980).

14. C.C. Adverse reactions to human diploid cells rabies vaccine. MMWR 29: 609- 10 (1980).

15. Bernard KW, Smith PW, Kader FJ, Moran MJ: Neuroparalytic illness and human diploid cell rabies vaccine. JAMA 248: 3136- 38 (1982).

16. Taylor DN, Wasi C, Bernard K: Chloroquine prophylaxis associated with a p.o. antibody response to human diploid cell rabies vaccine. Lancet 1: 1408 (1984).

17. Pappaioanou M, Fishbein DB, Dreesen DW, Schwartz IK, Campbell GH, Sumner JW, Patchen LC, Brown WJ: Antibody response to pre-exposure human diploid cell rabies vaccine given concurrently with chloroquine. N. Engl. J. Med. 314: 280- 84 (1986).

18. Bernard KW, Fishbein DB, Miller KD, Parker RA, Waterman S, Sumner JW, Reid FL, Johnson BK, Rollins AJ, Oster CN, Schonberger LB, Baer GM, Winkler WG: Pre-exposure rabies immunization with human diploid cell vaccine. Decreased antibody responses in persons immunized in developing countries. Am. J. Trop. Med. Hyg. 34: 633- 47 (1985).

19. Fridell E, Grandien M, Johansson R: Pre- exposure prophylaxis against rabies in children by human diploid cell vaccine. Lancet 1: 623 (1984).

20. Greenberg M, Childress J: Vaccination against rabies with duck embryo and Semple vaccines. JAMA 173: 333- 37 (1960).

21. C.C. ACIP Recommendations: Supplementary statement on pre- exposure rabies prophylaxis by the intradermal route. MMWR 31: 279- 85 (1982).

22. C.C. ACIP Recommendation: Supplementary statement on rabies vaccine and serologic testing. MMWR 30: 535- 36 (1981).

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