Data Sheet
ProQuad®
Measles, Mumps, Rubella and Varicella (Oka/Merck) Virus Vaccine Live
Subcutaneous injection
Presentation
The vaccine is supplied in vials as a sterile lyophilised preparation together with vials of diluent containing sterile water. Before reconstitution, the lyophilised vaccine is a white to pale yellow compact crystalline plug. ProQuad, when reconstituted, is a clear pale yellow to light pink liquid.
Therapeutic Class
ProQuad is a combined attenuated live virus vaccine containing measles, mumps, rubella, and varicella viruses. ProQuad is a sterile lyophilised preparation of (1) the components of M-M-R® II (Measles, Mumps and Rubella Virus Vaccine Live): Measles Virus Vaccine Live, a more attenuated line of measles virus, derived from Enders' attenuated Edmonston strain and propagated in chick embryo cell culture; Mumps Virus Vaccine Live, the Jeryl Lynn™ (B level) strain of mumps virus propagated in chick embryo cell culture; Rubella Virus Vaccine Live, the Wistar RA 27/3 strain of live attenuated rubella virus propagated in WI-38 human diploid lung fibroblasts; and (2) Varicella Virus Vaccine Live (Oka/Merck), the Oka/Merck strain of varicella-zoster virus propagated in MRC-5 cells (hereafter referred to as VARIVAX®).
Indications
ProQuad is indicated for vaccination against measles, mumps, rubella, and varicella in individuals 12 months through 12 years of age.
Dosage and Administration
Dosage
Individuals 12 months through 12 years of age should receive a single dose of ProQuad administered subcutaneously.
If a second dose of measles-containing vaccine is to be administered according to applicable official recommendations, then ProQuad may be used for this dose.
If the first dose of a measles-containing vaccine is given between 6 months of age and less than 12 months of age (in an at-risk situation such as measles outbreak, or due to official recommendations) the response to the vaccine may be adversely influenced by circulating maternal antibodies. Therefore, another dose of a measles-containing vaccine should be given at 12 months of age or later. A subsequent (third) dose can be administered if warranted by official recommendations for a measles-containing vaccine.
At least 1 month should elapse between a dose of M-M-R II and ProQuad. If for any reason a second dose of varicella-containing vaccine is required, at least 1 month should elapse between administration of the 2 doses.
Do not give immune globulin (IG) or Varicella Zoster Immune Globulin (VZIG) concomitantly with ProQuad (see Interactions).
Method of Administration
FOR SUBCUTANEOUS ADMINISTRATION. DO NOT INJECT INTRAVASCULARLY.
The vaccine is to be injected in the deltoid region of the upper arm or in the higher anterolateral area of the thigh.
CAUTION: A sterile syringe free of preservatives, antiseptics, detergents, and other antiviral substances must be used for each injection and/or reconstitution of ProQuad because these substances may inactivate the vaccine viruses.
To reconstitute the vaccine, use only the diluent supplied because it is free of preservatives or other antiviral substances, which might inactivate the vaccine viruses.
It is important to use a separate sterile syringe and needle for each patient to prevent transmission of infectious agents from one individual to another.
Withdraw the entire volume of solvent into a syringe (if a pre-filled syringe is available, this step is not necessary). Inject the entire content of the syringe into the vial containing the powder. Gently agitate to dissolve completely. Withdraw the entire content of the reconstituted vaccine from the vial into the same syringe and inject the entire volume.
IT IS RECOMMENDED THAT THE VACCINE BE ADMINISTERED IMMEDIATELY AFTER RECONSTITUTION, TO MINIMISE LOSS OF POTENCY. DISCARD IF RECONSTITUTED VACCINE IS NOT USED WITHIN 30 MINUTES.
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. Before reconstitution, the lyophilised vaccine is a white to pale yellow compact crystalline plug. ProQuad, when reconstituted, is a clear pale yellow to light pink liquid.
Contraindications
History of hypersensitivity to any component of the vaccine, including gelatin.
History of anaphylactoid reaction to neomycin.
Blood dyscrasias, leukaemia, lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic system.
Immunosuppressive therapy (including high-dose corticosteroids); however, ProQuad is not contraindicated for use in individuals who are receiving topical corticosteroids or low-dose corticosteroids, as are commonly used for asthma prophylaxis or in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison's disease. Vaccination with a live attenuated vaccine, such as varicella, can result in a more extensive vaccine-associated rash or disseminated disease in individuals on immunosuppressant doses of corticosteroids. Individuals who are on immunosuppressant drugs are more susceptible to infections than healthy individuals.
Primary and acquired immunodeficiency states, including immunosuppression in association with AIDS or other clinical manifestations of infection with human immunodeficiency viruses; cellular immune deficiencies; and hypogammaglobulinaemic and dysgammaglobulinaemic states. Measles inclusion body encephalitis, pneumonitis, and death as a direct consequence of disseminated measles vaccine virus infection have been reported in severely immunocompromised individuals inadvertently vaccinated with measles-containing vaccine.
Family history of congenital or hereditary immunodeficiency, unless the immune competence of the potential vaccine recipient is demonstrated.
Active untreated tuberculosis.
Any active febrile illness with fever >38.5°C (>101.3°F); however, low-grade fever itself is not a contraindication to vaccination.
Pregnancy; the possible effects of the vaccine on foetal development are unknown at this time. If vaccination of postpubertal females is undertaken, pregnancy should be avoided for 3 months following vaccination. (See Warnings and Precautions, Pregnancy.)
Warnings and Precautions
General
Adequate treatment provisions, including epinephrine injection (1:1000), should be available for immediate use should an anaphylactic or anaphylactoid reaction occur.
Due caution should be employed in administration of ProQuad to persons with individual or family history of convulsions, a history of cerebral injury or any other condition in which stress due to fever should be avoided. The physician should be alert to the temperature elevation that may occur following vaccination (see Adverse Effects).
The safety and efficacy of ProQuad have not been established in individuals who are known to be infected with human immunodeficiency viruses with or without evidence of immunosuppression (see Contraindications).
The duration of protection from measles, mumps, rubella, and varicella infection after vaccination with ProQuad is unknown (see Actions).
As for any vaccine, vaccination with ProQuad may not result in protection in all vaccine recipients.
Transmission
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 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 the more attenuated Enders' Edmonston strain of measles virus or the Jeryl Lynn™ strain of mumps virus from vaccine recipients to susceptible contacts.
Post-licensing experience with VARIVAX suggests that transmission of varicella vaccine virus may occur rarely between healthy vaccine recipients who develop a varicella-like rash and contacts susceptible to varicella, as well as high-risk individuals susceptible to varicella.
High-risk individuals susceptible to varicella include:
- Immunocompromised individuals (see Contraindications);
- Pregnant women without documented positive history of varicella (chickenpox) or laboratory evidence of prior infection;
- Newborn infants of mothers without documented positive history of varicella or laboratory evidence of prior infection.
Vaccine recipients should attempt to avoid, whenever possible, close association with high-risk individuals susceptible to varicella for up to 6 weeks following vaccination. In circumstances where contact with high-risk individuals susceptible to varicella is unavoidable, the potential risk of transmission of the varicella vaccine virus should be weighed against the risk of acquiring and transmitting wild-type varicella virus.
Hypersensitivity to Eggs
Live measles vaccine and live mumps vaccine are 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 may be at an enhanced risk of immediate-type hypersensitivity reactions after receiving vaccines containing traces of chick embryo antigen. The potential risk-to-benefit ratio should be carefully evaluated before considering vaccination in such cases. Such individuals may be vaccinated with extreme caution, having adequate treatment on hand should a reaction occur.
Thrombocytopaenia
No clinical data are available regarding the development or worsening of thrombocytopaenia in individuals vaccinated with ProQuad. However, post-marketing experience with live measles, mumps, and rubella vaccine indicates that individuals with current thrombocytopaenia may develop more severe thrombocytopaenia following vaccination. In addition, individuals who experienced thrombocytopaenia following the first dose of a live measles, mumps, and rubella vaccine may develop thrombocytopaenia with repeat doses. Serologic status may be evaluated to determine whether or not additional doses of vaccine are needed. The potential risk-to-benefit ratio should be carefully evaluated before considering vaccination with ProQuad in such cases (see Adverse Effects).
Post-Exposure Prophylaxis
No clinical data are available for ProQuad administered after exposure to measles, mumps, rubella, or varicella. However, post-exposure prophylaxis has been demonstrated for measles and varicella with a measles-containing vaccine and varicella-containing vaccine, respectively, when administered to the susceptible individuals within 3 days of exposure.
Females of Childbearing Age
In females of childbearing age, pregnancy should be avoided for 3 months following vaccination (see Pregnancy).
Adolescents and Adults
No clinical data are available on the safety, immunogenicity, and efficacy of ProQuad in adolescents and adults.
Tuberculin Test
It has been reported that live attenuated measles, mumps, 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 any time before, simultaneously with, or at least 4 to 6 weeks after ProQuad.
Tuberculosis
Children under treatment for tuberculosis have not experienced exacerbation of the disease when immunised with live measles virus vaccine; no studies have been reported to date of the effect of measles virus vaccines on children with untreated tuberculosis.
Albumin
This product contains albumin, a derivative of human blood. Although there is a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD), no cases of transmission of CJD or viral diseases have ever been identified that were associated with the use of albumin.
Pregnancy
Studies have not been conducted with ProQuad in pregnant women. It is also not known whether ProQuad can cause harm to the foetus when administered to a pregnant woman or can affect reproduction capacity. Therefore, ProQuad should not be administered to pregnant females; furthermore, pregnancy should be avoided for 3 months following vaccination (see Indications, Contraindications, and Warnings and Precautions).
In counselling 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) Reports have indicated that contracting wild-type measles during pregnancy enhances foetal risk. Increased rates of spontaneous abortion, stillbirth, congenital defects and prematurity have been observed subsequent to wild-type 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 foetal effects; (2) Mumps infection during the first trimester of pregnancy may increase the rate of spontaneous abortion. Although mumps vaccine virus has been shown to infect the placenta and foetus, there is no evidence that it causes congenital malformations in humans; (3) In a 15-year survey involving over 1100 pregnant women who received rubella vaccine within 3 months before or after conception (of whom 635 received the Wistar RA 27/3 strain), none of the newborns had abnormalities compatible with congenital rubella syndrome; and (4) Wild-type varicella can sometimes cause harm to the foetus.
Nursing Mothers
It is not known whether measles, mumps, or varicella virus is secreted in human milk. Studies have shown that lactating postpartum women immunised with live attenuated rubella vaccine may secrete the virus in breast milk and transmit it to breast-fed infants. In the infants who developed serological evidence of rubella infection, none exhibited severe disease; however, one exhibited mild clinical illness typical of acquired rubella. Therefore, caution should be exercised if ProQuad is inadvertently administered to a nursing woman.
Paediatric Use
ProQuad has not been studied in infants less than 12 months of age and is not recommended for administration in this age group.
Effects on Ability to Drive and Use Machines
There are no data to suggest that ProQuad affects the ability to drive or operate machinery.
Animal Toxicology
Carcinogenesis, Mutagenesis, Reproduction
ProQuad has not been evaluated for its carcinogenic or mutagenic potential, or its potential to impair fertility.
Adverse Effects
Children 12 through 23 months of age
In clinical trials, ProQuad was administered alone to 6038 children 12 through 23 months of age. ProQuad was generally well tolerated.
Children received either the refrigerator-stable formulation or the frozen formulation of ProQuad and were monitored for 6 weeks post-vaccination. The safety profiles were similar for the two formulations. The safety of the frozen formulation of ProQuad was compared with the safety of M-M-R II and VARIVAX given concomitantly at separate injection sites. The safety profile for ProQuad was similar to the component vaccines.
The only systemic vaccine-related adverse experiences that were reported at a significantly greater rate in individuals who received ProQuad than in individuals who received M-M-R II and VARIVAX concomitantly at separate injection sites were fever (≥38.9°C [≥102°F] oral equivalent or abnormal) (21.5% versus 14.9%, respectively), and measles-like rash (3.0% versus 2.1%, respectively). Both fever and measles-like rash usually occurred within 5 to 12 days following the vaccination, were of short duration, and resolved with no long-term sequelae. Pain/tenderness/soreness at the injection site was reported at a statistically lower rate in individuals who received ProQuad than in individuals who received M-M-R II and VARIVAX concomitantly at separate injection sites (22.0% versus 26.7%, respectively). The only vaccine related injection-site adverse experience that was more frequent among recipients of ProQuad than recipients of M-M-R II and VARIVAX was rash at the injection site (2.3% versus 1.5%, respectively).
Across clinical studies, the following adverse experiences were reported as
vaccine related by the investigator in individuals after a single dose of
ProQuad (excluding single events with a frequency ≤0.02%). Several adverse
experiences were solicited in the clinical studies and are designated with the
symbol (†).
[Very common (≥1/10); Common (≥1/100, <1/10); Uncommon (≥1/1,000, <1/100);
Rare (≥1/10,000, <1/1,000)]
Infections and infestations
Common: upper respiratory infection
Uncommon: gastroenteritis, ear infection/otitis, nasopharyngitis,
otitis media, pharyngitis, roseola, viral infection, viral rash
Rare: bronchiolitis, candidiasis, infectious croup, tonsillitis,
varicella†, viral gastroenteritis
Blood and lymphatic disorders
Rare: lymphadenopathy
Immune system disorders
Rare: allergy/hypersensitivity
Metabolism and nutrition disorders
Uncommon: anorexia, decreased appetite
Psychiatric disorders
Common: irritability
Uncommon: crying, insomnia, sleep disorder
Rare: agitation, clinging, emotional changes
Nervous system disorders
Uncommon: febrile seizure, somnolence
Rare: ataxia, headache, lethargy
Eye disorders
Rare: conjunctivitis, tearing, visual discomfort
Ear and labyrinth disorders
Rare: ear pain
Vascular disorders
Rare: flushing
Respiratory, thoracic, and mediastinal disorders
Uncommon: cough, nasal congestion, respiratory congestion, rhinorrhoea
Rare: wheezing
Gastrointestinal disorders
Common: diarrhoea, vomiting
Rare: flatulence, nausea, teething
Skin and subcutaneous tissue disorders
Common: measles-like rash†, rash, varicella-like rash†
Uncommon: dermatitis (including contact, atopic, and diaper rash),
eczema, erythema, miliaria rubra/heat rash, rubella-like rash†,
urticaria, viral exanthema
Rare: acne, drug eruption, exanthema
General disorders and administration site conditions
Very common: fever ≥38.9°C ([≥102°F] oral equivalent or abnormal)†,
erythema† or pain/tenderness/soreness† at the injection
site
Common: ecchymosis or swelling† at the injection site,
injection-site rash†
Uncommon: asthenia/fatigue, induration or warmth at the injection site,
injection site haemorrhage, injection site mass/lump, malaise
Rare: flu-like/influenza-like illness, injection site discolouration,
injection site reaction, pain, pain/tenderness/soreness
Injury and poisoning, and procedural complications
Rare: contusion, non-venomous bite/sting
Other Adverse Experiences
Additionally, adverse experiences reported with post-marketing use of ProQuad and/or in clinical studies and/or post-marketing use of M-M-R II, the component vaccines, and VARIVAX without regard to causality or frequency are summarised below.
Infections and infestations
atypical measles, cellulitis, epididymitis, herpes zoster, infection,
influenza, measles, orchitis, parotitis, respiratory infection, skin infection
Blood and the lymphatic system disorders
lymphadenitis, regional lymphadenopathy, thrombocytopaenia
Immune system disorders
anaphylactoid reaction, anaphylaxis and related phenomenon such as
angioneurotic oedema, facial oedema, and peripheral oedema, anaphylaxis in
individuals with or without an allergic history
Psychiatric disorders
apathy, nervousness
Nervous system disorders
afebrile convulsions or seizures, aseptic meningitis (see below), Bell's
palsy, cerebrovascular accident, dizziness, dream abnormality, encephalitis
(see below), encephalopathy (see below), Guillain-Barré syndrome, hypersomnia,
measles inclusion body encephalitis (see Contraindications), ocular palsies,
paraesthesia, polyneuritis, polyneuropathy, subacute sclerosing
panencephalitis (see below), syncope, transverse myelitis, tremor
Eye disorders
oedema of the eyelid, irritation, optic neuritis, retinitis, retrobulbar
neuritis
Ear and labyrinth disorders
nerve deafness
Vascular disorders
extravasation
Respiratory, thoracic and mediastinal disorders
bronchial spasm, bronchitis, epistaxis, pneumonitis (see
Contraindications), pneumonia, pulmonary congestion, rhinitis, sinusitis,
sneezing, sore throat, wheezing
Gastrointestinal disorders
abdominal pain, haematochezia, mouth ulcer
Skin and subcutaneous tissue disorders
erythema multiforme, Henoch-Schlein purpura, herpes simplex, impetigo,
panniculitis, pruritus, purpura, skin induration, Stevens-Johnson syndrome,
sunburn
Musculoskeletal, connective tissue and bone disorders
arthritis and/or arthralgia (usually transient and rarely chronic [see
below]), musculoskeletal pain, myalgia, pain of the hip, leg, or neck,
swelling
General disorders and administration site conditions
injection site complaints (burning and/or stinging of short duration,
eczema, oedema/swelling, hive-like rash, haematoma, induration, lump,
vesicles, wheal and flare), inflammation, lip abnormality, papillitis,
roughness/dryness, stiffness, trauma, varicella-like rash, venipuncture site
haemorrhage, warm sensation, warm to touch
Death from various, and in some cases unknown, causes has been reported rarely following vaccination with measles, mumps, and rubella vaccines; however, a causal relationship has not been established in healthy individuals (see Contraindications). No deaths or permanent sequelae were reported in a published post-marketing surveillance study in Finland involving 1.5 million children and adults who were vaccinated with M-M-R II during 1982 to 1993.
Encephalitis and encephalopathy have been reported approximately once for every 3 million doses of the combination of measles, mumps, and rubella vaccine contained in M-M-R II. Post-marketing surveillance of the more than 518 million doses that have been distributed worldwide (1978 to 2007) indicates that serious adverse events such as encephalitis and encephalopathy continue to be rarely reported. In no case has it been shown conclusively that reactions were actually caused by the vaccine; 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 wild-type measles (1 per 2000 reported cases).
Arthralgia and/or arthritis (usually transient and rarely chronic), and polyneuritis are features of infection with wild-type rubella and vary in frequency and severity with age and gender, being greatest in adult females and least in prepubertal children. Following vaccination in children, reactions in joints are generally uncommon (0 to 3%) and of brief duration. In women, incidence rates for arthritis and arthralgia are generally higher than those seen in children (12 to 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 adult women. Even in older women (35 to 45 years), these reactions are generally well tolerated and rarely interfere with normal activities.
Chronic arthritis has been associated with wild-type 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.
There have been reports of subacute sclerosing panencephalitis (SSPE) in children who did not have a history of infection with wild-type measles but did receive measles vaccine. Some of these cases may have resulted from unrecognised measles in the first year of life or possibly from the measles vaccination. Based on estimated measles vaccine distribution in the United States (US), 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 infection with wild-type measles, 6 to 22 cases of SSPE per million cases of measles. The results of a retrospective case-controlled study conducted by the US Centres for Disease Control and Prevention suggest that the overall effect of measles vaccine has been to protect against SSPE by preventing measles with its inherent higher risk of SSPE.
Cases of aseptic meningitis have been reported following measles, mumps, and rubella vaccination. Although a causal relationship between other strains of mumps vaccine and aseptic meningitis has been shown, there is no evidence to link Jeryl Lynn™ mumps vaccine to aseptic meningitis.
Febrile seizures have been reported in children receiving ProQuad. Consistent with clinical study data on the timing of fever and measles-like rash, an analysis of a post-marketing observational safety study in children (N=31,298, 99% in their second year of life) receiving their first dose of vaccine has shown that febrile seizures occurred more frequently 5-12 days following vaccination with ProQuad (n=22; 0.7 per 1000 children) when compared with data from children in a historical, age- and gender-matched, control group vaccinated with M-M-R II and VARIVAX concomitantly (N=31,298) before ProQuad was available (n=10; 0.3 per 1000 children). In the 0-30 day time period following vaccination, the incidence of febrile seizures with ProQuad (n=44; 1.4 per 1000 children) was similar to that observed in children receiving M-M-R II and VARIVAX concomitantly (n=40; 1.3 per 1000 children).
Interactions
At least 1 month should elapse between a dose of M-M-R II and a dose of ProQuad. If for any reason a second dose of varicella-containing vaccine is required, at least 1 month should elapse between administration of the 2 doses.
Administration of immune globulins (IG) concomitantly with ProQuad may interfere with the expected immune response. Vaccination should be deferred for at least 3 months following blood or plasma transfusions, or administration of IG. However, the appropriate suggested interval between transfusion or IG administration and vaccination will vary with the type of transfusion or indication for, and dose of, IG (e.g., 5 months for VZIG).
Following administration of ProQuad, any IG including VZIG should not be given for 1 month thereafter unless its use outweighs the benefits of vaccination.
Vaccine recipients should avoid use of salicylates for 6 weeks after vaccination with ProQuad as Reye's syndrome has been reported following the use of salicylates during wild-type varicella infection.
The fourth dose of DTaP (diphtheria, tetanus, acellular pertussis vaccine) is indicated for children 15 months of age and older. Limited data suggest that ProQuad may be administered concomitantly (at separate injection sites) with DTaP in children 15 months of age and older (for children less than 15 months of age see Actions).
There are no data for concurrent administration of ProQuad and DTaP containing vaccines registered in New Zealand (see Actions, Studies with Other Vaccines).
Results from clinical studies indicate that ProQuad may be administered concomitantly with Haemophilus b conjugate (meningococcal protein conjugate), hepatitis B (recombinant), pneumococcal conjugate, and hepatitis A (inactivated) vaccines.
There are no data for the administration of ProQuad with inactivated poliovirus vaccine.
Overdosage
There are no data with regard to overdose.
Actions
Clinical Pharmacology
Measles, mumps, rubella, and varicella are 4 common childhood diseases caused by measles virus, mumps virus, rubella virus, and varicella virus, respectively. These diseases may be associated with serious complications and/or death. For example, measles can be associated with pneumonia and encephalitis; mumps can be associated with aseptic meningitis, deafness, and orchitis; rubella occurring during pregnancy can cause congenital rubella syndrome in the infants of infected mothers; and wild-type varicella can be associated with bacterial superinfection, pneumonia, encephalitis, and Reye's syndrome.
Efficacy
Formal studies to evaluate the efficacy of ProQuad have not been performed. However, the efficacy of M-M-R II and VARIVAX has been demonstrated in numerous studies.
Efficacy of the measles, mumps, and rubella components of ProQuad was previously established in a series of double-blind controlled field trials with the monovalent vaccines produced by Merck, which demonstrated a high degree of protective efficacy. In these studies seroconversion in response to vaccination against measles, mumps, and rubella paralleled protection from these diseases. ProQuad elicits rates of antibody responses against measles, mumps, and rubella similar to those observed after vaccination with M-M-R II.
More than 428 million doses of M-M-R II have been distributed worldwide (1978 to 2005). Widespread use of a 2-dose vaccination schedule in the United States and countries such as Finland and Sweden has led to a >99% reduction in the incidence of each of the 3 targeted diseases. Vaccination against measles, mumps, and rubella has led to a significant reduction in the incidence of these diseases.
In combined clinical trials of VARIVAX, the protective efficacy of the vaccine against all forms of varicella ranged from 81 to 100%. In a large case-control study, the vaccine was estimated to be 85% effective against all forms of varicella and 97% effective against moderately severe and severe disease. Long-term estimated efficacy for the vaccine against all forms of varicella over 10 years was 94%. Antibody responses against varicella virus ≥5 units/mL in the glycoprotein enzyme-linked immunosorbent assay (gpELISA, a highly sensitive assay which is not commercially available) have been shown to be highly correlated with long-term protection. Clinical studies have shown that immunisation with ProQuad elicits rates of antibody responses against varicella virus ≥5 units/mL in the gpELISA similar to those observed after vaccination with VARIVAX.
Immunogenicity
Immunogenicity was studied in children 12 through 23 months of age with a negative clinical history of measles, mumps, rubella, and varicella who participated in -5 randomised clinical trials. The immunogenicity of the current refrigerator-stable formulation was shown to be similar to the immunogenicity of the earlier formulation of ProQuad. Clinical trials also established that the earlier formulation of ProQuad is similar to the individual component vaccines (M-M-R II and VARIVAX), which are currently used in routine vaccination in some countries.
Clinical trials involving 6987 subjects who received ProQuad demonstrated detectable immune responses to measles, mumps, rubella, and varicella in a high proportion of individuals. The presence of detectable antibody was assessed by an appropriately sensitive enzyme-linked immunosorbent assay (ELISA) for measles, mumps (wild-type and vaccine-type strains), and rubella, and by gpELISA for varicella. Following a single dose of ProQuad, the vaccine response rates were 97.7% for measles, 96.3 to 98.8% for mumps, and 98.8% for rubella. The vaccine response rate was 90.9% for varicella based on an antibody response rate ≥5 gpELISA units/mL (a response rate that has been shown to be highly correlated with long-term protection). These results were similar to the immune response rates induced by concomitant administration of M-M-R II and VARIVAX at separate injection sites.
Children who received a second dose of ProQuad
In 2 clinical trials, 1035 subjects were administered a second dose of ProQuad approximately 3 months after the first dose. The vaccine response rates were 99.4% for measles, 99.9% for mumps, 98.3% for rubella, and 99.4% for varicella (≥5 gpELISA units/mL). The geometric mean titres (GMTs) following the second dose of ProQuad increased approximately 2 fold each for measles, mumps, and rubella, and approximately 41 fold for varicella. In these trials, the rates of adverse experiences after the second dose of ProQuad were generally similar to, or lower than, those seen with the first dose. The fever rate was lower after the second dose than after the first dose.
Children who received ProQuad at 4 through 6 years of age after primary vaccination with M-M-R II and VARIVAX.
The immunogenicity and safety of ProQuad were evaluated in a clinical trial involving 799 subjects 4 through 6 years of age who had received M-M-R II and VARIVAX at least 1 month prior to study entry. Following the dose of ProQuad, GMTs for measles, mumps, rubella, and varicella were similar to those following a second dose of M-M-R II and VARIVAX administered concomitantly at separate injection sites. Additionally, GMTs for measles, mumps, and rubella were similar to those following a second dose of M-M-R II given concomitantly with placebo. In this trial, the rates and types of adverse experiences seen in the group that received ProQuad were generally similar to those seen in the control groups.
Persistence of Immune Response
The persistence of antibody at 1 year after vaccination was evaluated in a subset of 2108 subjects who were involved in 1 clinical trial. The antibody persistence rates 1 year postvaccination in recipients of a single dose of ProQuad were 98.9% (1722/1741) for measles, 96.7% (1676/1733) for mumps, 99.6% (1796/1804) for rubella, and 97.5% (1512/1550) for varicella (≥5 gpELISA units/mL).
Experience with M-M-R II demonstrates that antibodies to measles, mumps, and rubella viruses are still detectable in most individuals 11 to 13 years after primary vaccination. In clinical studies involving healthy subjects who received 1 dose of VARIVAX, detectable varicella antibodies were present in most individuals tested for up to 10 years post-vaccination.
Herpes Zoster
In a clinical trial, 2 cases of herpes zoster were reported in 2108 healthy subjects 12 through 23 months of age who were vaccinated with ProQuad and followed for 1 year. Both cases were unremarkable and no sequelae were reported.
The reported rate of zoster in recipients of VARIVAX appears not to exceed that previously determined in a population-based study of healthy children who had experienced wild-type varicella. In clinical trials, 12 cases of herpes zoster were reported in 9543 vaccinated individuals 12 months through 12 years of age during 84,414 person-years of follow-up. This resulted in a calculated incidence of at least 0.14 cases per 1,000 person-years. The incidence of herpes zoster following naturally acquired infection in subjects >5 years of age and persons 5 to 9 years of age has been reported to be 1.1 and 0.51 per 1,000 person-years, respectively. All 12 cases reported after VARIVAX were mild and no sequelae were reported. The long-term effect of VARIVAX on the incidence of herpes zoster is unknown at present.
Post-Exposure Prophylaxis
No clinical data are available for ProQuad administered after exposure to measles, mumps, rubella, or varicella; however, post-exposure prophylaxis has been demonstrated for measles and varicella with measles-containing vaccine and varicella virus vaccine, respectively. Vaccination of susceptible individuals within 3 days of exposure to wild-type measles may provide some protection. Vaccination of susceptible individuals within 3 days of exposure to natural varicella may prevent a clinically apparent infection or modify the course of the infection. In addition, there are limited data that indicate that vaccination up to 5 days after exposure to varicella may modify the course of the infection.
Reye's Syndrome
Reye's syndrome following wild-type varicella infection has occurred in children and adolescents, the majority of whom had received salicylates. In clinical studies of ProQuad and in the clinical studies of VARIVAX, physicians advised subjects not to use salicylates for 6 weeks after vaccination. There were no reports of Reye's syndrome in recipients of ProQuad or VARIVAX during these studies.
Studies With Other Vaccines
In a clinical trial involving 1913 healthy subjects 12 through 15 months of age, 949 received ProQuad, Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTaP) and Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine concomitantly at separate injection sites. Another 485 healthy subjects received ProQuad at the initial visit followed by DTaP and Haemophilus b Conjugate and Hepatitis B (Recombinant) Vaccine given concomitantly 6 weeks later. In subjects 13.5 months of age or older, seroconversion rates and antibody titres were comparable between the 2 groups at approximately 6 weeks postvaccination. However, in subjects less than 13.5 months of age, seroconversion rates and antibody titres were comparable between the 2 groups for each of the vaccine components except pertussis FHA (see Interactions). No clinically significant differences in adverse experiences were reported between the 2 treatment groups.
In a clinical trial involving 1027 healthy children 12 to 15 months of age, 510 were randomised to receive ProQuad and Prevnar* concomitantly at separate injection sites, and 517 were randomised to receive ProQuad and Prevnar non-concomitantly. Seroconversion rates and antibody titres for measles, mumps, rubella, varicella, and S. pneumoniae types 4, 6B, 9V, 14, 18C, 19F, and 23F were comparable in the concomitant and non-concomitant groups at 6 weeks post-vaccination indicating that ProQuad and Prevnar can be administered concomitantly at separate injection sites. No clinically significant differences in adverse events were reported between treatment groups.
In a clinical trial involving 1800 healthy children 12 to 23 months of age, 1453 were randomised to receive 2 doses of VAQTA, and 347 were randomised to receive 2 doses of VAQTA concomitantly with 2 doses ProQuad at least 6 months apart. Rates of adverse experiences were lower following a second dose than following the first dose of both vaccines given concomitantly.
In a clinical trial involving 653 healthy children 12 to 15 months of age, 330 were randomised to receive VAQTA, ProQuad, and Prevnar concomitantly, and 323 were randomised to receive ProQuad and Prevnar concomitantly followed by VAQTA 6 weeks later. Seroconversion rates and antibody titres for measles, mumps, rubella, varicella, and S. pneumoniae types 4, 6B, 9V, 14, 18C, 19F, and 23F were comparable between the 3 groups at 6 weeks post-vaccination indicating that ProQuad, VAQTA, and Prevnar can be administered concomitantly at separate injection sites. No clinically significant differences in adverse events were reported among treatment groups.
In the above 3 post-licensure clinical trials evaluating the concomitant use of ProQuad with other paediatric vaccines, a total of 1745 children 12 to 23 months of age received 2 doses of ProQuad, of which 1661 completed safety follow-up after both doses. Rates of adverse experiences after the second dose of ProQuad were generally similar to, or lower than, those seen with the first dose. The fever rate was lower after the second dose than after the first dose.
Pharmaceutical Precautions
During shipment, to ensure that there is no loss of potency, the vaccine must be maintained at a temperature of ≤8°C.
Before reconstitution, ProQuad has a shelf life of 18 months when refrigerated at 2° to 8°C.
Immediately upon receipt of the vaccine shipment, the vaccine must be kept in the refrigerator at a temperature of 2° to 8°C until ready for use. THE VACCINE SHOULD NOT BE FROZEN.
DO NOT STORE LYOPHILISED VACCINE AT ROOM TEMPERATURE.
IF LYOPHILISED VACCINE IS INADVERTENTLY STORED AT ROOM TEMPERATURE, IT SHOULD BE DISCARDED.
Protect the vaccine from light at all times since such exposure may inactivate the vaccine viruses.
DISCARD IF RECONSTITUTED VACCINE IS NOT USED WITHIN 30 MINUTES.
The diluent should be stored separately at room temperature (20° to 25°C, 68° to 77°F), or in the refrigerator (2° to 8°C, 36° to 46°F).
Composite packs containing the vaccine vial and diluent:
For composite packs with the vaccine vial and diluent packaged together, store
in the refrigerator at 2° to 8°C. DO NOT STORE THE COMPOSITE PACK IN THE
FREEZER.
Further Information
Active Ingredients
ProQuad, when reconstituted as directed, is a sterile preparation for subcutaneous administration. Each 0.5-mL dose contains not less than 3.00 log10 TCID50 (50% tissue culture infectious dose) of measles virus; 4.30 log10 TCID50 of mumps virus; 3.00 log10 TCID50 of rubella virus; and a minimum of 3.99 log10 PFU (plaque-forming units) of Oka/Merck varicella virus.
Inactive Ingredients
Each 0.5-mL dose of the vaccine nominally contains 20 mg of sucrose, 11 mg of hydrolysed gelatin, 2.5 mg of urea, 2.3 mg of sodium chloride, 16 mg of sorbitol, 0.38 mg of monosodium L-glutamate, 1.4 mg of sodium phosphate, 0.25 mg of human albumin, 0.13 mg of sodium bicarbonate, 94 mcg of potassium phosphate, 58 mcg of potassium chloride, residual components of MRC-5 cells including DNA and protein, 5 mcg of neomycin, bovine serum albumin (0.5 mcg), and other buffer and media ingredients. The product contains no preservative.
The cells, virus pools, bovine serum, and human albumin used in manufacturing are all screened to ensure the absence of adventitious agents.
Medicine Classification
Prescription Medicine
Package Quantities
ProQuad is supplied as:
- a single dose vial of lyophilised vaccine and a vial of diluent in a composite pack
- ten single dose vials of lyophilised vaccine and ten vials of diluent supplied in separate cartons.
Name and Address
Merck Sharp & Dohme (New Zealand) Limited
P O Box 99 851
Newmarket
Auckland
NEW ZEALAND
Tel: 0800 500 673
Date of Preparation
29 September 2008
DP-PRQ-0908(290908)
® Registered Trademark of Merck & Co Inc., Whitehouse Station,
NJ, USA
Copyright© 2008 Merck & Co., Inc.
™ Trademark
* Registered Trademark