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CLINICAL PHARMACOLOGY Clinical studies of 237 double seronegative children, 10 months to 10 years of age, demonstrated that M-R-VAX (measles and rubella virus vaccine live) II is highly immunogenic and generally well tolerated. In these studies, a single injection of the vaccine induced measles hemagglutination-inhibition (HI) antibodies in 95 percent and rubella HI antibodies in 99 percent of susceptible persons. The RA 27/3 rubella strain in M-R-VAX (measles and rubella virus vaccine live) II elicits higher immediate post-vaccination HI, complement-fixing and neutralizing antibody levels than other strains of rubella vaccine and has been shown to induce a broader profile of circulating antibodies including anti-theta and anti-iota precipitating antibodies. The RA 27/3 rubella strain immunologically simulates natural infection more closely than other rubella vaccine viruses. 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, and provide greater confidence for lasting immunity. Vaccine induced antibody levels following administration of M-R-VAX (measles and rubella virus vaccine live) II have been shown to persist up to 11 years without substantial decline. Continued surveillance will be necessary to determine further duration of antibody persistence.

DESCRIPTION M-R-VAX® II (measles and rubella virus vaccine live) (Measles and Rubella Virus Vaccine Live), is a live virus vaccine for immunization against measles (rubeola) and rubella (German measles). M-R-VAX (measles and rubella virus vaccine live) II is a sterile lyophilized preparation of (1) ATTENUVAX* (Measles Virus Vaccine Live), a more attenuated line of measles virus, derived from Enders' attenuated Edmonston strain and grown in cell cultures of chick embryo; and (2) MERUVAX* II (Rubella Virus Vaccine Live), the Wistar RA 27/3 strain of live attenuated rubella virus grown in human diploid cell (WI-38) culture. The vaccine viruses are the same as those used in the manufacture of ATTENUVAX (Measles Virus Vaccine Live) and MERUVAX II (Rubella Virus Vaccine Live). The two viruses are mixed before being lyophilized. The product contains no preservative. 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 TCID 50 (tissue culture infectious doses) of the U.S. Reference Measles Virus; and 1,000 TCID 50 of the U.S. Reference Rubella Virus. Each dose contains approximately 25 mcg of neomycin. The product contains no preservative. Sorbitol and hydrolized gelatin are added as stabilizers.

INDICATIONS M-R-VAX (measles and rubella virus vaccine live) II is indicated for simultaneous immunization against measles and rubella in persons 15 months of age or older. A second dose of M-R-VAX (measles and rubella virus vaccine live) II or monovalent measles vaccine is recommended (see Revaccination ). Infants who are less than 15 months of age may fail to respond to the measles component of the vaccine due to presence in the circulation of residual measles antibody of maternal origin; the younger the infant, the lower the likelihood of seroconversion. In geographically isolated or other relatively inaccessible populations for whom immunization programs are logistically difficult, and in population groups in which natural measles infection may occur in a significant proportion of infants before 15 months of age, it may be desirable to give the vaccine to infants at an earlier age. Infants vaccinated under these conditions at less than 12 months of age should be revaccinated after reaching 15 months of age. There is some evidence to suggest that infants immunized at less than one year of age may not develop sustained antibody levels when later reimmunized. The advantage of early protection must be weighed against the chance for failure to respond adequately on reimmunization. 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. 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 a 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. 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 below and 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. 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. 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 ). Revaccination: Children first vaccinated when younger than 12 months of age should be revaccinated at 15 months of age. The American Academy of Pediatrics (AAP), the Immunization Practices Advisory Committee (ACIP), and some state and local health agencies have recommended guidelines for routine measles revaccination and to help control measles outbreaks. **** Vaccines available for revaccination include monovalent measles vaccine [ATTENUVAX (Measles Virus Vaccine Live)] and polyvalent vaccines containing measles [e.g., M-M-R II (Measles, Mumps, and Rubella Virus Vaccine Live), M-R-VAX (measles and rubella virus vaccine live) II]. If the prevention of sporadic measles outbreaks is the sole objective, revaccination with a monovalent measles vaccine should be considered (see appropriate product circular). If concern also exists about immune status regarding mumps or rubella, revaccination with appropriate monovalent or polyvalent vaccines should be considered after consulting the appropriate product circulars. Unnecessary doses of a vaccine are best avoided by ensuring that written documentation of vaccination is preserved and a copy given to each vaccinee's parent or guardian. 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 M-R-VAX (measles and rubella virus vaccine live) II. M-R-VAX (measles and rubella virus vaccine live) II should not be given less than one month before or after administration of other virus vaccines. * Registered trademark of MERCK & CO., INC. ** 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." *** 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." **** NOTE: A primary difference among these recommendations is the timing of revaccination: the ACIP recommends routine revaccination at entry into Kindergarten or first grade, whereas the AAP recommends routine revaccination at entrance to middle school or junior high school. In addition, some public health jurisdictions mandate the age for revaccination. The complete text of applicable guidelines should be consulted. 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 M-R-VAX (measles and rubella virus vaccine live) II. During shipment, to insure that there is no loss of potency, the vaccine must be maintained at a temperature of 10°C (50°F) or less. Before reconstitution, store M-R-VAX (measles and rubella virus vaccine live) 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 [Prime ] 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 TCID 50 of the U.S. Reference Measles Virus and 1,000 TCID 50 of the U.S. Reference Rubella Virus. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. M-R-VAX (measles and rubella virus vaccine live) II, when reconstituted, is clear yellow. HOW SUPPLIED No. 4751 M-R-VAX (measles and rubella virus vaccine live) II is supplied as a single-dose vial of lyophilized vaccine, NDC 0006-4751-00, and a vial of diluent. No. 4677/4309 M-R-VAX (measles and rubella virus vaccine live) II is supplied as follows: (1) a box of 10 single-dose vials of lyophilized vaccine (package A), NDC 0006-4677-00; and (2) a box of 10 vials of diluent (package B). To conserve refrigerator space, the diluent may be stored separately at room temperature (6505-01-098-8004, Ten Pack). Available only to government agencies/institutions: No. 4678 M-R-VAX (measles and rubella virus vaccine live) II is supplied as one 10 dose vial of lyophilized vaccine, NDC 0006-4678-00, and one 7 mL vial of diluent. No. 4679 M-R-VAX (measles and rubella virus vaccine live) II is supplied as one 50 dose vial of lyophilized vaccine, NDC 0006-4679-00, and one 30 mL vial of diluent (6505-01-098-8005, 50 dose). 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. A.H.F.S. Category: 80:12 COPYRIGHT © MERCK & CO., INC., 1990

PATIENT INFORMATION No Information Provided.

OVERDOSE No Information Provided. CONTRAINDICATIONS Do not give M-R-VAX (measles and rubella virus vaccine live) 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). History of anaphylactic or anaphylactoid reactions to eggs (see HYPERSENSITIVITY TO EGGS below). 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; 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. HYPERSENSITIVITY TO EGGS Live measles vaccine is produced in chick embryo cell culture. Persons with a history of anaphylactic, anaphylactoid, or other immediate reactions (e.g., hives, swelling of the mouth and throat, difficulty breathing, hypotension, or shock) subsequent to egg ingestion should not be vaccinated. Evidence indicates that persons are not at increased risk if they have egg allergies that are not anaphylactic or anaphylactoid in nature. Such persons may be vaccinated in the usual manner. There is no evidence to indicate that persons with allergies to chickens or feathers are at increased risk of reaction to the vaccine.

SIDE EFFECTS Burning and/or stinging of short duration at the injection site have been reported. The adverse clinical reactions associated with the use of M-R-VAX (measles and rubella virus vaccine live) II are those expected to follow administration of the monovalent vaccines given separately. These may include malaise, sore throat, cough, rhinitis, headache, dizziness, fever, rash, nausea, vomiting or diarrhea; mild local reactions such as erythema, induration, tenderness and regional lymphadenopathy; thrombocytopenia and purpura; allergic reactions such as wheal and flare at the injection site or urticaria; polyneuritis, and arthralgia and/or arthritis (usually transient and rarely chronic). Anaphylaxis and anaphylactoid reactions have been reported. Vasculitis has been reported rarely. Moderate fever [101-102.9°F (38.3-39.4°C)] occurs occasionally, and high fever [above 103°F (39.4°C)] occurs less commonly. On rare occasions, children developing fever may exhibit febrile convulsions. Afebrile convulsions or seizures have occurred rarely following vaccination with live attenuated measles vaccine. Syncope, particularly at the time of mass vaccination, has been reported. Rash occurs infrequently and is usually minimal, but rarely may be generalized. Erythema multiforme has also been reported rarely. Forms of optic neuritis, including retrobulbar neuritis, papillitis, and retinitis may infrequently follow viral infections, and have been reported to occur 1 to 3 weeks following inoculation with some live virus vaccines. Clinical experience with live attenuated measles and rubella virus vaccines given individually indicates that encephalitis and other nervous system reactions have occurred very rarely. These might occur also with M-R-VAX (measles and rubella virus vaccine live) II. Experience from more than 80 million doses of all live measles vaccines given in the U.S. through 1975 indicates that significant central nervous system reactions such as encephalitis and encephalopathy, occurring within 30 days after vaccination, have been temporally associated with measles vaccine very rarely. In no case has it been shown that reactions were actually caused by vaccine. The Center for Disease Control has pointed out that "a certain number of cases of encephalitis may be expected to occur in a large childhood population in a defined period of time even when no vaccines are administered". However, the data suggest the possibility that some of these cases may have been caused by measles vaccines. The risk of such serious neurological disorders following live measles virus vaccine administration remains far less than that for encephalitis and encephalopathy with natural measles (one per two thousand reported cases). There have been rare reports of ocular palsies, Guillain-Barr© syndrome, or ataxia occurring after immunization with vaccines containing live attenuated measles virus. The ocular palsies have occurred approximately 3-24 days following vaccination. No definite causal relationship has been established between these events and vaccination. Isolated reports of polyneuropathy including Guillain-Barr© syndrome have also been reported after immunization with rubella-containing vaccines. There have been reports of subacute sclerosing panencephalitis (SSPE) in children who did not have a history of natural measles but did receive measles vaccine. Some of these cases may have resulted from unrecognized measles in the first year of life or possibly from the measles vaccination. Based on estimated nationwide measles vaccine distribution, the association of SSPE cases to measles vaccination is about one case per million vaccine doses distributed. This is far less than the association with natural measles, 6-22 cases of SSPE per million cases of measles. The results of a retrospective case-controlled study conducted by the Center for Disease Control suggest that the overall effect of measles vaccine has been to protect against SSPE by preventing measles with its inherent higher risk of SSPE. Local reactions characterized by marked swelling, redness and vesiculation at the injection site of attenuated live measles virus vaccines, and systemic reactions including atypical measles, have occurred in persons who received killed measles vaccine previously. M-R-VAX (measles and rubella virus vaccine live) II was not given under this condition in clinical trials. Rarely, more severe reactions that require hospitalization, including prolonged high fevers and extensive local reactions, have been reported. Panniculitis has been reported rarely following administration of measles vaccine. Arthralgia and/or arthritis (usually transient and rarely chronic), and polyneuritis are features of natural rubella and vary in frequency and severity with age and sex, being greatest in adult females and least in prepubertal children. This type of involvement as well as myalgia and paresthesia have also been reported following administration of MERUVAX II (Rubella Virus Vaccine Live). Chronic arthritis has been associated with natural rubella infection and has been related to persistent virus and/or viral antigen isolated 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%), 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. DRUG INTERACTIONS No Information Provided.

WARNINGS No Information Provided. PRECAUTIONS General Adequate treatment provisions including epinephrine, should be available for immediate use should an anaphylactic or anaphylactoid reaction occur. Due caution should be employed in administration of M-R-VAX (measles and rubella virus vaccine live) II to persons with a history of cerebral injury, individual or family histories of convulsions, or any other condition in which stress due to fever should be avoided. The physician should be alert to the temperature elevation which may occur following vaccination. (See ADVERSE REACTIONS .) 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. Vaccination should be deferred for at least 3 months following blood or plasma transfusions, or administration of human immune serum globulin. 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. However, transmission of the rubella vaccine virus to infants via breast milk has been documented (see Nursing Mothers ). There are no reports of transmission of live attenuated measles virus from vaccinees to susceptible contacts. It has been reported that live attenuated measles and rubella virus vaccines given individually 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 M-R-VAX (measles and rubella virus vaccine live) II. Children under treatment for tuberculosis have not experienced exacerbation of the disease when immunized with live measles virus vaccine; no studies have been reported to date of the effect of measles virus vaccines on untreated tuberculous children. As for any vaccine, vaccination with M-R-VAX (measles and rubella virus vaccine live) II may not result in seroconversion in 100% of susceptible persons given the vaccine. Pregnancy Pregnancy Category C Animal reproduction studies have not been conducted with M-R-VAX (measles and rubella virus vaccine live) II. It is also not known whether M-R-VAX (measles and rubella virus vaccine live) II can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Therefore, the vaccine should not be administered to pregnant females; futhermore, pregnancy should be avoided for three months following vaccination (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: (1) 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; (2) Reports have indicated that contracting of natural measles during pregnancy enhances fetal risk. Increased rates of spontaneous abortion, stillbirth, congenital defects and prematurity have been observed subsequent to natural measles during pregnancy. There are no adequate studies of the attenuated (vaccine) strain of measles virus in pregnancy. However, it would be prudent to assume that the vaccine strain of virus is also capable of inducing adverse fetal effects. Nursing Mothers It is not known whether measles vaccine virus is secreted in human milk. 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. In the infants with serological evidence of rubella infection, none exhibited severe disease; however, one exhibited mild clinical illness typical of acquired rubella. Caution should be exercised when M-R-VAX (measles and rubella virus vaccine live) II is administered to a nursing woman.