“Meruvax II is a sterile lyophilized preparation of the Wistar Institute RA

27/3 strain of

live attenuated rubella virus. The virus was adapted to and propagated in

human diploid

cell (WI-38) culture.1-2”

Mosby’s GenRx®, 10^th ed.

Copyright © 2000 Mosby, Inc.

Rubella Virus Vaccine Live (002196)

CATEGORIES:

Indications: Immunization, rubella

Pregnancy Category C

WHO Formulary

FDA Pre 1938 Drugs

FDA DRUG CLASS: Vaccines/Antisera

BRAND NAMES: Cendevax (Benin, Burkina-Faso, Ethiopia, Gambia, Ghana, Guinea, Ivory-Coast, Kenya, Liberia, Malawi, Mali, Mauritania, Mauritius, Morocco, Niger, Nigeria, Senegal, Seychelles, Sierra-Leone, Sudan, Tanzania, Tunia, Uganda, Zambia, Zimbabwe); Ervevax (Australia, Austria, Bulgaria, Czech-Republic, England, Germany, Italy, Netherlands, Switzerland, Malaysia, Philippines, Taiwan, Thailand); Gunevax (Philippines, Thailand);

Meruvax II

(US); Rubavax (England); Rubeaten (Austria, Czech-Republic, Greece, Italy, Spain, Switzerland); Rubeaten Berna (Malaysia, Philippines, Taiwan, Thailand, South-Africa);

Rudivax (Malaysia, Taiwan);

(International brand names outside U.S. in italics)

DESCRIPTION:

Meruvax II (Rubella Virus Vaccine Live) is a live virus vaccine for immunization against rubella (German measles).

Meruvax II is a sterile lyophilized preparation of the Wistar Institute RA

27/3 strain of

live attenuated rubella virus. The virus was adapted to and propagated in

human diploid

cell (WI-38) culture.1-2

The reconstituted vaccine is for subcutaneous administration. When reconstituted as directed, the dose for injection is 0.5 ml and contains not less than the equivalent of 1,000 TCID50 (tissue culture infectious doses) of the U.S. Reference Rubella Virus.

Each dose also contains approximately 25 mcg of neomycin. The product contains no preservative. Sorbitol and hydrolyzed gelatin are added as stabilizers.

CLINICAL PHARMACOLOGY:

Meruvax II produces a modified, non-communicable rubella infection in susceptible persons.

Extensive clinical trials of rubella virus vaccines, prepared using RA 27/3 strain rubella virus, have been carried out in more than 28,000 human subjects (approximately 11,000 with Meruvax II) in the U.S.A. and more than 20 additional countries. A single injection of the vaccine has been shown to induce rubella hemagglutination-inhibiting (HI) antibodies in 97% or more of susceptible persons. The RA 27/3 rubella strain elicits higher immediate post-vaccination HI, complement-fixing and neutralizing antibody levels than other strains of rubella vaccine3-9 and has been shown to induce a broader profile of circulating antibodies including anti-theta and anti-iota precipitating antibodies.10,11 The RA 27/3 rubella strain immunologically simulates natural infection more closely than other rubella vaccine viruses.11-13 The increased levels and broader profile of antibodies produced by RA 27/3 strain rubella virus vaccine appear to correlate with greater resistance to subclinical reinfection with the wild virus,11,13-15 and provide greater confidence for lasting immunity.

Vaccine-induced antibody levels have been shown to persist for at least 10 years without substantial decline.16 If the present pattern continues, it will provide a basis for the expectation that immunity following vaccination will be permanent.  However, continued surveillance will be required to demonstrate this point.

INDICATIONS AND USAGE:

(This section is based, in part, on the recommendation for rubella vaccine use of the Immunitazation Practices Advisory Committee (AICP), MMWR Report: 33 (22):

301-310, 315-318, June 8, 1984).

Children Between 12 Months of Age and Puberty: Meruvax II is indicated for immunization against rubella (German measles) in persons from 12 months of age to puberty. A booster is not needed. It is not recommended for infants younger than 12 months because they may retain maternal rubella neutralizing antibodies that may interfere with the immune response. Children in kindergarten and the first grades of elementary school deserve priority for vaccination because often they are epidemiologically the major source of virus dissemination in the community.  A history of rubella illness is usually not reliable enough to exclude children from immunization.

Previously unimmunized children of susceptible pregnant women should receive live attenuated rubella vaccine, because an immunized child will be less likely to acquire natural rubella and introduce the virus into the household.

Adolescent and Adult Males: Vaccination of adolescent or adult males may be a useful procedure in preventing or controlling outbreaks of rubella in circumscribed population groups (e.g., military bases and schools).

Non-Pregnant Adolescent and Adult Females: Immunization of susceptible

non-pregnant adolescent and adult females of childbearing age with live

attenuated

rubella virus vaccine is indicated if certain precautions are observed (see

PRECAUTIONS.) Vaccinating susceptible postpubertal females confers individual

protection against subsequently acquiring rubella infection during

pregnancy, which in

turn prevents infection of the fetus and consequent congenital rubella

injury.17

Women of childbearing age should be advised not to become pregnant for

three months

after vaccination and should be informed of the reason for this precaution.*

It is recommended that rubella susceptibility be determined by serologic testing prior to immunization.** If immune, as evidenced by a specific rubella antibody titer of 1:8 or greater (hemagglutination-inhibition test), vaccination is unnecessary.  Congenital malformations do occur in up to seven percent of all live births.18 Their chance appearance after vaccination could lead to misinterpretation of the cause, particularly if the prior rubella-immune status of vaccinees is unknown.

Postpubertal females should be informed of the frequent occurrence of generally self-limited arthralgia and/or arthritis beginning 2 to 4 weeks after vaccination (see ADVERSE REACTIONS.)

Postpartum Women: It has been found convenient in many instances to vaccinate rubella susceptible women in the immediate postpartum period (see Nursing Mothers.)

International Travelers: Individuals planning travel outside the United

States, if not

immune can acquire measles, mumps or rubella and import these diseases to

the United

States. Therefore, prior to International travel, individuals known to be

susceptible to

one or more of these diseases can receive either a single antigen vaccine

(measles,

mumps or rubella), or a combined antigen vaccine as appropriate. However,

M-M-R

II (Measles Mumps, and Rubella Virus Vaccine Live) is preferred for persons

likely to

be susceptible to mumps and rubella; and if single-antigen measles vaccine

is not readily

available, travelers should receive M-M-R II (Measles, Mumps, and Rubella

Virus

Vaccine Live) regardless of their immune status to mumps or rubella.19,20,21

Revaccination: Children vaccinated when younger than 12 months of age should be revaccinated. Based on available evidence, there is no reason to routinely revaccinate persons who were vaccinated originally when 12 months of age or older.  However, persons should be revaccinated if there is evidence to suggest that initial immunization was ineffective.

Use with Other Vaccines: Routine administration of DTP (diphtheria, tetanus,

pertussis) and/or OPV (oral poliovirus vaccine) concomitantly with measles,

mumps

and rubella vaccines is not recommended because there are insufficient data

relating to

the simultaneous administration of these antigens. However, the American

Academy of

Pediatrics has noted that in some circumstances, particularly when the

patient may not

return, some practitioners prefer to administer all these antigens on a

single day. If done,

separate sites and syringes should be used for DTP and Meruvax II.22

Meruvax II should not be given less than one month before or after administration of other virus vaccines.

·        NOTE: The Immunization Practices Advisory Committee (ACIP) has recommended “In view of the importance of protecting this age group against rubella, reasonable precautions in a rubella immunization program include asking females if they are pregnant, excluding those who say they are, and explaining the theoretical risks to the others.”17

**NOTE: The Immunization Practices Advisory Committee (ACIP) has stated “When practical, and when reliable laboratory services are available, potential vaccinees of childbearing age can have serologic tests to determine susceptibility to rubella....

However, routinely performing serologic tests for all females of

childbearing age to

determine susceptibility so that vaccine is given only to proven

susceptibles is expensive

and has been ineffective in some areas. Accordingly, the ACIP believes that

rubella

vaccination of a woman who is not known to be pregnant and has no history of

vaccination is justifiable without serologic testing.”17

CONTRAINDICATIONS:

Do not give Meruvax II to pregnant females; the possible effects of the vaccine on fetal development are unknown at this time. If vaccination of postpubertal females is undertaken, pregnancy should be avoided for three months following vaccination. (See PRECAUTIONS, Pregnancy .)

Anaphylactic or anaphylactoid reactions to neomycin (each dose of reconstituted vaccine contains approximately 25 mcg of neomycin).

Any febrile respiratory illness or other active febrile infection.

Active untreated tuberculosis.

Patients receiving immunosuppressive therapy. This contraindication does not apply to patients who are receiving corticosteroids as replacement therapy, e.g., for Addison’s disease.

Individuals with blood dyscrasias, leukemia, lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic systems.

Primary and acquired immunodeficiency states, including patients who are immunosuppressed in association with AIDS or other clinical manifestations of infection with human immunodeficiency viruses;23,24 cellular immune deficiencies; and hypogammaglobulinemic and dysgammaglobulinemic states.

Individuals with a family history of congenital or hereditary

immunodeficiency, until the

immune competence of the potential vaccine recipient is demonstrated.25

PRECAUTIONS:

General

Adequate treatment provisions including epinephrine, should be available for immediate use should an anaphylactic or anaphylactoid reaction occur.

Excretion of small amounts of the live attenuated rubella virus from the nose or throat has occurred in the majority of susceptible individuals 7-28 days after vaccination.

There is no confirmed evidence to indicate that such virus is transmitted to susceptible persons who are in contact with the vaccinated individuals. Consequently, transmission through close personal contact, while accepted as a theoretical possibility, is not regarded as a significant risk.17 However, transmission of the vaccine virus to infants via breast milk has been documented (see Nursing Mothers.)

There is no evidence that live rubella virus vaccine given after exposure to natural rubella virus will prevent illness. There is, however, no contraindication to vaccinating children already exposed to natural rubella.

Children and young adults who are known to be infected with human

immunodeficiency

viruses but without overt clinical manifestations of immunosuppression may be

vaccinated; however, the vaccinees should be monitored closely for

vaccine-preventable diseases because immunization may be less effective

than for

uninfected persons.23,24

Vaccination should be deferred for at least three months following blood or plasma transfusions, or administration of human immune serum globulin. However, susceptible postpartum patients who received blood products may receive Meruvax II prior to discharge provided that a repeat HI titer is drawn 6-8 weeks after vaccination to insure seroconversion. Similarly, although studies with other live rubella virus vaccines suggest that Meruvax II may be given in the immediate postpartum period to those non-immune women who have received anti-Rho (D) globulin (human) without interfering with vaccine effectiveness, a follow-up post-vaccination HI titer should also be determined.

It has been reported that attenuated rubella virus vaccine, live, may result in a temporary depression of tuberculin skin sensitivity. Therefore, if a tuberculin test is to be done, it should be administered either before or simultaneously with Meruvax II.

As for any vaccine, vaccination with Meruvax II may not result in seroconversion in 100% of susceptible persons given the vaccine.

Pregnancy Category C

Animal reproduction studies have not been conducted with Meruvax II. It is also not known whether Meruvax II can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. There is evidence suggesting transmission of rubella vaccine viruses to products of conception.26 Therefore, rubella vaccine should not be administered to pregnant females (see CONTRAINDICATIONS.)

In counseling women who are inadvertently vaccinated when pregnant or who become pregnant within 3 months of vaccination, the physician should be aware of the following:

In a 10 year survey involving over 700 pregnant women who received rubella

vaccine

within 3 months before or after conception, (of whom 189 received the

Wistar RA 27/3

strain) none of the newborns had abnormalities compatible with congenital

rubella

syndrome.26

Nursing Mothers

Recent studies have shown that lactating postpartum women immunized with live attenuated rubella vaccine may secrete the virus in breast milk and transmit it to breast-fed infants.27 In the infants with serological evidence of rubella infection, none exhibited severe disease; however, one exhibited mild clinical illness typical of acquired rubella.28,29 Caution should be exercised when Meruvax II is administered to a nursing woman.

ADVERSE REACTIONS:

Burning and/or stinging of short duration at the injection site have been reported.

Symptoms of the same kind as those seen following natural rubella may occur after vaccination. These include mild regional lymphadenopathy, urticaria, rash, malaise, sore throat, fever headache, dizziness, nausea, vomiting, diarrhea, polyneuritis, and a thralgia and/or arthritis (usually transient and rarely chronic). Local pain, wheal and flare, induration, and erythema may occur at the site injection. Reactions are usually mild and transient. Erythema multiforme has also been reported rarely.

Cough and rhinitis have also been reported.

Vasculitis has been reported rarely.

Anaphylaxis and anaphylactoid reactions have been reported.

Moderate fever (101 - 102.9°F (38.3 - 39.4°C)) occurs occasionally, and high fever (over 103°F (39.4°C)) occurs less commonly.

Syncope, particularly at the time of mass vaccination, has been reported.

Chronic arthritis has been associated with natural rubella infection and has been related to persistent virus and/or viral antigen isolate from body tissues. Only rarely have vaccine recipients developed chronic joint symptoms.

Following vaccination in children, reactions in joints are uncommon and generally of brief duration. In women, incidence rates for arthritis and arthralgia are generally higher than those seen in children (children: 0-3%; women: 12-20%)30 and the reactions tend to be more marked and of longer duration. Symptoms may persist for a matter of months or on rare occasions for years. In adolescent girls, the reactions appear to be intermediate in incidence between those seen in children and in adult women. Even in older women (35 - 45 years), these reactions are generally well tolerated and rarely interfere with normal activities. Myalgia and paresthesia have been reported rarely after administration of Meruvax II.

Forms of optic neuritis, including retrobulbar neuritis and papillitis, may infrequently follow viral infections, and have been reported to occur 1 to 3 weeks following inoculation with some live virus vaccines.

Isolated reports of polyneuropathy including Guillain-Barre syndrome have been reported after immunization with rubella-containing vaccines.

Clinical experience with live rubella vaccines thus far indicates that encephalitis and other nervous system reactions have occurred very rarely in subjects who were given the vaccines, but a cause and effect relationship has not been established.

Thrombocytopenia with or without purpura has been reported.

DOSAGE AND ADMINISTRATION:

FOR SUBCUTANEOUS ADMINISTRATION

Do not inject intravenously

The dosage of vaccine is the same for all persons. Inject the total volume of the single dose vial (about 0.5 ml) or 0.5 ml of the multiple dose vial of reconstituted vaccine subcutaneously, preferably into the outer aspect of upper arm. Do not give immune globulin (IG) concurrently with Meruvax II.

To insure that there is no loss of potency during shipment, the vaccine must be maintained at a temperature of 10°C (50°F) or less.

Before reconstitution, store Meruvax II at 2 - 8°C (36 - 46°F). Protect from light.

CAUTION: A sterile syringe free of preservatives, antiseptics, and detergents should be used for each injection and/or reconstitution of the vaccine because these substances may inactivate the live virus vaccine. A 25 gauge, 5/8” needle is recommended.

To reconstitute, use only the diluent supplied, since it is free of preservatives or other antiviral substances which might inactivate the vaccine.

Single Dose Vial: First withdraw the entire volume of diluent into the syringe to be used for reconstitution. Inject all the diluent in the syringe into the vial of lyophilized vaccine, and agitate to mix thoroughly. Withdraw the entire contents into a syringe and inject the total volume of restored vaccine subcutaneously.

It is important to use a separate sterile syringe and needle for each individual patient to prevent transmission of hepatitis B and other infectious agents from one person to another.

10 Dose Vial (available only to government agencies/institutions): Withdraw the entire contents (7 ml) of the diluent vial into the sterile syringe to be used for reconstitution, and introduce into the 10 dose vial of lyophilized vaccine.  Agitate to ensure thorough mixing. The outer labeling suggests “For Jet Injector or Syringe Use”.

Use with separate sterile syringes is permitted for containers of 10 doses or less. The vaccine and diluent do not contain preservatives; therefore, the user must recognize the potential contamination hazards and exercise special precautions to protect the sterility and potency of the product. The use of aseptic techniques and proper storage prior to and after restoration of the vaccine and subsequent withdrawal of the individual doses is essential. Use 0.5 ml of the reconstituted vaccine for subcutaneous injection.

It is important to use a separate sterile syringe and needle for each individual patient to prevent transmission of hepatitis B and other infectious agents from one person to another.

50 Dose Vial (available only to government agencies/institutions): Withdraw the entire contents (30 ml) of diluent vial into the sterile syringe to be used for reconstitution and introduce into the 50 dose vial of lyophilized vaccine. Agitate to ensure thorough mixing. With full aseptic precautions, attach the vial to the sterilized multidose jet injector apparatus. Use 0.5 ml of the reconstituted vaccine for subcutaneous injection.

Each dose contains not less than the equivalent of 1,000 TCID50 of the U.S.

Reference

Rubella Virus.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Meruvax II, when reconstituted, is clear yellow.

Storage

It is recommended that the vaccine be used as soon as possible after reconstitution.

Protect vaccine from light at all times, since such exposure may inactivate the virus.

Store reconstituted vaccine in the vaccine vial in a dark place at 2 - 8°C (36 - 46°F) and discard if not used within 8 hours.

REFERENCES:

1.   Plotkin, S. A.; Cornfeld, D.; Ingalls, T. H.: Studies of immunization with living rubella virus: Trials in children with a strain cultured from an aborted fetus, Am.  J. Dis. Child.

110: 381-389, 1965.

2.   Plotkin, S. A.; Farquhar, J.; Katz, M.; Ingalls, T. H.: A new attenuated rubella virus grown in human fibroblasts: Evidence for reduced nasopharyngeal excretion, Am. J.

Epidemiol. 86: 468-477, 1967.

3.   Fogel, A.; Moshkowitz, A.; Rannon, L.; Gerichter, Ch. B.: Comparative trials of RA 27/3 and Cendehill rubella vaccines in adult and adolescent females, Am. J.  Epidemiol.

93: 392-398, 1971.

4.   Andzhaparidze, O. G.; Desyatskova, R. G.; Chervonski, G. I.;

Pryanichnikova, L.

V.: Immunogenicity and reactogenicity of live attenuated rubella virus vaccines, Am. J.

Epidemiol. 91: 527-530, 1970.

5.   Freestone, D. S.; Reynolds, G. M.; McKinnon, J. A.; Prydie, J.:

Vaccination of schoolgirls against rubella. Assessment of serological status and a comparative trial of Wistar RA 27/3 and Cendehill strain live attenuated rubella vaccines in 13-year-old schoolgirls in Dudley, Br. J. Prev. Soc. Med. 29: 258-261, 1975.

6.   Grillner, L.; Hedstrom, C. E.; Bergstrom, H.; Forssman, L.; Rigner,A.;

Lycke, E.:

Vaccination against rubella of newly delivered women, Scand.J. Infect. Dis. 5:

237-241, 1973.

7.   Grillner, L.: Neutralizing antibodies after rubella vaccination of newly delivered women: a comparison between three vaccines, Scand. J. Infect. Dis. 7: 169-172, 1975.

8.   Wallace, R. B.; Isacson, P.: Comparative trial of HPV-77, DE-5 and RA 27/3 live-attenuated rubella vaccines, Am. J. Dis. Child. 124: 536-538, 1972.

9.   Lalla, M.; Vesikari, T.; Virolainen, M.: Lymphoblast proliferation and humoral antibody response after rubella vaccination, Clin. Exp. Immunol.15:

193-202, 1973.

10. LeBouvier, G. L.; Plotkin, S. A.: Precipitin responses to rubella vaccine RA 27/3, J. Infect. Dis. 123: 220-223, 1971.

11. Horstmann, D. M.: Rubella: the challenge of its control, J. Infect.

Dis. 123:

640-654, 1971.

12. Ogra, P. L.; Kerr-Grant, D.; Umana, G.; Dzierba, J.; Weintraub, D.:

Antibody response in serum and nasopharynx after naturally acquired and vaccine-induced infection with rubella virus, N. Engl. J. Med.285: 1333-1339, 1971.

13. Plotkin, S. A.; Farquhar, J. D.; Ogra, P. L.: Immunologic properties of

RA 27/3 rubella virus vaccine, J. Am. Med. Assoc. 225: 585-590, 1973.

14. Liebhaber, H.; Ingalls, T. H.; LeBouvier, G. L.; Horstmann, D. M.:

Vaccination with RA 27/3 rubella vaccine. Persistence of immunity and resistance to challenge after two years, Am. J. Dis. Child. 123: 133-136, 1972.

15. Farquhar, J. D.: Follow-up on rubella vaccinations and experience with subclinical reinfection, J. Pediatr. 81: 460-465, 1972.

16. Hillary, I. B.; Griffith, A. H.: Persistence of antibody 10 years after vaccination with Wistar RA 27/3 strain live attenuated rubella vaccine. Br. Med. J. 280 (6231):

1580-1581, 1980.

17. Recommendation of the Immunization Practices Advisory Committee (ACIP), Morbidity and Mortality Weekly Report 33 (22): 301-310, 315-318, June 8, 1984.

18. Mclntosh, R.; Merritt, K. K.; Richards, M. R.; Samuels, M. H.; Bellows, M. T.:

The incidence of congenital malformations: A study of 5,964 pregnancies, Pediatrics 14:

505-521, 1954.

19. Recommendations of the Immunization Practices Advisory Committee (ACIP), Measles Prevention, MMWR 36 (26): 409-425, July 10, 1987.

20. Jong, E. C., The Travel and Tropical Medicine Manual, W. B. Saunders Company, p. 12-16, 1987.

21. Committee on Immunization Council of Medical Societies, American

College of

Physicians, Phila., PA, Guide for Adult Immunization, First Edition, 1985.

22. American Academy of Pediatrics: Report of the Committee on Infectious Disease, Evanston, III., 1982, p. 17.

23. Center for Disease Control: Immunization of Children Infected with Human T-Lymphotropic Virus Type III/Lymphadenopathy-Associated Virus, Annals of Internal Medicine, 106: 75-78, 1987.

24. Krasinski, K.; Borkowsky, W.; Krugman, S.: Antibody following measles immunization in children infected with human T-cell lymphotropic virus-type III/lymphadenopathy associated virus (HTLV-III/LAV) (Abstract). In: Program and abstracts of the International Conference on Acquired Immunodeficiency Syndrome, Paris, France, June 23-25, 1986.

25. Recommendation of the Immunization Practices Advisory Committee (ACIP), General Recommendations on Immunization, Morbidity and Mortality Weekly Report 32 (1): 13, January 14, 1983.

26. Rubella vaccination during pregnancy—United States, 1971-1981,

Morbidity and

Mortality Weekly Report 31 (35): 477-481, September 10, 1982.

27. Losonsky, G. A.; Fishaut, J. M.; Strussenberg, J.; Ogra, P. L.: Effect of immunization against rubella on lactation products. II. Maternal-neonatal interactions, J.

Infect. Dis. 145: 661-666, 1982.

28. Landes, R. D.; Bass, J. W.; Millunchick, E. W.; Oetgen, W. J.: Neonatal rubella following postpartum maternal immunization, J. Pediatr.97: 465-467, 1980.  (Letter)

29. Lerman, S. J.: Neonatal rubella following postpartum maternal immunization, J.  Pediatr. 98: 668, 1981. (Letter)

30. Unpublished data from the files of Merck Sharp & Dohme Research Laboratories.

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ALL INFORMATION, DATA, AND MATERIAL CONTAINED, PRESENTED, OR PROVIDED HERE IS FOR GENERAL INFORMATION PURPOSES ONLY AND IS NOT TO BE CONSTRUED AS REFLECTING THE KNOWLEDGE OR OPINIONS OF THE PUBLISHER, AND IS NOT TO BE CONSTRUED OR INTENDED AS PROVIDING MEDICAL OR LEGAL ADVICE.  THE DECISION WHETHER OR NOT TO VACCINATE IS AN IMPORTANT AND COMPLEX ISSUE AND SHOULD BE MADE BY YOU, AND YOU ALONE, IN CONSULTATION WITH YOUR HEALTH CARE PROVIDER.