Professional Drug Information > M-M-R II

Measles, Mumps, and Rubella Virus Vaccine Live (Systemic )

VA CLASSIFICATION
Primary: IM100


Note: This monograph is specific for the sterile lyophilized preparation of a more attenuated line of measles virus, derived from Enders" attenuated Edmonston strain and grown in cell cultures of chick embryo, the Jeryl Lynn (B level) strain of mumps virus grown in cell cultures of chick embryo, and the Wistar RA 27/3 strain of live attenuated rubella virus grown in human diploid cell (WI-38) culture ^{01}.

Commonly used brand name(s): M-M-R II.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Immunizing agent (active)—

Indications

General considerations
Measles is an acute disease characterized by fever, cough, coryza, conjunctivitis, an erythematous maculopapular rash, and a pathognomonic enanthema (Koplik's spots). Complications such as otitis media, bronchopneumonia, laryngotracheobronchitis (croup), and diarrhea occur more commonly in young children than in older patients ^{02}. Acute encephalitis, which frequently results in permanent brain damage, occurs in approximately 1 of every 1000 cases ^{02}. Death, predominantly due to respiratory and neurologic complications, occurs in 1 to 2 of every 1000 cases reported in the U.S. ^{02}

Subacute sclerosing panencephalitis (SSPE), a rare degenerative central nervous system (CNS) disease characterized by behavioral and intellectual deterioration and convulsions, is a result of a persistent measles virus infection that develops years after the original infection ^{{02} {03}}. Widespread use of measles vaccine has essentially eliminated SSPE from the U.S. ^{{02} {03}}

Measles illness during pregnancy is responsible for increased rates of premature labor, spontaneous abortion, and low birth weight in affected infants ^{03}. Birth defects, with no definable pattern of malformation, have been reported in infants born to women infected with measles during pregnancy, but measles infection has not been confirmed as the cause of the malformations ^{03}.

Measles can be severe and prolonged in immunocompromised persons, particularly those who have certain leukemias, lymphomas, or human immunodeficiency virus (HIV) infection ^{{02} {03}}. In these persons, measles may occur without the typical rash, and they may shed measles virus for several weeks after the acute illness ^{{02} {03}}.

Mumps is a systemic disease characterized by bilateral or, less commonly, unilateral parotitis ^{{03} {04}}. Parotitis may be preceded by fever, headache, malaise, myalgia, and anorexia ^{03}. Only 30 to 40% of mumps infections produce typical acute parotitis; 15 to 20% of infections are asymptomatic, and up to 50% of infections are associated with nonspecific or primarily respiratory symptoms ^{03}. Inapparent infection may be more common in adults than in children; parotitis occurs more commonly in children 2 to 9 years of age ^{03}. Serious complications of mumps infection can occur without evidence of parotitis ^{03}.

Most serious complications of mumps are more common in adults than in children ^{{03} {04}}. Although orchitis may occur in 38% of postpubertal men in whom mumps develops, sterility is thought to occur only rarely ^{{03} {04}}.

Aseptic meningitis affects 4 to 6% of persons with clinical cases of mumps and typically is mild ^{03}. However, mumps meningoencephalitis can cause permanent sequelae, including paralysis, seizures, cranial nerve palsies, aqueductal stenosis, and hydrocephalus ^{03}. In the prevaccine era, mumps was a major cause of sensorineural deafness in children ^{03}. Deafness may be sudden in onset, bilateral, and permanent ^{03}.

Among women in whom mumps develops during the first trimester of pregnancy, an increased risk for fetal death has been observed ^{03}. However, mumps infection during pregnancy is not associated with congenital malformations ^{03}.

Postnatal rubella usually is a mild disease characterized by an erythematous, maculopapular, discrete rash, generalized lymphadenopathy (most commonly suboccipital, postauricular, and cervical), and slight fever ^{{03} {05}}. Transient polyarthralgia and polyarthritis occasionally occur in children and are common in adolescents and adults, especially females ^{{03} {05}}. Encephalitis and thrombocytopenia are rare complications ^{{03} {05}}.

The most important consequences of rubella are the miscarriages, stillbirths, fetal anomalies, and therapeutic abortions that result when rubella infection occurs during early pregnancy, especially during the first trimester ^{03}. An estimated 20,000 cases of congenital rubella syndrome (CRS) occurred during the 1964–1965 epidemic, the last U.S. rubella epidemic before rubella vaccine became available ^{03}. Fetal infection without clinical signs of CRS can occur during any stage of pregnancy ^{03}.

The anomalies most commonly associated with CRS are auditory (e.g., sensorineural deafness), ophthalmic (e.g., cataracts, microphthalmia, glaucoma, chorioretinitis), cardiac (e.g., patent ductus arteriosus, peripheral pulmonary artery astenosis, atrial or ventricular septal defects), and neurologic (e.g., microcephaly, meningoencephalitis, mental retardation) ^{{03} {05}}. In addition, infants with CRS frequently exhibit both intrauterine and postnatal growth retardation ^{{03} {05}}. Other conditions sometimes observed in patients who have CRS include radiolucent bone defects, hepatosplenomegaly, thrombocytopenia, and purpuric skin lesions ^{{03} {05}}.

Accepted

Measles, mumps, and rubella (prophylaxis)—Measles, mumps, and rubella virus vaccine is indicated for simultaneous immunization against measles (rubeola; morbilli; coughing, hard, red, or 10-day measles), mumps, and rubella (German measles) in persons 12 to 15 months of age or older ^{{01} {06}}. The main objective of measles, mumps, and rubella immunization is to prevent severe complications and death, which may arise from measles, mumps, and/or rubella infections (see General Considerations ) ^{{02} {03} {04} {05}}.
—Unless otherwise contraindicated, all susceptible persons 12 to 15 months of age or older should be immunized against measles, mumps, and rubella, including:

   • Preschool-aged children ^{{02} {03} {04} {05}}. Children should receive the first dose of measles, mumps, and rubella virus vaccine live at 12 to 15 months of age (i.e., on or after their first birthday) ^{{02} {03} {04} {05}}. In areas where risk for measles is high, initial vaccination with measles, mumps, and rubella virus vaccine live is recommended for all children as soon as possible upon reaching the first birthday (i.e., at age 12 months) ^{03}. An area where measles risk is high is defined as:    —A country with a large inner-city population ^{03}.
   —A country where a recent measles outbreak has occurred among unvaccinated preschool-aged children ^{03}.
   —A country in which more than five cases of measles have occurred among preschool-aged children during each of the last 5 years ^{03}.

   • School-aged children and adolescents ^{{02} {03} {04} {05}}. The second dose of measles, mumps, and rubella virus vaccine live is recommended for children 4 to 6 years of age (i.e., before a child enters kindergarten or first grade) ^{{02} {03} {04} {05}}.
   • Adults ^{03}. Persons born in 1957 or later who are 18 years of age or older and who do not have a medical contraindication should receive at least one dose of measles, mumps, and rubella virus vaccine live unless they have documentation of vaccination with at least one dose of measles, mumps, and rubella-containing vaccine or other acceptable evidence of immunity to these three diseases ^{03}. Persons born before 1957 can generally be considered immune to measles and mumps ^{03}. In addition, persons born before 1957, except women who could become pregnant, generally can be considered immune to rubella ^{03}.
   • Women of childbearing potential ^{{01} {03} {07} {08} {09}}. Measles, mumps, and rubella virus vaccine live should be offered to all women of childbearing age (i.e., adolescent girls and premenopausal adult women) who do not have acceptable evidence of rubella immunity whenever they make contact with the health care system ^{03}. Opportunities to vaccinate susceptible women include occasions when their children undergo routine examinations or vaccinations ^{03}. The continuing occurrence of rubella among women of childbearing age indicates the need to continue vaccination of susceptible adolescent and adult women of childbearing age, and the absence of evidence of vaccine teratogenicity indicates that the practice is safe ^{03}.
   • Postpartum women who do not plan to breast-feed, preferably before discharge from the hospital ^{{01} {03}}. Although problems in humans have not been documented, postpartum women who plan to breast-feed should consult their physicians to consider risk-benefit before receiving immunization with measles, mumps, and rubella virus vaccine live ^{01}.
   • Persons traveling outside the U.S. ^{{01} {03}} These persons should receive measles, mumps, and rubella virus vaccine live prior to international travel ^{{01} {10}}.
   • Persons infected with HIV ^{03}. Measles, mumps, and rubella virus vaccine live is recommended for all asymptomatic HIV-infected persons who do not have evidence of severe immunosuppression and for whom measles vaccination would otherwise be indicated ^{03}. Measles, mumps, and rubella virus vaccine live also should be considered for all symptomatic HIV-infected persons who do not have evidence of severe immunosuppression ^{03}. Testing asymptomatic persons for HIV infection is not necessary before administering measles, mumps, and rubella virus vaccine live or other measles-containing vaccine ^{03}.

—Some persons vaccinated according to earlier recommendations for use of individual measles, mumps, and/or rubella vaccines or measles, mumps, and rubella virus vaccine live should be revaccinated to ensure that they are adequately protected ^{03}. Unless one of its component vaccines is contraindicated, measles, mumps, and rubella virus vaccine live should be used for revaccination in the following situations:    • Previous vaccination with live measles, rubella, and mumps vaccines ^{03}. Persons vaccinated with live measles, rubella, and mumps vaccines before their first birthday who were not revaccinated on or after their first birthday should be considered unvaccinated ^{03}. Unless they have other acceptable evidence of immunity to measles, rubella, and mumps, these persons should be revaccinated with measles, mumps, and rubella virus vaccine live ^{03}.
   • Previous vaccination with inactivated measles vaccine or measles vaccine of unknown type ^{03}. Inactivated (killed) measles vaccine was available in the U.S. only from 1963 to 1967 but was available through the early 1970s in some other countries ^{03}. It was frequently administered as a series of two or three injections ^{03}. Because persons who received inactivated vaccine are at risk for developing severe atypical measles syndrome when exposed to the natural virus, they should receive two doses of measles, mumps, and rubella virus vaccine live or other live measles vaccine, separated by at least 28 days ^{03}. Persons who received inactivated vaccine followed within 3 months by live virus vaccine should also be revaccinated with two more doses of measles, mumps, and rubella virus vaccine live or other live measles vaccine. Revaccination is particularly important when the risk for exposure to natural measles virus is increased (i.e., during international travel) ^{03}. Persons vaccinated during 1963 through 1967 with vaccine of unknown type may have received inactivated vaccine and also should be revaccinated ^{03}. Persons who received a vaccine of unknown type after 1967 need not be revaccinated unless the original vaccination occurred before their first birthday or was accompanied by immune globulin (Ig) or measles immune globulin (MIg) ^{03}. However, such persons should receive a second dose before entering college, beginning work within a health care facility, or undertaking international travel ^{03}.
   • Previous vaccination with inactivated mumps vaccine or mumps vaccine of unknown origin ^{03}. A killed mumps virus vaccine was licensed for use in the U.S. from 1950 through 1978 ^{03}. Although this vaccine induced antibody, the immunity was transient ^{03}. The number of doses of killed mumps vaccine administered between licensure of live attenuated mumps vaccine in 1967 until the killed vaccine was withdrawn in 1978 is unknown but appears to have been limited ^{03}. Revaccination with measles, mumps, and rubella virus vaccine live should be considered for certain persons vaccinated before 1979 with either killed mumps vaccine or mumps vaccine of unknown type who are at high risk for mumps infection (e.g., persons who work in health care facilities during a mumps outbreak) ^{03}. No evidence exists that persons who have had mumps disease or who have previously received mumps vaccine (killed or live) are at increased risk for local or systemic reactions upon receiving measles, mumps, and rubella virus vaccine live or live mumps vaccine ^{03}.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Measles, mumps, and rubella virus vaccine live contains a sterile lyophilized preparation of a more attenuated line of measles virus, derived from Enders' attenuated Edmonston strain and grown in cell cultures of chick embryo, the Jeryl Lynn (B level) strain of mumps virus grown in cell cultures of chick embryo, and the Wistar RA 27/3 strain of live attenuated rubella virus grown in human diploid cell (WI-38) culture ^{01}. The vaccine viruses are the same as those used in the manufacture of measles virus vaccine live, mumps virus vaccine live, and rubella virus vaccine live. The three viruses are mixed before being lyophilized ^{01}.

Mechanism of action/Effect:

Following subcutaneous injection, measles, mumps, and rubella virus vaccine live produces a modified, noncommunicable measles, mumps, and rubella infection and provides active immunity to measles, mumps, and rubella ^{{01} {08}}.


Protective effect

Clinical studies of 279 triple seronegative children 11 months to 7 years of age demonstrated that measles, mumps, and rubella virus vaccine live is highly immunogenic and generally well tolerated. In these studies, a single injection of measles, mumps, and rubella virus vaccine live induced measles hemagglutinin-inhibition (HI) antibodies in 95%, mumps neutralizing antibodies in 96%, and rubella HI antibodies in 99% of susceptible individuals ^{{01} {06}}. The presence of these antibodies has been correlated with clinical protection and their absence considered indicative of susceptibility to these diseases ^{11}.

Studies have shown that measles, mumps, and rubella virus vaccine live is as effective in producing immunity as each of the separate vaccines, and that the immunity induced by immunization with measles, mumps, and rubella virus vaccine is long-lasting and may even be lifelong ^{08}.

The RA 27/3 rubella strain in measles, mumps, and rubella virus vaccine live elicits higher immediate postvaccination HI, complement-fixing, and neutralizing antibody levels than do 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 ^{12} 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 a greater probability of lasting immunity ^{{01} {06}}.


Duration of protective effect

The immunity conferred by measles, mumps, and rubella virus vaccine appears to be long-lasting ^{13}. Vaccine-induced antibody levels following administration of measles, mumps, and rubella virus vaccine live have been shown to persist for up to 11 years without substantial decline ^{{01} {06}}. Protective antibodies have been observed 21 years after measles vaccination and 18 years after rubella vaccination ^{13}. Administration of a second dose of vaccine some years after the first dose may ensure that protective antibody titers are maintained ^{13}. Continued surveillance will be necessary to determine further duration of antibody persistence ^{{01} {06} {14} {15}}. Continuous serosurveillance is important to monitor the immunity status in the population and especially to ensure that the immunity is sufficient during childbearing years ^{{15} {16}}.


Precautions to Consider

Pregnancy/Reproduction

Pregnancy—
Although adequate studies have not been done in humans, use in pregnant women is not recommended ^{{01} {17}}. Considerable complications ^{18}, including increased rates of spontaneous abortion, premature births, low-birth-weight neonates, and, possibly, congenital defects, have been observed with natural measles infection during pregnancy, and the possibility exists that the measles vaccine may cause similar effects ^{{01} {06}}.

Although mumps vaccine virus has not been isolated from electively aborted fetuses of women who were vaccinated during pregnancy, the vaccine virus may infect the placenta ^{{01} {19}}. In addition, natural mumps infection can infect the placenta and fetus, but there is no evidence that natural mumps infection during pregnancy causes congenital malformations. Therefore, there is no reason to suspect or evidence to indicate that mumps vaccine would cause congenital malformations ^{{01} {19}}.

Rubella vaccine virus crosses the placenta and has been recovered from the products of conception of some aborted fetuses of women who received the vaccine just prior to or during pregnancy; however, from 1971 through 1988, the Centers for Disease Control (CDC) monitored 210 pregnant women who had received the RA 27/3 strain of rubella virus vaccine 3 months before or after conception and carried their pregnancies to term. Although some neonates had serological evidence of rubella virus infection, none had malformations associated with congenital rubella syndrome ^{{01} {20} {21} {22}}. Therefore, vaccination of a pregnant woman should not in itself indicate the need for abortion, although the final decision rests with the woman and her physician ^{22}. The risk of congenital rubella syndrome associated with maternal infection with the wild virus during the first trimester of pregnancy is at least 20% ^{22}. Although the risk of teratogenicity is not known, and appears to be minimal, there is still a theoretical risk of fetal abnormality caused by the vaccine virus ^{01}.

It is recommended that pregnancy be avoided for 3 months following vaccination ^{{01} {19} {20} {23}}.

Studies have not been done in animals ^{{01} {19} {20} {23}}.

FDA Pregnancy Category C ^{{01} {19} {20} {23}}.

Breast-feeding

It is not known whether measles or mumps vaccine is distributed into breast milk. Although rubella vaccine may be distributed into breast milk and infants may subsequently show serological evidence of rubella infection or mild clinical illness typical of acquired rubella, studies have not shown that these effects cause serious clinical problems ^{{01} {20} {24}}.

Pediatrics

Infants younger than 15 months of age may fail to respond to the measles component of the vaccine ^{25} due to the presence of residual circulating measles antibody of maternal origin ^{{01} {26} {27} {28}}. This effect usually starts to wane after the child reaches 6 months of age ^{28}. However, children born to younger mothers might respond well to measles vaccine administered at 12 months of age ^{29}. In one study, children randomly received measles vaccine at either 12 or 15 months of age. The measles antibody response to measles, mumps, and rubella virus vaccine was 93 ^{29} to 95% ^{28} when the vaccine was administered at 12 months of age, and 98% when it was administered at 15 months of age ^{{28} {29}}. Among children of mothers born after 1961, who probably had received a measles vaccine and were less likely to have had measles infection than women born in previous years, the seroconversion rate was 96% among children vaccinated at 12 months of age and 98% among those vaccinated at 15 months of age ^{29}. Based on these findings, the Committee on Infectious Diseases of the American Academy of Pediatrics (AAP) and the Advisory Committee on Immunization Practices (ACIP) recommend administration of the first dose of measles, mumps, and rubella virus vaccine live at 12 to 15 months of age ^{29}. Both AAP and ACIP recommend that all children receive a second dose of measles-containing vaccine ^{{29} {30}}. The second dose of measles, mumps, and rubella virus vaccine live is routinely recommended at 4 to 6 years of age or at 11 to 12 years of age, but may be administered at any visit, provided at least 1 month has elapsed since receipt of the first dose ^{{31} {32}}. Children who were vaccinated when younger than 12 months of age should be revaccinated at 15 months of age ^{{01} {24}}. Children who received monovalent measles vaccine rather than measles, mumps, and rubella virus vaccine on or after their first birthdays also should receive a primary dose of mumps and rubella vaccines, and doses of measles, mumps, and rubella virus vaccine or other measles-containing vaccines should be separated by at least 1 month ^{24}.

If exposure to measles infection has occurred within 72 hours or is imminent, children between 6 and 15 months of age can be vaccinated, provided that those vaccinated before their first birthdays are revaccinated at 15 months of age. There is some evidence to suggest, however, that infants immunized before 12 months 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 ^{01}.

It is also very important to vaccinate HIV-infected children against measles ^{33}.

Children with end-stage renal disease receiving maintenance hemodialysis have a degree of immunosuppression that reduces their response to vaccination ^{13}. One small trial showed that 80% of these vaccinated children developed antibodies to measles and rubella, while only 50% developed mumps antibodies. Moreover, only 30% developed antibodies to all three viruses ^{13}. Therefore, it may be necessary to monitor postvaccination antibody levels in children with end-stage renal disease, and to revaccinate those children who have failed to demonstrate seroconversion ^{13}.

AAP recommends the routine use of measles vaccine (including measles, mumps, and rubella virus vaccine live) in patients with nonanaphylactic allergy to eggs and in patients with allergies to chicken and chickenfeathers ^{34}. One recent study showed that measles, mumps, and rubella virus vaccine live can be administered safely in a single dose to children with allergy to eggs, even those with severe hypersensitivity ^{34}.


Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Blood products or
Immune globulins    (concurrent administration with measles, mumps, and rubella virus vaccine live may interfere with the patient's immune response to the vaccine because of the possibility of antibodies to measles, mumps, and rubella viruses in these products; measles, mumps, and rubella virus vaccine live should be administered at least 14 days before, or more than 5 to 6 ^{12} months after, administration of blood products or immune globulins ^{{01} {24}})


» Immunosuppressive agents or
» Radiation therapy    (because normal host defense mechanisms are suppressed, concurrent use with measles, mumps, and rubella virus vaccine live may potentiate the replication of the vaccine virus, increase the side/adverse effects of the vaccine virus, and/or decrease the patient's antibody response to measles, mumps, and rubella virus vaccine live. The reaction may be severe enough to cause death. The interval between discontinuing medications that cause immunosuppression and regaining the ability to respond to measles, mumps, and rubella virus vaccine live depends on the intensity and type of immunosuppressive medication being used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Patients with leukemia that is in remission should not receive measles, mumps, and rubella virus vaccine live until at least 3 months after their last dose of chemotherapy. This precaution does not apply to corticosteroids used as replacement therapy, for short-term [less than 2 weeks] systemic therapy, or for other routes of administration that do not cause immunosuppression ^{01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
» Tuberculin skin test    (short-term suppression lasting several weeks may occur and may result in false-negative tests; if required, tuberculin skin tests should be done before, simultaneously with, or at least 8 weeks after administration of measles, mumps, and rubella virus vaccine ^{01})


Skin tests, other    (decreased responsiveness to skin test antigens may occur because of vaccine-induced transient suppression of delayed-type hypersensitivity; the period of time for which responsiveness is decreased depends upon the particular skin test used)

With physiology/laboratory test values
Platelets, blood    (counts may be decreased)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Febrile illness, severe    (manifestations of illness may be confused with possible side/adverse effects of vaccine; however, minor illnesses, such as upper respiratory infection, do not preclude administration of vaccine ^{{17} {24} {35} {36}})


» Immune deficiency conditions, congenital or hereditary, family history of or
» Immune deficiency conditions, primary or acquired    (because of reduced or suppressed defense mechanisms, the use of live virus vaccines, including measles, mumps, and rubella virus vaccine live, may potentiate the replication of the vaccine virus, and/or may decrease the patient's antibody response to measles, mumps, and rubella ^{{01} {06} {37}})

    (persons with leukemia that is in remission may receive live virus vaccines if at least 3 months have passed since the last chemotherapy treatment ^{{01} {06}})

    (persons infected with human immunodeficiency virus [HIV] may receive measles, mumps, and rubella virus vaccine live if they are not severely lymphopenic ^{12})

    (when there is a family history of congenital or hereditary immune deficiency conditions, the patient should not be vaccinated until immune competence is demonstrated ^{{01} {06}})


Risk-benefit should be considered when the following medical problems exist
Allergy to eggs    (patients allergic to eggs also may be allergic to measles, mumps, and rubella virus vaccine live, since measles and mumps virus vaccines are produced in chick embryo cell cultures ^{{38} {39}}. A history of hypersensitivity reactions other than anaphylaxis generally does not preclude immunization. In addition, no allergy to measles, mumps, and rubella virus vaccine live has been found in patients allergic to chicken feathers or chicken ^{{01} {06} {40}})


Allergy to gelatin    (patients allergic to gelatin also may be allergic to measles, mumps, and rubella virus vaccine live, since gelatin is used as a stabilizer in the production of the vaccine ^{41})


Allergy to neomycin    (patients allergic to neomycin also may be allergic to measles, mumps, and rubella virus vaccine live, since neomycin is used in the production of the vaccine ^{41})


Sensitivity to measles, mumps, and rubella virus vaccine
Thrombocytopenia or history of vaccine-associated thrombocytopenia    (persons who experienced thrombocytopenia with the first dose of vaccine may develop thrombocytopenia with additional doses ^{41}. These persons should have serological testing performed in order to determine the need for additional doses of vaccine ^{41}. The risk-benefit ratio should be evaluated before considering vaccination in such cases ^{41})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Seroconversion test    (may be performed 6 to 8 weeks following vaccination in patients for whom immunity is considered crucial [e.g., persons traveling outside the U.S. or women in high-risk areas who intend to become pregnant], since vaccination with measles, mumps, and rubella virus vaccine live may not result in seroconversion in all susceptible patients ^{{01} {06}})




Side/Adverse Effects

Note: The side/adverse effects associated with the use of measles, mumps, and rubella virus vaccine live are the same as those expected to follow administration of the monovalent vaccines given separately ^{{01} {06}}. However, it is very important to differentiate between vaccine-induced side/adverse effects and natural infection.
Encephalitis with resultant residual permanent CNS impairment (encephalopathy) develops in approximately 1 per 1000 persons infected with measles virus ^{03}. Whether attenuated live viral measles vaccine can also produce such a syndrome has been a concern since the earliest days of measles vaccine use ^{03}.
Although cases of encephalopathy have been reported after administration of measles-containing vaccine, lack of a unique clinical syndrome or specific laboratory test hampered causality assessment ^{03}. However, four independent passive surveillance systems in the U.S. have reported cases of encephalopathy in which a similar timing of reported events following vaccine administration was apparent ^{03}. In all four case series, onset of encephalopathies followed a nonrandom distribution with onset approximately 10 days after vaccination, a timing consistent with onset of encephalopathy after infection with wild measles virus ^{03}. Although this pattern may be in part attributable to consistent biases of these passive surveillance systems, it is also consistent with a causal relationship between measles vaccine and encephalopathies ^{03}. During the period in which these four systems have collected data, 166 cases of encephalopathy occurring 6 to 15 days after vaccination have been identified and an estimated 313 million cases of measles-containing vaccines have been distributed (i.e., approximately 1 case per 2 million doses distributed) ^{03}. Thus, encephalopathy occurs less frequently after administration of measles vaccine than after measles infection ^{03}.
Cases of Guillain-Barré syndrome (GBS) occurring after administration of measles, mumps, and rubella virus vaccine live or its component vaccines have been reported, but the Institute of Medicine (IOM) judged the evidence insufficient to accept or reject a causal relationship ^{03}. Some studies provide evidence against this potential association ^{03}. After mass vaccination campaigns that involved approximately 8 million doses of measles and rubella virus vaccine in the United Kingdom and more than 70 million doses of measles virus vaccine in Latin America, evaluations of GBS incidence demonstrated no increases over background rates ^{03}.
Measles vaccination substantially reduces the occurrence of subacute sclerosing panencephalitis (SSPE), as evidenced by the near-elimination of SSPE cases after widespread measles vaccination ^{{02} {03}}. SSPE has been reported rarely among children who had no history of natural measles infection, but who had received measles vaccine ^{{02} {03}}. Evidence indicates that at least some of these children had unrecognized measles infection before they were vaccinated and that the SSPE was directly related to natural measles infection ^{{02} {03}}. The administration of live measles vaccine does not increase the risk for SSPE, even among persons who have previously had measles disease or received live measles vaccine ^{{02} {03}}.
Persons who are immune to measles, mumps, and/or rubella virus because of past vaccination or infection usually do not experience side/adverse effects from the vaccine ^{{01} {06}}. However, some recipients of inactivated measles vaccine who were later revaccinated with live measles vaccine had adverse reactions to the live vaccine; the percentage who reported adverse reactions ranged from 4 to 55% ^{03}. In most cases, these reactions were mild (e.g., local swelling and erythema, low-grade fever lasting 1 to 2 days), but rarely more severe reactions (e.g., prolonged high fevers, extensive local reactions) were reported ^{03}. However, natural measles infection is more likely to cause serious illness among recipients of inactivated measles vaccine than is live measles virus vaccine ^{03}.
Excretion of small amounts of the live attenuated rubella virus from the nose or throat has occurred in the majority of susceptible individuals 7 to 28 days after vaccination. There is, however, no confirmed evidence to indicate that the vaccine virus is transmitted to susceptible persons who are in contact with the vaccinated individuals ^{20}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Fever higher than 39.4 ºC (103 ºF) ^{{01} {06}}

Incidence less frequent
    
Optic neuritis ( pain or tenderness of eyes)—may occur from 1 to 4 weeks after immunization, lasting less than 1 week ^{{01} {06}}

Incidence rare
    
Anaphylactic reaction ( difficulty in breathing or swallowing; hives; itching, especially of soles or palms; reddening of skin, especially around ears; swelling of eyes, face, or inside of nose; unusual tiredness or weakness, sudden and severe ^{{01} {06} {42}})
    
encephalitis or meningoencephalitis (confusion ; headache, severe or continuing; irritability; stiff neck; or vomiting ^{{01} {06} {43} {44} {45}})
    
ocular palsies (double vision ^{{01} {06}})
    
orchitis in postpubescent and adult men ( pain, tenderness, or swelling in testicles and scrotum ^{{01} {06}})
    
peripheral neuropathy, polyneuritis, or polyneuropathy ( pain, numbness, or tingling of hands, arms, legs, or feet ^{{01} {06}})— may occur from 1 to 4 weeks after immunization, lasting less than 1 week
    
seizures ( convulsions ^{{01} {06}})
    
thrombocytopenic purpura ( bruising or purple spots on skin ^{{01} {06}})

Note: Hypersensitivity reactions, usually consisting of urticaria or a wheal and flare at injection site, occur rarely after administration of measles, mumps, and rubella virus vaccine live or any of its component vaccines ^{03}. Immediate anaphylactic reaction to these vaccines is very rare ^{03}. The reported rate of possible anaphylaxis after vaccination with measles-containing vaccine is less than 1 case per 1 million doses distributed ^{03}. Allergic reactions including rash, pruritus, and purpura have been temporally associated with vaccination but are uncommon, usually mild, and of brief duration ^{03}.
Surveillance of adverse reactions in the U.S. and other countries indicates that measles, mumps, and rubella virus vaccine live can, in rare instances, cause clinically apparent thrombocytopenia within 2 months after vaccination ^{03}. In prospective studies, the reported frequency of clinically apparent thrombocytopenia after immunization with measles, mumps, and rubella virus vaccine live ranged from 1 case per 30,000 vaccinated children in Finland and Great Britain to 1 case per 40,000 in Sweden, with temporal clustering of cases occurring 2 to 3 weeks after vaccination ^{03}. Based on passive surveillance, the reported frequency of thrombocytopenia was approximately 1 case per 100,000 vaccine doses distributed in Canada and France, and approximately 1 case per 1 million doses distributed in the U.S. ^{03} The clinical course of these cases usually was transient and benign, although hemorrhage occurred rarely ^{03}. The risk of thrombocytopenia during rubella or measles infection is much greater than the risk after vaccination ^{03}. Based on case reports, the risk of measles, mumps, and rubella virus vaccine live–associated thrombocytopenia may be increased for persons who have previously had immune thrombocytopenic purpura, particularly for those who had thrombocytopenic purpura after an earlier dose of measles, mumps, and rubella virus vaccine live ^{03}.




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Fever between 37.7 and 39.4 ºC (100 and 103 ºF) ^{{01} {06}}
    
lymphadenopathy or parotitis (swelling of glands in neck)— may occur from 1 to 4 weeks after immunization, lasting less than 1 week ^{{01} {06}}
    
reaction to acid pH of vaccine (burning or stinging at injection site ^{{01} {06}})
    
skin rash ^{{01} {06} {08}}

Incidence less frequent
    
Allergic reaction, delayed-type, cell-mediated (itching, swelling, redness, tenderness, or hard lump at injection site)
    
arthralgia or arthritis (aches or pain in joints)— may occur from 1 to 10 weeks after immunization, lasting less than 1 week ^{{01} {06} {08}}
    
malaise (vague feeling of bodily discomfort )—may occur from 1 to 4 weeks after immunization, lasting less than 1 week
    
mild headache, sore throat, or runny nose — may occur from 1 to 4 weeks after immunization, lasting less than 1 week
    
nausea

Note: One study showed that the RA 27/3 strain of rubella vaccine administered to susceptible ^{43} adult women is not associated with clinically important acute or chronic joint disease ^{46}. Therefore, rubella vaccination should continue to be used to protect susceptible ^{43} adult women from rubella in order to advance the goal of eliminating the congenital rubella syndrome ^{46}. The incidence of arthralgia or arthritis is increased greatly in women ^{09} of childbearing age. Generally the older the woman, the greater the incidence, severity, and duration of arthralgia or arthritis. However, even in older women, the symptoms generally are well tolerated and rarely interfere with normal activities. No persistent joint disorders ^{{12} {47}} have been reported ^{01}.






Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Measles, Mumps, and Rubella Virus Vaccine Live (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before receiving this vaccine
  Conditions affecting use, especially:
Sensitivity to measles, mumps, and rubella virus vaccine live, or allergy to eggs, gelatin, or neomycin

Pregnancy—Use of measles, mumps, and rubella virus vaccine during pregnancy or pregnancy within 3 months of immunization is not recommended





Breast-feeding—Consulting physician if breast-feeding is considered





Use in children—Use is not recommended for infants younger than 12 months of age

Other medications, especially immunosuppressive agents or radiation therapy
Other medical problems, especially severe febrile illness, family history of congenital or hereditary immune deficiency conditions, or primary or acquired immune deficiency conditions

Proper use of this medication

» Proper dosing

Precautions after receiving this vaccine
» Not becoming pregnant for 3 months because of possible problems during pregnancy

Checking with physician before receiving:    • Tuberculin skin test within 8 weeks of this vaccine, since the results of the test may be affected by the vaccine
   • Any other live-virus vaccines within 1 month of this vaccine
   • Blood transfusions or other blood products within 2 weeks of this vaccine
   • Gamma globulin or other globulins within 2 weeks of this vaccine



Side/adverse effects
Signs of potential side effects, especially fever higher than 39.4 ºC (103 ºF), optic neuritis, anaphylactic reaction, encephalitis or meningoencephalitis, ocular palsies, orchitis in postpubescent and adult males, peripheral neuropathy, polyneuritis, or polyneuropathy, seizures, and thrombocytopenic purpura


General Dosing Information
The dosage of measles, mumps, and rubella virus vaccine live is the same for both children and adults ^{01}.

Measles, mumps, and rubella virus vaccine live is administered subcutaneously ^{{01} {24}}. It should not be injected intravenously ^{{01} {06}}.

When sterilizing syringes and skin before vaccination, care should be taken to avoid preservatives, antiseptics, detergents, and disinfectants, because the vaccine virus is easily inactivated by these substances ^{{01} {06}}.

To prevent inactivation of the vaccine, it is recommended that only the diluent provided by the manufacturer be used ^{{01} {06}}.

A 25-gauge, 5/8th-inch needle is recommended for administration of the vaccine ^{{01} {06} {24}}.

Although measles, mumps, and rubella vaccines are available as a combination vaccine (measles, mumps, and rubella virus vaccine live) and, as such, are administered as a single injection, the commercially available individual vaccines should not be mixed in the same syringe or administered at the same body site ^{01}.

Simultaneous administration of measles, mumps, and rubella virus vaccine live, diphtheria and tetanus toxoids and pertussis vaccine (DTP), and oral poliovirus vaccine (OPV) has resulted in rates of seroconversion and of side effects similar to those observed when the vaccines are administered at separate times ^{48}. Since simultaneous administration of common vaccines is not known to affect the efficacy or safety of any of the routinely recommended childhood vaccines, if return of a vaccine recipient for further immunization is doubtful, simultaneous administration of all vaccines (DTP, OPV or poliovirus vaccine inactivated enhanced-potency [eIPV], measles, mumps, and rubella virus vaccine live, varicella virus vaccine live, hepatitis B vaccine, and Haemophilus influenzae type b vaccine [Hib]) appropriate for the age and previous vaccination status of the recipient is recommended ^{48}.

For treatment of adverse effects
Recommended treatment consists of the following:
   • For mild hypersensitivity reaction—Administering antihistamines, and, if necessary, corticosteroids.
   • For severe hypersensitivity or anaphylactic reaction—Administering epinephrine. Antihistamines or corticosteroids also may be administered as required ^{01}.


Parenteral Dosage Forms

MEASLES, MUMPS, AND RUBELLA VIRUS VACCINE LIVE (FOR INJECTION) USP

Usual adult and adolescent dose
Immunizing agent (active)
Subcutaneous, 0.5 mL, preferably into the outer aspect of the upper arm ^{01}.


Usual pediatric dose
Immunizing agent (active)
Infants up to 12 months of age: Use is not recommended.

Infants and children 12 months of age and older: See Usual adult and adolescent dose ^{{24} {29}}.


Note: The Committee on Infectious Diseases of the American Academy of Pediatrics (AAP) and the Advisory Committee on Immunization Practices (ACIP) recommend that all children receive a second dose of measles-containing vaccine ^{29}. The second dose of measles, mumps, and rubella virus vaccine live is routinely recommended at 4 to 6 years of age or at 11 to 12 years of age, but may be administered at any visit, provided at least 1 month has elapsed since receipt of the first dose ^{{31} {32}}.


Strength(s) usually available
U.S.—


Not less than the equivalent of 1000 TCID ₅₀ of the U.S. Reference Measles Virus, not less than the equivalent of 20,000 TCID ₅₀ of the U.S. Reference Mumps Virus, and not less than the equivalent of 1000 TCID ₅₀ of the U.S. Reference Rubella Virus in each 0.5-mL dose (Rx) [M-M-R II (neomycin approximately 25 mcg^{01})]

Canada—


Not less than the equivalent of 1000 TCID ₅₀ of the U.S. Reference Measles Virus, not less than the equivalent of 20,000 TCID ₅₀ of the U.S. Reference Mumps Virus, and not less than the equivalent of 1000 TCID ₅₀ of the U.S. Reference Rubella Virus in each 0.5-mL dose (Rx) [M-M-R II (neomycin approximately 25 mcg^{01})]

Packaging and storage:
Store the lyophilized form of the vaccine, the diluent, and the reconstituted form of the vaccine between 2 and 8 ºC (36 and 46 ºF) ^{49}.

Alternatively, the diluent for the single-dose vials may be stored between 15 and 30 ºC (59 and 86 ºF). ^{01}

Protect both the lyophilized form and the reconstituted form of the vaccine from light ^{49}.

Preparation of dosage form:
To reconstitute, use only the diluent provided by the manufacturer, since it is free of preservatives and other substances that might inactivate the vaccine.

Single-dose vial—The entire volume of diluent (approximately 0.5 mL) should be withdrawn into the syringe. All the diluent in the syringe should be injected into the vial of lyophilized vaccine and agitated to mix thoroughly. The entire contents of the vial should be withdrawn into the syringe and the total volume of restored vaccine injected subcutaneously ^{01}.

10-dose vial (in U.S., available only to government agencies/institutions)—The entire contents (7 mL) of the diluent vial should be withdrawn into the syringe to be used for reconstitution. All of the diluent in the syringe should be injected into the 10-dose vial of lyophilized vaccine and agitated to mix thoroughly. The 10-dose container can be used with either syringes or a jet injector. Since the vaccine and diluent do not contain preservatives, special care should be taken to prevent contamination of the multiple-dose vial of vaccine. In addition, the vial should be stored properly until the reconstituted vaccine is used. Unused vaccine should be discarded after 8 hours ^{01}.

Stability:
Both the lyophilized and the reconstituted vaccine should be stored between 2 and 8 ºC (36 and 46 ºF) and protected from light. Improper storage and protection may inactivate the vaccine ^{{01} {49}}.

The reconstituted vaccine should be used as soon as possible. Unused reconstituted vaccine should be discarded after 8 hours ^{{01} {49}}.

The reconstituted vaccine is clear yellow. It should not be used if it is discolored.

Incompatibilities:
Preservatives or other substances may inactivate the vaccine; therefore, only the diluent supplied by the manufacturer should be used for reconstitution ^{01}.

A sterile syringe free of preservatives, antiseptics, disinfectants, and detergents should be used for each injection and/or reconstitution of the vaccine. These substances may inactivate the live virus vaccine ^{01}.

Auxiliary labeling:
   • Protect from light ^{01}.
   • Store in refrigerator ^{01}.
   • Discard reconstituted vaccine if not used within 8 hours ^{{01} {49}}.

Note: The date and the time of reconstitution should be indicated on the vial if the reconstituted vaccine is not used at once.

Revised: 04/15/1999

References

1. M-M-R II package insert (Merck—US), Rev 3/95, Rec 1/96.
   

2. American Academy of Pediatrics. Measles. In: Peter G, editor. 1997 Red book: report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village, IL: American Academy of Pediatrics; 1997. p. 344-57.
   

3. Centers for Disease Control and Prevention (CDC). Recommendations of the Advisory Committee on Immunization Practices (ACIP): measles, mumps, and rubella—vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps. MMWR Morb Mortal Wkly Rep 1998; 47(RR-8): 1-57.
   

4. American Academy of Pediatrics. Mumps. In: Peter G, editor. 1997 Red book: report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village, IL: American Academy of Pediatrics; 1997. p. 366-9.
   

5. American Academy of Pediatrics. Rubella. In: Peter G, editor. 1997 Red book: report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village, IL: American Academy of Pediatrics; 1997. p. 456-62.
   

6. Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 31st ed. Ottawa: Canadian Pharmaceutical Association, 1996. p. 896-7.
   

7. Arya SC. Human immunization in developing countries: practical and theoretical problems and prospects. Vaccine 1994; 12(15): 1423-35.
   

8. Carter H, Campbell H. Rational use of measles, mumps and rubella (MMR) vaccine. Drugs 1993; 45(5): 677-83.
   

9. Preblud SR. Some current issues relating to rubella vaccine. JAMA 1985; 254(2): 253-6.
   

10. Hilton E, Singer C, Kozarsky P, et al. Status of immunity to tetanus, measles, mumps, rubella, and polio among U.S. travelers. Ann Intern Med 1991; 115: 32-3.
    

11. Chen RT, Markowitz LE, Albrecht P, et al. Measles antibody: reevaluation of protective titers. J Infect Dis 1990; 162: 1036-42.
    

12. Panel comment, 10/96.
    

13. Measles, mumps, and rubella vaccine: an essential drug [editorial]. Drugs 1993; 2(7): 1-4.
    

14. Christenson B, Böttiger M. Measles antibody: comparison of long-term vaccination titers, early vaccination titers and naturally acquired immunity to and booster effects on the measles virus. Vaccine 1994; 12(2): 129-33.
    

15. Christenson B, Böttiger M. Long-term follow-up study of rubella antibodies in naturally immune and vaccinated young adults. Vaccine 1994; 12(1): 41-5.
    

16. Böttiger M. Immunity to rubella before and after vaccination against measles, mumps, and rubella (MMR) at 12 years of age of the first generation offered MMR vaccination in Sweden at 18 months. Vaccine 1995; 13(18): 1759-62.
    

17. Weber DJ, Rutala WA, Orenstein WA. Prevention of mumps, measles, and rubella among hospital personnel. J Pediatr 1991; 119(2): 322-6.
    

18. Atmar RL, Englund JA, Hammill H. Complications of measles during pregnancy. Clin Infect Dis 1992; 14: 217-26.
    

19. Mumpsvax package insert (Merck—US), Rev 3/95, Rec 2/96.
    

20. Meruvax package insert (Merck—US), Rev 3/95, Rec 2/96.
    

21. Centers for Disease Control and Prevention (CDC). Recommendations of the Advisory Committee on Immunization Practices (ACIP): rubella prevention. MMWR Morb Mortal Wkly Rep 1990; 39(RR-15): 1-18.
    

22. Centers for Disease Control and Prevention (CDC). Rubella vaccination during pregnancy—United States, 1971-1986. JAMA 1987; 258(6): 753, 757.
    

23. Attenuvax package insert (Merck—US), Rev 3/95, Rec 1/96.
    

24. Centers for Disease Control and Prevention (CDC). Recommendations of the Advisory Committee on Immunization Practices (ACIP): general recommendations on immunization. MMWR Morb Mortal Wkly Rep 1994; 43(RR-1): 1-38.
    

25. Sha BE, Harris AA, Benson CA, et al. Prevalence of measles antibodies in asymptomatic human immunodeficiency virus-infected adults. J Infect Dis 1991; 164: 973-5.
    

26. Krober MS, Stracener CE, Bass JW. Decreased measles antibody response after measles-mumps-rubella vaccine in infants with colds. JAMA 1991; 265(16): 2095-6.
    

27. Fennelly GJ, Flynn JL, Meulen VT, et al. Recombinant BCG priming against measles. J Infect Dis 1995; 172: 698-705.
    

28. de Quadros CA, Olivé JM, Hersh BS, et al. Measles elimination in the Americas: evolving strategies. JAMA 1996; 275(3): 224-9.
    

29. Centers for Disease Control and Prevention (CDC). Recommended childhood immunization schedule—United States, 1995. MMWR Morb Mortal Wkly Rep 1995; 44(RR-5): 1-9.
    

30. Wittler RR, Veit BC, McIntyre S, et al. Measles revaccination response in a school-age population. Pediatrics 1991; 88(5): 1024-30.
    

31. Centers for Disease Control and Prevention (CDC). Immunization of adolescents—recommendations of the Advisory Committee on Immunization Practices, the American Academy of Pediatrics, the American Academy of Family Physicians, and the American Medical Association. MMWR Morb Mortal Wkly Rep 1996; 45(RR-13): 3.
    

32. American Academy of Pediatrics, Committee on Infectious Diseases. Recommended childhood immunization schedule—United States, July–December 1996. Pediatrics 1996; 98(1): 158-60.
    

33. Panel comment, 10/96.
    

34. James JM, Burks AW, Roberson PK, et al. Safe administration of the measles vaccine to children allergic to eggs. N Engl J Med 1995; 332: 1262-6.
    

35. King GE, Markowitz LE, Heath J, et al. Antibody response to measles-mumps-rubella vaccine of children with mild illness at the time of vaccination. JAMA 1996; 275(9): 704-7.
    

36. Dennehy PH, Saracen CL, Peter G. Seroconversion rates to combined measles, mumps, rubella, and varicella of children with upper respiratory tract infection. Pediatrics 1994; 94: 514-6.
    

37. Centers for Disease Control and Prevention (CDC). Recommendations of the Advisory Committee on Immunization Practices (ACIP): use of vaccines and immune globulins for persons with altered immunocompetence. MMWR Morb Mortal Wkly Rep 1993; 42(RR-4): 1-18.
    

38. Lavi S, Zimmerman B, Koren G, et al. Administration of measles, mumps, and rubella virus vaccine (live) to egg-allergic children. JAMA 1990; 263(2): 269-71.
    

39. Puvvada L, Silverman B, Bassett C, et al. Systemic reactions to measles-mumps-rubella vaccine skin testing. Pediatrics 1993; 91(4): 835-6.
    

40. Beck SA, Williams LW, Shirrell MA. Egg hypersensitivity and measles-mumps-rubella vaccine administration. Pediatrics 1991; 88(5): 913-7.
    

41. Reviewer comment, 10/96.
    

42. Kelso JM, Jones RT, Yunginger JW. Anaphylaxis to measles, mumps, and rubella vaccine mediated by IgE to gelatin. J Allergy Clin Immunol 1993: 867-72.
    

43. Begg T, Noah ND. Mumps, measles, and rubella vaccination and encephalitis. BMJ 1989; 299: 978.
    

44. Crowley S, Al-Jawad ST, Kovar IZ. Measles, mumps, and rubella vaccination and encephalitis. BMJ 1989; 299: 660.
    

45. Griffin MR, Ray WA, Mortimer EA, et al. Risk of seizures after measles-mumps-rubella immunization. Pediatrics 1991; 88(5): 881-5.
    

46. Slater PE, Ben-Zvi T, Fogel A, et al. Absence of an association between rubella vaccination and arthritis in underimmune postpartum women. Vaccine 1995; 13(16): 1529-32.
    

47. Panel comment, 10/96.
    

48. American Academy of Pediatrics. Simultaneous administration of multiple vaccines. In: Peter G, editor. 1997 Red book: report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village, IL: American Academy of Pediatrics; 1997. p. 21-2.
    

49. The United States pharmacopeia. The national formulary. USP 23rd revision (January 1, 1995). NF 18th ed (January 1, 1995). Rockville, MD: The United States Pharmacopeial Convention, Inc; 1994. p. 933-4.
    

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