ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
ProQuad powder and solvent for suspension for injection.
Measles, mumps, rubella and varicella vaccine (live).
2.
After reconstitution, one dose (0.5
ml) contains:
Measles virus
1
Enders’ Edmonston strain (live, attenuated)........ not less than 3.00 log
10
CCID
50
*
Mumps virus1 Jeryl Lynn™ (Level B) strain (live, attenuated) .. not less than 4.30 log10 CCID
50
*
Rubella virus2 Wistar RA 27/3 strain (live, attenuated).............. not less than 3.00 log10 CCID
50
*
Varicella virus3 Oka/Merck strain (live, attenuated)................... not less than 3.99 log10 PFU**
*50% cell culture infectious dose
**plaque-forming units
(
1
) Produced in chick embryo cells.
(
2
) Produced in human diploid lung (WI-38) fibroblasts.
(
3
) Produced in human diploid (MRC-5) cells.
For a full list of excipients, see section 6.1.
3.
Powder and solvent for suspension for injection.
Before reconstitution, the powder is a white to pale yellow compact crystalline cake and the solvent is
a clear colourless liquid.
4.
ProQuad is indicated for simultaneous vaccination against measles, mumps, rubella and varicella in
individuals from 12 months of age.
Posology
Individuals from 12 months of age should receive two doses of ProQuad or a single dose of ProQuad
followed by a second dose of a monovalent varicella vaccine to ensure optimal protection against
varicella (see section 5.1). At least one month must elapse between the first and second dose of any
live viral attenuated vaccine. It is preferred that the second dose be administered within three months
following the first dose.
Note: applicable official recommendations may vary regarding the interval between doses and the
need for two or one doses of measles, mumps and rubella and of varicella-containing vaccine.
ProQuad may be used as the second dose in individuals from 12 months of age who have previously
received measles, mumps, and rubella vaccine and varicella vaccine.
2
Method of administration
The vaccine is to be injected by the subcutaneous route in the deltoid region of the upper arm or in the
higher anterolateral area of the thigh.
See section 6.6 for preparation instructions.
DO NOT INJECT INTRAVASCULARLY.
History of hypersensitivity to any varicella vaccine or measles, mumps, or rubella vaccine, to any of
the excipients, or to neomycin, which may be present as trace residues (see sections
2, 4.4 and 6.1).
Blood dyscrasias, leukaemia, lymphomas of any type, or other malignant neoplasms affecting the
haematopoietic and lymphatic system.
Current immunosuppressive therapy (including high doses of corticosteroids). ProQuad is not
contraindicated in individuals who are receiving topical or low-dose parenteral corticosteroids (e.g.
for asthma prophylaxis or replacement therapy).
Humoral or cellular (primary or acquired) immunodeficiency, including hypogammaglobulinemia and
dysgammaglobulinemia and AIDS, or symptomatic HIV infection or a CDC Class 2 or higher or an
age-specific CD4+ T-lymphocyte percentage <25% (see section
4.4). In severely
immunocompromised individuals inadvertently vaccinated with measles-containing vaccine, measles
inclusion body encephalitis, pneumonitis, and fatal outcome as a direct consequence of disseminated
measles vaccine virus infection have been reported.
Family history of congenital or hereditary immunodeficiency, unless the immune competence of the
potential vaccine recipient is demonstrated.
Active untreated tuberculosis (see section 4.4).
Vaccination should be postponed during any illness with fever >38.5
°
C.
Pregnancy (see also sections 4.4 and 4.6).
Appropriate medical treatment and supervision should always be readily available in case of a rare
anaphylactic reaction following the administration of the vaccine.
Additionally, 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. The potential risk-
to-benefit ratio should be carefully evaluated before considering vaccination in such cases.
Due caution should be employed in the administration of ProQuad to persons with individual or
family history of convulsions, or a history of cerebral injury. The physician should be alert to the
temperature elevation that may occur following vaccination (see section
4.8).
This vaccine contains 16 mg of sorbitol as an excipient. Patients with rare hereditary problems of
fructose intolerance should not take this vaccine.
3
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.
As for any vaccine, vaccination with ProQuad may not result in protection in all vaccine recipients.
Pregnancy
See sections 4.3 and 4.6.
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 without any evidence of clinical disease
(see section
4.6).
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 Varicella Vaccine live (Oka/Merck) suggests that transmission of
varicella vaccine virus may rarely occur between healthy vaccine recipients who develop a varicella-
like rash and contacts susceptible to varicella, as well as high-risk individuals susceptible to varicella
(see section
4.8).
High-risk individuals susceptible to varicella include:
•
immunocompromised individuals (see section
4.3),
•
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.
Thrombocytopenia
No clinical data are available regarding the development or worsening of thrombocytopenia in
individuals vaccinated with ProQuad. However, post-marketing experience with live measles, mumps,
and rubella vaccine indicates that individuals with current thrombocytopenia may develop more
severe thrombocytopenia following vaccination. In addition, individuals who experienced
thrombocytopenia following the first dose of a live measles, mumps, and rubella vaccine may develop
thrombocytopenia 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
section
4.8).
Other
No clinical data are available for ProQuad in individuals who are known to be infected with human
immunodeficiency viruses without evidence of immunosuppression. Careful risk-to-benefit evaluation
should be done for these subjects (see section
4.3).
4
Children under treatment for tuberculosis have not experienced exacerbation of the disease when
immunized with live measles virus vaccine. No studies have been reported to date on the effect of
measles virus vaccines on children with untreated tuberculosis (see section
4.3).
Post-exposure prophylaxis
No clinical data are available for ProQuad administered after exposure to measles, mumps, rubella, or
varicella. However, post-exposure prophylaxis for varicella and measles has been demonstrated with
Varicella Vaccine live (Oka/Merck) and the measles-containing vaccines manufactured by Merck &
Co., Inc., respectively.
At least 1
month should elapse between receipt of a live virus vaccine and ProQuad.
Vaccine recipients should avoid use of salicylates for 6 weeks after vaccination with ProQuad (see
section
4.4).
Do not give immunoglobulin (IG) or Varicella Zoster Immune Globulin (VZIG) concomitantly with
ProQuad.
Administration of immune globulins 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 immune globulins (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).
Administration of varicella zoster virus antibody-containing blood products, including VZIG or other
immune globulin preparations, within 1 month following a dose of ProQuad may reduce the immune
response to the vaccine and hence reduce its protective efficacy. Therefore, administration of any of
these products should be avoided within 1 month after a dose of ProQuad unless considered to be
essential.
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 immunization with ProQuad.
Concomitant use with other vaccines:
Clinical studies have demonstrated that ProQuad can be given simultaneously (but at separate
injection sites) with any of the following vaccines: Prevenar and/or hepatitis A vaccine. In these
clinical studies, it was demonstrated that the immune responses were unaffected. The safety profiles
of the administered vaccines were similar (see section 4.8).
There are insufficient data to support the use of ProQuad with any other vaccines.
Studies have not been conducted with ProQuad in pregnant women. It is not known whether ProQuad
can cause foetal harm when administered to a pregnant woman or affect reproduction capacity.
Therefore, ProQuad should not be administered to pregnant females; furthermore, pregnancy should
be avoided for 3
months following vaccination (see sections
4.1, 4.3 and 4.4).
In order to advise women who are inadvertently vaccinated when pregnant or who become pregnant
within 3
months after vaccination, the physician should be aware of the following: (1) Reports have
indicated that contracting of wild-type measles during pregnancy enhances foetal risk. Increased rates
of spontaneous abortion, stillbirth, congenital defects and prematurity have been observed subsequent
5
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 is known to cause foetal harm, and is associated with an increased risk of
herpes zoster in the first year of life and severe varicella in the newborn infant.
Note: official recommendations may vary regarding the duration of the waiting period that is
recommended for avoiding pregnancy following vaccination.
Studies have shown that breast-feeding postpartum women vaccinated with live attenuated rubella
vaccine may secrete the virus in breast milk and transmit it to breast-fed infants. In the infants with
serological evidence of rubella infection, none had symptomatic disease. There is no evidence that
varicella vaccine virus is excreted in breast milk. It is not known whether measles or mumps vaccine
virus is secreted in human milk. Therefore, caution should be exercised when considering whether to
administer ProQuad to a breast-feeding woman.
No studies on the affects on the ability to drive or use machinery have been performed.
In 5 clinical trials, ProQuad was administered without concomitant vaccines to 6038
children 12
through 23
months of age. The children in these studies received either the current refrigerator-stable
formulation or an earlier formulation of ProQuad. Children in these studies were monitored for six
weeks post vaccination. The safety profiles were comparable for the two different formulations after a
single dose. The only vaccine-related systemic adverse reactions reported at a significantly greater
rate in individuals who received the earlier formulation of ProQuad compared to individuals who
received the measles, mumps, and rubella vaccine manufactured by Merck & Co., Inc. and Varicella
Vaccine live (Oka/Merck)
were fever (≥38.9°C oral equivalent or abnormal) and measles-like rash.
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.
The only vaccine related injection-site adverse reaction that was more frequent among recipients of
ProQuad than among recipients of Varicella Vaccine live (Oka/Merck) and the measles, mumps, and
rubella vaccine manufactured by Merck & Co. Inc. was rash at the injection site.
Following concomitant administration of ProQuad with Prevenar and/or hepatitis A vaccine, although
the percentage of reported fever was slightly higher (concomitant administration group 20.2% vs.
ProQuad only group 13.5%), the overall safety profile of the administered vaccines was similar.
Children who received a second dose of ProQuad
The rates of adverse reactions after a 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 (see section
5.1 for study description).
6
Children who received ProQuad at 4 through 6 years of age after primary immunization with
Varicella Vaccine live (Oka/Merck) and the measles, mumps, and rubella vaccine manufactured by
Merck & Co., Inc.
The rates and types of adverse reactions seen in the study group that received ProQuad were generally
similar to those seen in the groups that received Varicella Vaccine live (Oka/Merck) and the measles,
mumps, and rubella vaccine manufactured by Merck & Co., Inc. (see section
5.1 for study
description).
No specific studies have been conducted in individuals from 2
years of age who had not previously
received measles, mumps, rubella, and varicella vaccines.
The following adverse reactions were reported as vaccine related by the investigator in individuals
after a single dose of ProQuad. Several adverse events were solicited in the clinical studies and are
designated with the symbol (
‡
). Additionally, other adverse experiences have been reported with post-
marketing use of ProQuad and/or in clinical studies and post-marketing use of either the measles,
mumps, and rubella vaccine manufactured by Merck & Co., Inc., the monovalent component vaccines
of the measles, mumps, and rubella vaccine manufactured by Merck & Co., Inc., or
Varicella Vaccine
live (Oka/Merck). These adverse effects are listed below without regard to causality or frequency
(frequency
not known
).
[Very common (≥1/10); Common (≥1/100, <1/10); Uncommon (≥1/1,000, <1/100); Rare (≥1/10,000,
<1/1,000), including isolated reports; not known (cannot be estimated from the available data)]
Infections and infestations
Common:
upper respiratory infection.
Uncommon:
ear infection, gastroenteritis, nasopharyngitis, otitis media, pharyngitis, roseola, viral
infection, viral rash.
Rare:
bronchiolitis, candida nappy rash, candidiasis, cellulitis, infectious croup, viral gastroenteritis,
hand-foot-mouth disease, influenza, pseudocroup, respiratory infection, skin infection, tonsillitis,
varicella
‡
, viral conjunctivitis.
Not known
: aseptic meningitis (see below), atypical measles, epididymitis, herpes zoster, infection,
influenza, measles, orchitis, parotitis.
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.
Blood and the lymphatic system disorders
Rare:
leukocytosis, lymphadenopathy.
Not known
: lymphadenitis, regional lymphadenopathy, thrombocytopenia.
Immune system disorders
Rare:
hypersensitivity.
Not known
: anaphylactoid reaction, anaphylaxis and related phenomenon such as angioneurotic
oedema, facial oedema, and peripheral oedema, anaphylaxis in individuals with or without an allergic
history.
Metabolism and nutrition disorders
Uncommon:
anorexia, decreased appetite.
Rare:
dehydration.
Psychiatric disorders
Common:
irritability.
Uncommon:
crying, insomnia, sleep disorder.
Rare:
agitation, apathy, clinging, emotional changes, nervousness, restlessness.
7
Nervous system disorders
Uncommon:
febrile seizure, somnolence.
Rare:
ataxia, convulsion, headache, high pitched crying, hyperkinesia, hypersomnia, lethargy, tremor.
Not known
: afebrile convulsions or seizures, Bell’s palsy, cerebrovascular accident, dizziness, dream
abnormality, encephalitis (see below), encephalopathy (see below), Guillain-Barré syndrome, measles
inclusion body encephalitis (see section
4.3), ocular palsies, paraesthesia, polyneuritis,
polyneuropathy, subacute sclerosing panencephalitis (see below), syncope, transverse myelitis,
tremor.
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 the measles, mumps, and rubella vaccine manufactured by
Merck & Co., Inc., and the Varicella Vaccine live (Oka/Merck) 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 the measles, mumps, and rubella vaccine manufactured by
Merck & Co., Inc., and the Varicella Vaccine live (Oka/Merck) concomitantly (n=40; 1.3 per 1000
children).
Encephalitis and encephalopathy (excluding subacute sclerosing panencephalitis [SSPE]) have been
reported approximately once for every 3
million doses of the measles-containing vaccines
manufactured by Merck & Co., Inc. Post-marketing surveillance of the more than 428 million doses
that have been distributed worldwide (1978 to 2005) 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.
There is no evidence that measles vaccine can cause SSPE. There have been reports of 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 unrecognized measles in the first year of life or
possibly from the measles vaccination. The results of a retrospective case-controlled study conducted
by the US Centers for Disease Control and Prevention show that the overall effect of measles vaccine
has been to protect against SSPE by preventing measles with its inherent risk of SSPE.
Eye disorders
Rare:
conjunctivitis, eye discharge, eyelid inflammation, eye irritation, eye swelling, ocular
hyperaemia, tearing, visual discomfort.
Not known
: oedema of the eyelid, irritation, optic neuritis, retinitis, retrobulbar neuritis.
Ear and labyrinth disorders
Rare:
ear pain.
Not known
: nerve deafness.
Vascular disorders
Rare:
flushing, pallor.
Not known
: extravasation.
Respiratory, thoracic, and mediastinal disorders
Uncommon:
cough, nasal congestion, respiratory congestion, rhinorrhoea.
Rare:
asthma, pulmonary congestion, sinus disorder, sneezing, wheezing.
Not known
: bronchial spasm, bronchitis, epistaxis, pneumonitis (see section
4.3), pneumonia,
pulmonary congestion, rhinitis, sinusitis, sore throat.
8
Gastrointestinal disorders
Common:
diarrhoea, vomiting.
Rare:
abdominal pain upper, abnormal faeces, constipation, flatulence, nausea, salivation increase,
stomatitis, teething.
Not known
: abdominal pain, haematochezia, mouth ulcer.
Skin and subcutaneous tissue disorders
Common:
measles-like rash
‡
, rash, varicella-like rash
‡
,.
Uncommon:
dermatitis (including contact, atopic, and diaper rash), heat rash, rubella-like rash
‡
,
urticaria, viral exanthema, eczema, erythema.
Rare:
acne, clammy skin, exfoliative dermatitis, drug eruption, exanthema, livedo reticularis, papular
rash, pruritus, skin discoloration, skin lesion, zosteriform rash.
Not known
: erythema multiforme, Henoch-Schönlein purpura, herpes simplex, impetigo, panniculitis,
purpura, skin induration, Stevens-Johnson syndrome, sunburn.
Musculoskeletal, connective tissue and bone disorders
Rare:
arm pain, musculoskeletal stiffness.
Not known
: arthritis and/or arthralgia (usually transient and rarely chronic [see below]),
musculoskeletal pain, myalgia, pain of the hip, leg, or neck, swelling.
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.
General disorders and administration site conditions
Very common:
fever
≥
38.9
°
C (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, injection-site haemorrhage, injection-site induration or warmth,
injection-site mass, malaise.
Rare:
influenza-like illness, injection-site desquamation, injection-site discoloration, injection-site
pruritus, injection-site rash non-specific, injection-site reaction, injection-site scar, hyperthermia,
pain, pain/tenderness/soreness.
Not known
: injection site complaints (burning and/or stinging of short duration, eczema,
oedema/swelling, hive-like rash, hematoma, 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.
Investigations
Rare:
weight loss.
Injury and poisoning, and procedural complications
Rare:
contusion, non-venomous bite/sting.
Social circumstances
Rare:
activities of daily living impaired.
9
Cases of herpes zoster in clinical studies
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 one dose of ProQuad and followed for 1
year. Both cases
were unremarkable and no sequelae were reported.
Surveillance data on varicella vaccinated individuals for up to nine years suggest no increase in the
frequency of herpes zoster in this population. However, the long term effect of varicella vaccination
on the incidence of herpes zoster is unknown at present. There are no long term data currently
available for ProQuad.
Transmission
The varicella vaccine virus may rarely be transmitted to contacts of recipients of Varicella Vaccine
live (Oka/Merck) who develop a varicella-like rash (see section
4.4). In particular, this kind of
transmission has been documented 3
times out of more than 40
million doses of Varicella Vaccine
live (Oka/Merck) that have been distributed. Transmission of varicella vaccine virus from recipients
of Varicella Vaccine live (Oka/Merck) without a varicella-like rash has been reported but has not
been confirmed.
No case of overdose has been reported.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Viral Vaccine; ATC code: J07BD54.
Efficacy
Formal studies to evaluate the efficacy of ProQuad have not been performed. However, the efficacy
of Varicella Vaccine live (Oka/Merck) and the measles, mumps, and rubella vaccine manufactured by
Merck & Co., Inc. 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 manufactured by Merck &
Co., Inc., 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 the measles, mumps, and rubella vaccine manufactured by
Merck & Co., Inc.
More than 518 million doses of the measles, mumps, and rubella vaccine manufactured by Merck &
Co., Inc. have been distributed worldwide (1978 to 2007). 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.
In combined clinical trials of a single dose of Varicella Vaccine live (Oka/Merck) in healthy children,
the protective efficacy of the vaccine against all severities of varicella disease 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.
In a study comparing 1
dose (N=1114) to 2
doses (N=1102) of
Varicella Vaccine live (Oka/Merck),
the estimated vaccine efficacy against all severities of varicella disease for the 10-year observation
period was 94% for 1
dose and 98% for 2
doses (p<0.001). Over the 10-year observation period, the
10
cumulative rate of varicella was 7.5% after 1
dose and 2.2% after 2
doses. Most cases of varicella
reported in recipients of 1
dose or 2
doses of vaccine were mild.
Antibody responses against varicella virus ≥5
gpELISA 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
immunization with ProQuad elicits rates of antibody responses against varicella virus ≥5
gpELISA
Units/ml similar to those observed after vaccination with
Varicella Vaccine live (Oka/Merck).
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
randomized clinical trials.The
immunogenicity of the current refrigerator-stable formulation was shown to be similar to the
immunogenicity of the earlier formulation of ProQuad six weeks after a single dose of the vaccine.
The immunogenicity of a single dose of an earlier formulation of ProQuad was comparable to the
immunogenicity of a single dose of its individual component vaccines (Varicella Vaccine live
(Oka/Merck) and the measles, mumps, and rubella vaccine manufactured by Merck & Co., Inc.),
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. While the seroconversion rate for varicella was
uniformly high (97.9% to 99.8% across all studies), seroconversion has not been shown to correlate
well with protection. The vaccine response rate was 90.9% (range 80.8% to 94.5%) for varicella
based on a post-vaccination antibody titer ≥5
gpELISA units/ml (an antibody titer 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 a single dose of Varicella Vaccine live
(Oka/Merck) and the measles, mumps, and rubella vaccine manufactured by Merck & Co., Inc. 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 titers
(GMTs) following the second dose of ProQuad increased approximately 2
fold each for measles,
mumps, and rubella, and approximately 41
fold for varicella (for safety information, see section
4.8).
Children who received ProQuad at 4 through 6 years of age after primary vaccination with Varicella
Vaccine live (Oka/Merck) and the measles, mumps, and rubella vaccine manufactured by Merck &
Co., Inc.
The immunogenicity and safety of ProQuad were evaluated in a clinical trial involving 799
subjects 4
through 6
years of age who had received Varicella Vaccine live (Oka/Merck) and the measles,
mumps, and rubella vaccine manufactured by Merck & Co., Inc. 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 Varicella Vaccine live (Oka/Merck) and the measles, mumps, and
rubella vaccine manufactured by Merck & Co., Inc. administered concomitantly at separate injection
sites. Additionally, GMTs for measles, mumps, and rubella were similar to those following a second
dose of the measles, mumps, and rubella vaccine manufactured by Merck & Co., Inc. given
concomitantly with placebo (for safety information, see section
4.8).
11
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 the measles, mumps, and rubella vaccine manufactured by Merck & Co., Inc.
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
Varicella Vaccine live (Oka/Merck), detectable varicella antibodies were
present in most individuals tested for up to 10
years postvaccination.
5.2 Pharmacokinetic properties
Evaluation of pharmacokinetic properties is not required for vaccines.
5.3 Preclinical safety data
Traditional non-clinical studies were not performed, but there are no non-clinical concerns considered
relevant to clinical safety beyond data included in other sections of the SPC.
6.
6.1 List of excipients
Powder
Sucrose
Hydrolysed gelatin
Sodium chloride
Sorbitol
Monosodium glutamate
Sodium phosphate
Sodium bicarbonate
Potassium phosphate
Potassium chloride
Medium
199 with Hanks’ Salts
Minimum Essential Medium, Eagle (MEM)
Neomycin
Phenol red
Hydrochloric acid (to adjust pH)
Sodium hydroxide (to adjust pH)
Urea
Solvent
Water for injections.
6.2 Incompatibilities
In the absence of compatibility studies, the vaccine must not be mixed with other medicinal products.
6.3 Shelf life
18
months.
12
After reconstitution, the vaccine should be used immediately. However, the in-use stability has been
demonstrated for 30
minutes between 20
°
C and 25
°
C.
6.4 Special precautions for storage
Store and transport refrigerated (2°C-8°C). Store in the original package in order to protect from light.
For storage conditions of the reconstituted medicinal product, see section
6.3.
6.5 Nature and contents of container
Powder in a vial (Type
1 glass) with a stopper (butyl rubber) and solvent in a vial (Type
1 glass) with
stopper (chlorobutyl rubber) in a pack size of 1 and 10.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
To reconstitute the vaccine, use only the solvent supplied, because it is free of preservatives or other
antiviral substances, which might inactivate the vaccine. ProQuad, when reconstituted, is clear pale
yellow to light pink liquid.
It is important to use a separate sterile syringe and needle for each individual to prevent transmission
of infectious agents from one individual to another.
ProQuad must not be mixed in a syringe with other vaccines.
Reconstitution instructions
Withdraw the entire volume of solvent into a syringe. 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 MINIMIZE LOSS OF POTENCY. DISCARD IF
RECONSTITUTED VACCINE IS NOT USED WITHIN 30 MINUTES.
The reconstituted vaccine must not be used if any particulate matter is noted or if the appearance of
the vaccine differs from that described above.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
SANOFI PASTEUR MSD SNC
8 rue Jonas Salk
F-69007 Lyon
France
8.
EU/1/05/323/001
EU/1/05/323/002
13
9.
06/04/2006
14
1.
ProQuad powder and solvent for suspension for injection in a pre-filled syringe.
Measles, mumps, rubella and varicella vaccine (live).
2.
After reconstitution, one dose (0.5 ml) contains:
Measles virus
1
Enders’ Edmonston strain (live, attenuated)..................not less than 3.00 log
10
CCID
50
*
Mumps virus
1
Jeryl Lynn™ (Level B) strain (live, attenuated).............not less than 4.30 log
10
CCID
50
*
Rubella virus
2
Wistar RA 27/3 strain (live, attenuated).........................not less than 3.00 log
10
CCID
50
*
Varicella virus
3
Oka/Merck strain (live, attenuated) .............................not less than 3.99 log
10
PFU**
*50% cell culture infectious dose
**plaque-forming units
(
1
) Produced in chick embryo cells.
(
2
) Produced in human diploid lung (WI-38) fibroblasts.
(
3
) Produced in human diploid (MRC-5) cells.
For a full list of excipients, see section 6.1.
3.
Powder and solvent for suspension for injection in a pre-filled syringe.
Before reconstitution, the powder is a white to pale yellow compact crystalline cake and the solvent is
a clear colourless liquid.
4.
ProQuad is indicated for simultaneous vaccination against measles, mumps, rubella, and varicella in
individuals from 12 months of age.
Posology
Individuals from 12 months of age should receive two doses of ProQuad or a single dose of ProQuad
followed by a second dose of a monovalent varicella vaccine to ensure optimal protection against
varicella (see section 5.1). At least one month must elapse between the first and second dose of any
live viral attenuated vaccine. It is preferred that the second dose be administered within three months
following the first dose.
Note: applicable official recommendations may vary regarding the interval between doses and the
need for two or one doses of measles, mumps and rubella and of varicella-containing vaccine.
ProQuad may be used as the second dose in individuals from 12 months of age who have previously
received measles, mumps, and rubella vaccine and varicella vaccine.
15
Method of administration
The vaccine is to be injected by the subcutaneous route in the deltoid region of the upper arm or in the
higher anterolateral area of the thigh.
See section 6.6 for preparation instructions.
DO NOT INJECT INTRAVASCULARLY.
History of hypersensitivity to any varicella vaccine or measles, mumps, or rubella vaccine, to any of
the excipients, or to neomycin, which may be present as trace residues (see sections
2, 4.4 and 6.1).
Blood dyscrasias, leukaemia, lymphomas of any type, or other malignant neoplasms affecting the
haematopoietic and lymphatic system.
Current immunosuppressive therapy (including high doses of corticosteroids). ProQuad is not
contraindicated in individuals who are receiving topical or low-dose parenteral corticosteroids (e.g.
for asthma prophylaxis or replacement therapy).
Humoral or cellular (primary or acquired) immunodeficiency, including hypogammaglobulinemia and
dysgammaglobulinemia and AIDS, or symptomatic HIV infection or a CDC Class 2 or higher or an
age-specific CD4+ T-lymphocyte percentage <25% (see section
4.4). In severely
immunocompromised individuals inadvertently vaccinated with measles-containing vaccine, measles
inclusion body encephalitis, pneumonitis, and fatal outcome as a direct consequence of disseminated
measles vaccine virus infection have been reported.
Family history of congenital or hereditary immunodeficiency, unless the immune competence of the
potential vaccine recipient is demonstrated.
Active untreated tuberculosis (see section 4.4).
Vaccination should be postponed during any illness with fever >38.5
°
C.
Pregnancy (see also sections 4.4 and 4.6).
Appropriate medical treatment and supervision should always be readily available in case of a rare
anaphylactic reaction following the administration of the vaccine.
Additionally, 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. The potential risk-
to-benefit ratio should be carefully evaluated before considering vaccination in such cases.
Due caution should be employed in the administration of ProQuad to persons with individual or
family history of convulsions, or a history of cerebral injury. The physician should be alert to the
temperature elevation that may occur following vaccination (see section
4.8).
This vaccine contains 16 mg of sorbitol as an excipient. Patients with rare hereditary problems of
fructose intolerance should not take this vaccine.
16
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.
As for any vaccine, vaccination with ProQuad may not result in protection in all vaccine recipients.
Pregnancy
See sections 4.3 and 4.6.
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 without any evidence of clinical disease
(see section 4.6).
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 Varicella Vaccine live (Oka/Merck) suggests that transmission of
varicella vaccine virus may rarely occur between healthy vaccine recipients who develop a varicella-
like rash and contacts susceptible to varicella, as well as high-risk individuals susceptible to varicella
(see section 4.8).
High-risk individuals susceptible to varicella include:
•
immunocompromised individuals (see section 4.3),
•
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.
Thrombocytopenia
No clinical data are available regarding the development or worsening of thrombocytopenia in
individuals vaccinated with ProQuad. However, post-marketing experience with live measles, mumps,
and rubella vaccine indicates that individuals with current thrombocytopenia may develop more
severe thrombocytopenia following vaccination. In addition, individuals who experienced
thrombocytopenia following the first dose of a live measles, mumps, and rubella vaccine may develop
thrombocytopenia 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
section 4.8).
Other
No clinical data are available for ProQuad in individuals who are known to be infected with human
immunodeficiency viruses without evidence of immunosuppression. Careful risk-to-benefit evaluation
should be done for these subjects (see section 4.3).
17
Children under treatment for tuberculosis have not experienced exacerbation of the disease when
immunized with live measles virus vaccine. No studies have been reported to date on the effect of
measles virus vaccines on children with untreated tuberculosis (see section 4.3).
Post-exposure prophylaxis
No clinical data are available for ProQuad administered after exposure to measles, mumps, rubella, or
varicella. However, post-exposure prophylaxis for varicella and measles has been demonstrated with
Varicella Vaccine live (Oka/Merck) and the measles-containing vaccines manufactured by Merck &
Co., Inc., respectively.
At least 1 month should elapse between receipt of a live virus vaccine and ProQuad.
Vaccine recipients should avoid use of salicylates for 6 weeks after vaccination with ProQuad (see
section 4.4).
Do not give immunoglobulin (IG) or Varicella Zoster Immune Globulin (VZIG) concomitantly with
ProQuad.
Administration of immune globulins 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 immune globulins (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).
Administration of varicella zoster virus antibody-containing blood products, including VZIG or other
immune globulin preparations, within 1 month following a dose of ProQuad may reduce the immune
response to the vaccine and hence reduce its protective efficacy. Therefore, administration of any of
these products should be avoided within 1 month after a dose of ProQuad unless considered to be
essential.
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 immunization with ProQuad.
Concomitant use with other vaccines:
Clinical studies have demonstrated that ProQuad can be given simultaneously (but at separate
injection sites) with any of the following vaccines: Prevenar and/or hepatitis A vaccine. In these
clinical studies, it was demonstrated that the immune responses were unaffected. The safety profiles
of the administered vaccines were similar (see section 4.8).
There are insufficient data to support the use of ProQuad with any other vaccines.
Studies have not been conducted with ProQuad in pregnant women. It is not known whether ProQuad
can cause foetal harm when administered to a pregnant woman or affect reproduction capacity.
Therefore, ProQuad should not be administered to pregnant females; furthermore, pregnancy should
be avoided for 3 months following vaccination (see sections 4.1, 4.3 and 4.4).
In order to advise women who are inadvertently vaccinated when pregnant or who become pregnant
within 3 months after vaccination, the physician should be aware of the following: (1) Reports have
indicated that contracting of wild-type measles during pregnancy enhances foetal risk. Increased rates
of spontaneous abortion, stillbirth, congenital defects and prematurity have been observed subsequent
18
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 is known to cause foetal harm, and is associated with an increased risk of
herpes zoster in the first year of life and severe varicella in the newborn infant.
Note: official recommendations may vary regarding the duration of the waiting period that is
recommended for avoiding pregnancy following vaccination.
Studies have shown that breast-feeding postpartum women vaccinated with live attenuated rubella
vaccine may secrete the virus in breast milk and transmit it to breast-fed infants. In the infants with
serological evidence of rubella infection, none had symptomatic disease. There is no evidence that
varicella vaccine virus is excreted in breast milk. It is not known whether measles or mumps vaccine
virus is secreted in human milk. Therefore, caution should be exercised when considering whether to
administer ProQuad to a breast-feeding woman.
No studies on the affects on the ability to drive or use machinery have been performed.
In 5 clinical trials, ProQuad was administered without concomitant vaccines to 6038 children 12
through 23 months of age. The children in these studies received either the current refrigerator-stable
formulation or an earlier formulation of ProQuad. Children in these studies were monitored for six
weeks post vaccination. The safety profiles were comparable for the two different formulations after a
single dose. The only vaccine-related systemic adverse reactions reported at a significantly greater
rate in individuals who received the earlier formulation of ProQuad compared to individuals who
received the measles, mumps, and rubella vaccine manufactured by Merck & Co., Inc. and Varicella
Vaccine live (Oka/Merck) were fever (≥38.9°C oral equivalent or abnormal) and measles-like rash.
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.
The only vaccine related injection-site adverse reaction that was more frequent among recipients of
ProQuad than among recipients of Varicella Vaccine live (Oka/Merck) and the measles, mumps, and
rubella vaccine manufactured by Merck & Co. Inc. was rash at the injection site.
Following concomitant administration of ProQuad with Prevenar and/or hepatitis A vaccine, although
the percentage of reported fever was slightly higher (concomitant administration group 20.2% vs.
ProQuad only group 13.5%), the overall safety profile of the administered vaccines was similar.
Children who received a second dose of ProQuad
The rates of adverse reactions after a 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 (see section 5.1 for study description).
19
Children who received ProQuad at 4 through 6 years of age after primary immunization with Varicella
Vaccine live (Oka/Merck) and the measles, mumps, and rubella vaccine manufactured by Merck &
Co., Inc.
The rates and types of adverse reactions seen in the study group that received ProQuad were generally
similar to those seen in the groups that received Varicella Vaccine live (Oka/Merck) and the measles,
mumps, and rubella vaccine manufactured by Merck & Co., Inc. (see section 5.1 for study
description).
No specific studies have been conducted in individuals from 2 years of age who had not previously
received measles, mumps, rubella, and varicella vaccines.
The following adverse reactions were reported as vaccine related by the investigator in individuals
after a single dose of ProQuad. Several adverse events were solicited in the clinical studies and are
designated with the symbol (
‡
). Additionally, other adverse experiences have been reported with post-
marketing use of ProQuad and/or in clinical studies and post-marketing use of either the measles,
mumps, and rubella vaccine manufactured by Merck & Co., Inc., the monovalent component vaccines
of the measles, mumps, and rubella vaccine manufactured by Merck & Co., Inc., or Varicella Vaccine
live (Oka/Merck). These adverse effects are listed below without regard to causality or frequency
(frequency
not known
).
[Very common (≥1/10); Common (≥1/100, <1/10); Uncommon (≥1/1,000, <1/100); Rare (≥1/10,000,
<1/1,000), including isolated reports; not known (cannot be estimated from the available data)]
Infections and infestations
Common:
upper respiratory infection.
Uncommon:
ear infection, gastroenteritis, nasopharyngitis, otitis media, pharyngitis, roseola, viral
infection, viral rash.
Rare:
bronchiolitis, candida nappy rash, candidiasis, cellulitis, infectious croup, viral gastroenteritis,
hand-foot-mouth disease, influenza, pseudocroup, respiratory infection, skin infection, tonsillitis,
varicella
‡
, viral conjunctivitis.
Not known
: aseptic meningitis (see below), atypical measles, epididymitis, herpes zoster, infection,
influenza, measles, orchitis, parotitis.
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.
Blood and the lymphatic system disorders
Rare:
leukocytosis, lymphadenopathy.
Not known
: lymphadenitis, regional lymphadenopathy, thrombocytopenia.
Immune system disorders
Rare:
hypersensitivity.
Not known
: anaphylactoid reaction, anaphylaxis and related phenomenon such as angioneurotic
oedema, facial oedema, and peripheral oedema, anaphylaxis in individuals with or without an allergic
history.
Metabolism and nutrition disorders
Uncommon:
anorexia, decreased appetite.
Rare:
dehydration.
Psychiatric disorders
Common:
irritability.
Uncommon:
crying, insomnia, sleep disorder.
Rare:
agitation, apathy, clinging, emotional changes, nervousness, restlessness.
20
Nervous system disorders
Uncommon:
febrile seizure, somnolence.
Rare:
ataxia, convulsion, headache, high pitched crying, hyperkinesia, hypersomnia, lethargy, tremor.
Not known
: afebrile convulsions or seizures, Bell’s palsy, cerebrovascular accident, dizziness, dream
abnormality, encephalitis (see below), encephalopathy (see below), Guillain-Barré syndrome, measles
inclusion body encephalitis (see section
4.3), ocular palsies, paraesthesia, polyneuritis,
polyneuropathy, subacute sclerosing panencephalitis (see below), syncope, transverse myelitis,
tremor.
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 the measles, mumps, and rubella vaccine manufactured by
Merck & Co., Inc., and the Varicella Vaccine live (Oka/Merck) 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 the measles, mumps, and rubella vaccine manufactured by
Merck & Co., Inc., and the Varicella Vaccine live (Oka/Merck) concomitantly (n=40; 1.3 per 1000
children).
Encephalitis and encephalopathy (excluding subacute sclerosing panencephalitis [SSPE]) have been
reported approximately once for every 3
million doses of the measles-containing vaccines
manufactured by Merck & Co., Inc. Post-marketing surveillance of the more than 428 million doses
that have been distributed worldwide (1978 to 2005) 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.
There is no evidence that measles vaccine can cause SSPE. There have been reports of 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 unrecognized measles in the first year of life or
possibly from the measles vaccination. The results of a retrospective case-controlled study conducted
by the US Centers for Disease Control and Prevention show that the overall effect of measles vaccine
has been to protect against SSPE by preventing measles with its inherent risk of SSPE.
Eye disorders
Rare:
conjunctivitis, eye discharge, eyelid inflammation, eye irritation, eye swelling, ocular
hyperaemia, tearing, visual discomfort.
Not known
: oedema of the eyelid, irritation, optic neuritis, retinitis, retrobulbar neuritis.
Ear and labyrinth disorders
Rare:
ear pain.
Not known
: nerve deafness.
Vascular disorders
Rare:
flushing, pallor.
Not known
: extravasation.
Respiratory, thoracic, and mediastinal disorders
Uncommon:
cough, nasal congestion, respiratory congestion, rhinorrhoea.
Rare:
asthma, pulmonary congestion, sinus disorder, sneezing, wheezing.
Not known
: bronchial spasm, bronchitis, epistaxis, pneumonitis (see section
4.3), pneumonia,
pulmonary congestion, rhinitis, sinusitis, sore throat.
21
Gastrointestinal disorders
Common:
diarrhoea, vomiting.
Rare:
abdominal pain upper, abnormal faeces, constipation, flatulence, nausea, salivation increase,
stomatitis, teething.
Not known
: abdominal pain, haematochezia, mouth ulcer.
Skin and subcutaneous tissue disorders
Common:
measles-like rash
‡
, rash, varicella-like rash
‡
,.
Uncommon:
dermatitis (including contact, atopic, and diaper rash), heat rash, rubella-like rash
‡
,
urticaria, viral exanthema, eczema, erythema.
Rare:
acne, clammy skin, exfoliative dermatitis, drug eruption, exanthema, livedo reticularis, papular
rash, pruritus, skin discoloration, skin lesion, zosteriform rash.
Not known
: erythema multiforme, Henoch-Schönlein purpura, herpes simplex, impetigo, panniculitis,
purpura, skin induration, Stevens-Johnson syndrome, sunburn.
Musculoskeletal, connective tissue and bone disorders
Rare:
arm pain, musculoskeletal stiffness.
Not known
: arthritis and/or arthralgia (usually transient and rarely chronic [see below]),
musculoskeletal pain, myalgia, pain of the hip, leg, or neck, swelling.
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.
General disorders and administration site conditions
Very common:
fever
≥
38.9
°
C (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, injection-site haemorrhage, injection-site induration or warmth,
injection-site mass, malaise.
Rare:
influenza-like illness, injection-site desquamation, injection-site discoloration, injection-site
pruritus, injection-site rash non-specific, injection-site reaction, injection-site scar, hyperthermia,
pain, pain/tenderness/soreness.
Not known
: injection site complaints (burning and/or stinging of short duration, eczema,
oedema/swelling, hive-like rash, hematoma, 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.
Investigations
Rare:
weight loss.
Injury and poisoning, and procedural complications
Rare:
contusion, non-venomous bite/sting.
Social circumstances
Rare:
activities of daily living impaired.
22
Cases of herpes zoster in clinical studies
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 one dose of ProQuad and followed for 1 year. Both cases
were unremarkable and no sequelae were reported.
Surveillance data on varicella vaccinated individuals for up to nine years suggest no increase in the
frequency of herpes zoster in this population. However, the long term effect of varicella vaccination
on the incidence of herpes zoster is unknown at present. There are no long term data currently
available for ProQuad.
Transmission
The varicella vaccine virus may rarely be transmitted to contacts of recipients of Varicella Vaccine
live (Oka/Merck) who develop a varicella-like rash (see section 4.4). In particular, this kind of
transmission has been documented 3 times out of more than 40 million doses of Varicella Vaccine
live (Oka/Merck) that have been distributed. Transmission of varicella vaccine virus from recipients
of Varicella Vaccine live (Oka/Merck) without a varicella-like rash has been reported but has not
been confirmed.
No case of overdose has been reported.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Viral Vaccine; ATC code: J07BD54.
Efficacy
Formal studies to evaluate the efficacy of ProQuad have not been performed. However, the efficacy
of Varicella Vaccine live (Oka/Merck) and the measles, mumps, and rubella vaccine manufactured by
Merck & Co., Inc. 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 manufactured by Merck &
Co., Inc., 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 the measles, mumps, and rubella vaccine manufactured by
Merck & Co., Inc.
More than 518 million doses of the measles, mumps, and rubella vaccine manufactured by Merck &
Co., Inc. have been distributed worldwide (1978 to 2007). 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.
In combined clinical trials of a single dose of Varicella Vaccine live (Oka/Merck) in healthy children,
the protective efficacy of the vaccine against all severities of varicella disease 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.
In a study comparing 1 dose (N=1114) to 2 doses (N=1102) of Varicella Vaccine live (Oka/Merck),
the estimated vaccine efficacy against all severities of varicella disease for the 10-year observation
period was 94% for 1 dose and 98% for 2 doses (p<0.001). Over the 10-year observation period, the
23
cumulative rate of varicella was 7.5% after 1 dose and 2.2% after 2 doses. Most cases of varicella
reported in recipients of 1 dose or 2 doses of vaccine were mild.
Antibody responses against varicella virus ≥5 gpELISA 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
immunization with ProQuad elicits rates of antibody responses against varicella virus ≥5 gpELISA
Units/ml similar to those observed after vaccination with
Varicella Vaccine live (Oka/Merck).
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
randomized clinical trials.The
immunogenicity of the current refrigerator-stable formulation was shown to be similar to the
immunogenicity of the earlier formulation of ProQuad six weeks after a single dose of the vaccine.
The immunogenicity of a single dose of an earlier formulation of ProQuad was comparable to the
immunogenicity of a single dose of its individual component vaccines (Varicella Vaccine live
(Oka/Merck) and the measles, mumps, and rubella vaccine manufactured by Merck & Co., Inc.),
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. While the seroconversion rate for varicella was
uniformly high (97.9% to 99.8% across all studies), seroconversion has not been shown to correlate
well with protection. The vaccine response rate was 90.9% (range 80.8% to 94.5%) for varicella
based on a postvaccination antibody titer ≥5 gpELISA units/ml (an antibody titer 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 a single dose of Varicella Vaccine live (Oka/Merck)
and the measles, mumps, and rubella vaccine manufactured by Merck & Co., Inc. 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 titers
(GMTs) following the second dose of ProQuad increased approximately 2 fold each for measles,
mumps, and rubella, and approximately 41 fold for varicella (for safety information, see section 4.8).
Children who received ProQuad at 4 through 6 years of age after primary vaccination with Varicella
Vaccine live (Oka/Merck) and the measles, mumps, and rubella vaccine manufactured by Merck &
Co., Inc.
The immunogenicity and safety of ProQuad were evaluated in a clinical trial involving 799 subjects 4
through 6 years of age who had received Varicella Vaccine live (Oka/Merck) and the measles,
mumps, and rubella vaccine manufactured by Merck & Co., Inc. 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 Varicella Vaccine live (Oka/Merck) and the measles, mumps, and
rubella vaccine manufactured by Merck & Co., Inc. administered concomitantly at separate injection
sites. Additionally, GMTs for measles, mumps, and rubella were similar to those following a second
dose of the measles, mumps, and rubella vaccine manufactured by Merck & Co., Inc. given
concomitantly with placebo (for safety information, see section 4.8).
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
24
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 the measles, mumps, and rubella vaccine manufactured by Merck & Co., Inc.
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 Varicella Vaccine live (Oka/Merck), detectable varicella antibodies were
present in most individuals tested for up to 10 years postvaccination.
5.2 Pharmacokinetic properties
Evaluation of pharmacokinetic properties is not required for vaccines.
5.3 Preclinical safety data
Traditional non-clinical studies were not performed, but there are no non-clinical concerns considered
relevant to clinical safety beyond data included in other sections of the SPC.
6.
6.1 List of excipients
Powder
Sucrose
Hydrolysed gelatin
Sodium chloride
Sorbitol
Monosodium glutamate
Sodium phosphate
Sodium bicarbonate
Potassium phosphate
Potassium chloride
Medium 199 with Hanks’ Salts
Minimum Essential Medium, Eagle (MEM)
Neomycin
Phenol red
Hydrochloric acid (to adjust pH)
Sodium hydroxide (to adjust pH)
Urea
Solvent
Water for injections.
6.2 Incompatibilities
In the absence of compatibility studies, the vaccine must not be mixed with other medicinal products.
6.3 Shelf life
18 months.
After reconstitution, the vaccine should be used immediately. However, the in-use stability has been
demonstrated for 30 minutes between 20
°
C and 25
°
C.
25
6.4 Special precautions for storage
Store and transport refrigerated (2°C-8°C). Store in the original package in order to protect from light.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature and contents of container
Powder in a vial (Type 1 glass) with a stopper (butyl rubber) and solvent in a pre-filled syringe (Type
1 glass) with attached needle with plunger stopper (chlorobutyl rubber) and needle shield (natural
rubber) in a pack size of 1 and 10.
Powder in a vial (Type 1 glass) with a stopper (butyl rubber) and solvent in a pre-filled syringe (Type
1 glass) with plunger stopper and tip cap (chlorobutyl rubber), without needle, in a pack size of 1, 10
and 20.
Powder in a vial (Type 1 glass) with a stopper (butyl rubber) and solvent in a pre-filled syringe (Type
1 glass) with plunger stopper and tip cap (chlorobutyl rubber), with one or two unattached needles, in
a pack size of 1, 10 and 20.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
To reconstitute the vaccine, use only the solvent supplied, because it is free of preservatives or other
antiviral substances, which might inactivate the vaccine. ProQuad, when reconstituted, is clear pale
yellow to light pink liquid.
It is important to use a separate sterile syringe and needle for each individual to prevent transmission
of infectious agents from one individual to another.
ProQuad must not be mixed in a syringe with other vaccines.
Reconstitution instructions
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 MINIMIZE LOSS OF POTENCY. DISCARD IF
RECONSTITUTED VACCINE IS NOT USED WITHIN 30 MINUTES.
The reconstituted vaccine must not be used if any particulate matter is noted or if the appearance of
the vaccine differs from that described above.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
SANOFI PASTEUR MSD SNC
8 rue Jonas Salk
F-69007 Lyon
France
26
8.
EU/1/05/323/003
EU/1/05/323/004
EU/1/05/323/005
EU/1/05/323/006
EU/1/05/323/007
EU/1/05/323/008
EU/1/05/323/009
EU/1/05/323/010
EU/1/05/323/011
EU/1/05/323/012
EU/1/05/323/013
9.
06/04/2006
27
ANNEX II
A
MANUFACTURER OF THE BIOLOGICAL ACTIVE
SUBSTANCE ANDMANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH RELEASE
B
CONDITIONS OF THE MARKETING AUTHORISATION
28
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer of the biological active substance
Merck Sharp & Dohme Corp.
Sumneytown Pike
West Point
Pennsylvania 19486
U.S.A.
Name and address of the manufacturer responsible for batch release
Merck Sharp & Dohme BV
Waarderweg 39, 2031 BN Haarlem
P.O. BOX 581, 2003 PC Haarlem
The Netherlands
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 2.0 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Official batch release: in accordance with Article 114 Directive 2001/83/EC as amended, the official
batch release will be undertaken by a state laboratory or a laboratory designated for that purpose.
29
ANNEX III
LABELLING AND PACKAGE LEAFLET
30
A. LABELLING
31
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
ProQuad - Powder in vial and solvent in vial - Pack of 1, 10
1.
ProQuad powder and solvent for suspension for injection
Measles, mumps, rubella and varicella vaccine (live)
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
After reconstitution, one dose (0.5 ml) contains (live, attenuated):
Measles virus Enders’ Edmonston strain .....................................≥ 3.00 log10 CCID
50
*
Mumps virus Jeryl Lynn™ (Level B) strain ................................≥ 4.30 log
10
CCID
50
*
Rubella virus Wistar RA 27/3 strain ............................................≥ 3.00 log
10
CCID
50
*
Varicella virus Oka/Merck strain .................................................≥ 3.99 log
10
PFU**
*50% cell culture infectious dose
**plaque-forming units
3.
LIST OF EXCIPIENTS
Sucrose, hydrolysed gelatin, urea, sodium chloride, sorbitol, monosodium glutamate, sodium
phosphate, sodium bicarbonate, potassium phosphate, potassium chloride, medium 199 with Hanks’
Salts, MEM, neomycin, phenol red, HCl, NaOH.
4.
Powder and solvent for suspension for injection.
Pack of 1 single dose vial (powder) + 1 vial (solvent)
.
Pack of 10 single dose vials (powder) + 10 vials (solvent)
.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Subcutaneous use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
32
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
STORE AND TRANSPORT REFRIGERATED. Keep the vial of powder in the outer carton to
protect from light.
After reconstitution, use immediately or within 30 minutes if stored between 20°C and 25°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Read the package leaflet for disposal of medicines no longer required.
SANOFI PASTEUR MSD SNC
8 rue Jonas Salk
F-69007 Lyon
France
EU/1/05/323/001 - pack of 1
EU/1/05/323/002 - pack of 10
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
33
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL OF POWDER
1.
ProQuad powder for suspension for injection
SC
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
1 dose
6.
OTHER
SANOFI PASTEUR MSD SNC
34
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL OF SOLVENT
1.
Solvent for ProQuad
Water for injections
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
6.
OTHER
35
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
ProQuad - Powder in vial and solvent in pre-filled syringe with attached needle - Pack of 1, 10
1.
ProQuad powder and solvent for suspension for injection in a pre-filled syringe
Measles, mumps, rubella and varicella vaccine (live)
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
After reconstitution, one dose (0.5 ml) contains (live, attenuated):
Measles virus Enders’ Edmonston strain .....................................≥ 3.00 log
10
CCID
50
*
Mumps virus Jeryl Lynn™ (Level B) strain ................................≥ 4.30 log
10
CCID
50
*
Rubella virus Wistar RA 27/3 strain ............................................≥ 3.00 log
10
CCID
50
*
Varicella virus Oka/Merck strain .................................................≥ 3.99 log
10
PFU**
*50% cell culture infectious dose
**plaque-forming units
3.
LIST OF EXCIPIENTS
Sucrose, hydrolysed gelatin, urea, sodium chloride, sorbitol, monosodium glutamate, sodium
phosphate, sodium bicarbonate, potassium phosphate, potassium chloride, medium 199 with Hanks’
Salts, MEM, neomycin, phenol red, HCl, NaOH.
4.
Powder and solvent for suspension for injection in a pre-filled syringe.
Pack of 1 single dose vial (powder) + 1 pre-filled syringe with attached needle (solvent)
.
Pack of 10 single dose vials (powder) + 10 pre-filled syringes with attached needle (solvent)
.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Subcutaneous use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
36
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
STORE AND TRANSPORT REFRIGERATED. Keep the vial of powder in the outer carton to
protect from light.
After reconstitution, use immediately or within 30 minutes if stored between 20°C and 25°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Read the package leaflet for disposal of medicines no longer required.
SANOFI PASTEUR MSD SNC
8 rue Jonas Salk
F-69007 Lyon
France
EU/1/05/323/003 – pack of 1
EU/1/05/323/004 – pack of 10
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
37
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
ProQuad - Powder in vial and solvent in pre-filled syringe without needle - Pack of 1, 10, 20
1.
ProQuad powder and solvent for suspension for injection in a pre-filled syringe
Measles, mumps, rubella and varicella vaccine (live)
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
After reconstitution, one dose (0.5 ml) contains (live, attenuated):
Measles virus Enders’ Edmonston strain .....................................≥ 3.00 log
10
CCID
50
*
Mumps virus Jeryl Lynn™ (Level B) strain ................................≥ 4.30 log
10
CCID
50
*
Rubella virus Wistar RA 27/3 strain ............................................≥ 3.00 log
10
CCID
50
*
Varicella virus Oka/Merck strain .................................................≥ 3.99 log
10
PFU**
*50% cell culture infectious dose
**plaque-forming units
3.
LIST OF EXCIPIENTS
Sucrose, hydrolysed gelatin, urea, sodium chloride, sorbitol, monosodium glutamate, sodium
phosphate, sodium bicarbonate, potassium phosphate, potassium chloride, medium 199 with Hanks’
Salts, MEM, neomycin, phenol red, HCl, NaOH.
4.
Powder and solvent for suspension for injection in a pre-filled syringe.
Pack of 1 single dose vial
(powder) + 1 pre-filled syringe without needle (solvent)
.
Pack of 10 single dose vials (powder) + 10 pre-filled syringes without needle (solvent)
.
Pack of 20 single dose vials (powder) + 20 pre-filled syringes without needle (solvent)
.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Subcutaneous use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
38
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
STORE AND TRANSPORT REFRIGERATED. Keep the vial of powder in the outer carton to
protect from light.
After reconstitution, use immediately or within 30 minutes if stored between 20°C and 25°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Read the package leaflet for disposal of medicines no longer required.
SANOFI PASTEUR MSD SNC
8 rue Jonas Salk
F-69007 Lyon
France
EU/1/05/323/005 – pack of 1
EU/1/05/323/006 – pack of 10
EU/1/05/323/007 – pack of 20
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
39
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
ProQuad - Powder in vial and solvent in pre-filled syringe with 1 unattached needle - Pack of 1,
10, 20
1.
ProQuad powder and solvent for suspension for injection in a pre-filled syringe
Measles, mumps, rubella and varicella vaccine (live)
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
After reconstitution, one dose (0.5 ml) contains (live, attenuated):
Measles virus Enders’ Edmonston strain .....................................≥ 3.00 log
10
CCID
50
*
Mumps virus Jeryl Lynn™ (Level B) strain ................................≥ 4.30 log
10
CCID
50
*
Rubella virus Wistar RA 27/3 strain ............................................≥ 3.00 log
10
CCID
50
*
Varicella virus Oka/Merck strain .................................................≥ 3.99 log
10
PFU**
*50% cell culture infectious dose
**plaque-forming units
3.
LIST OF EXCIPIENTS
Sucrose, hydrolysed gelatin, urea, sodium chloride, sorbitol, monosodium glutamate, sodium
phosphate, sodium bicarbonate, potassium phosphate, potassium chloride, medium 199 with Hanks’
Salts, MEM, neomycin, phenol red, HCl, NaOH.
4.
Powder and solvent for suspension for injection in a pre-filled syringe.
Pack of 1 single dose vial (powder) + 1 pre-filled syringe (solvent)+ 1 unattached needle.
Pack of 10 single dose vials (powder) + 10 pre-filled syringes (solvent)+ 10 unattached needles.
Pack of 20 single dose vials (powder) + 20 pre-filled syringes (solvent)+ 20 unattached needles.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Subcutaneous use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
40
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
STORE AND TRANSPORT REFRIGERATED. Keep the vial of powder in the outer carton to
protect from light.
After reconstitution, use immediately or within 30 minutes if stored between 20°C and 25°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Read the package leaflet for disposal of medicines no longer required.
SANOFI PASTEUR MSD SNC
8 rue Jonas Salk
F-69007 Lyon
France
EU/1/05/323/008 – pack of 1
EU/1/05/323/009 – pack of 10
EU/1/05/323/012 – pack of 20
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
41
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
ProQuad - Powder in vial and solvent in pre-filled syringe with 2 unattached needles - Pack of
1, 10, 20
1.
ProQuad powder and solvent for suspension for injection in a pre-filled syringe
Measles, mumps, rubella and varicella vaccine (live)
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
After reconstitution, one dose (0.5 ml) contains (live, attenuated) :
Measles virus Enders’ Edmonston strain .....................................≥ 3.00 log
10
CCID
50
*
Mumps virus Jeryl Lynn™ (Level B) strain ................................≥ 4.30 log
10
CCID
50
*
Rubella virus Wistar RA 27/3 strain ............................................≥ 3.00 log
10
CCID
50
*
Varicella virus Oka/Merck strain .................................................≥ 3.99 log
10
PFU**
*50% cell culture infectious dose
**plaque-forming units
3.
LIST OF EXCIPIENTS
Sucrose, hydrolysed gelatin, urea, sodium chloride, sorbitol, monosodium glutamate, sodium
phosphate, sodium bicarbonate, potassium phosphate, potassium chloride, medium 199 with Hanks’
Salts, MEM, neomycin, phenol red, HCl, NaOH.
4.
Powder and solvent for suspension for injection in a pre-filled syringe.
Pack of 1 single dose vial (powder) + 1 pre-filled syringe (solvent)+ 2 unattached needles.
Pack of 10 single dose vials (powder) + 10 pre-filled syringes (solvent)+ 20 unattached needles
.
Pack of 20 single dose vials (powder) + 20 pre-filled syringes (solvent)+ 40 unattached needles
.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Subcutaneous use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
42
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
STORE AND TRANSPORT REFRIGERATED. Keep the vial of powder in the outer carton to
protect from light.
After reconstitution, use immediately or within 30 minutes if stored between 20°C and 25°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Read the package leaflet for disposal of medicines no longer required.
SANOFI PASTEUR MSD SNC
8 rue Jonas Salk
F-69007 Lyon
France
EU/1/05/323/010 – pack of 1
EU/1/05/323/011 – pack of 10
EU/1/05/323/013 – pack of 20
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
43
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL OF POWDER
1.
ProQuad powder for suspension for injection
SC
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
1 dose
6.
OTHER
SANOFI PASTEUR MSD SNC
44
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
SYRINGE OF SOLVENT
1.
Solvent for ProQuad
Water for injections
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
6.
OTHER
45
B. PACKAGE LEAFLET
46
PACKAGE LEAFLET: INFORMATION FOR THE USER
ProQuad
Powder and solvent for suspension for injection
Measles, mumps, rubella and varicella vaccine (live)
Read all of this leaflet before your child is vaccinated.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or your pharmacist.
-
This vaccine has been prescribed for your child. Do not pass it on to others.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What ProQuad is and what it is used for
2.
Before you use ProQuad
3.
How to use ProQuad
4.
Possible side effects
5.
How to store ProQuad
6.
Further information
1.
WHAT ProQuad IS AND WHAT IT IS USED FOR
ProQuad is a vaccine containing measles, mumps, rubella, and varicella (chickenpox) viruses that
have been weakened. When a person is given the vaccine, the immune system (the body’s natural
defences) will make antibodies against the measles, mumps, rubella, and varicella viruses. The
antibodies help protect against diseases caused by these viruses.
ProQuad is given to help protect your child against measles, mumps, rubella, and varicella
(chickenpox). The vaccine may be administered to persons from 12 months of age.
Although ProQuad contains live viruses, they are too weak to cause measles, mumps, rubella, or
varicella (chickenpox) in healthy people.
2.
BEFORE YOU USE ProQuad
Do not use ProQuad
•
If your child is allergic (hypersensitive) to any of the components of ProQuad (including
neomycin or any of the ingredients listed under
“other ingredients”-see
section 6, Further
information
).
•
If your child has a blood disorder or any type of cancer that affects the immune system.
•
If your child is receiving treatment or taking medications that may weaken the immune system
(except low-dose corticosteroid therapy for asthma or replacement therapy).
•
If your child has a weakened immune system because of a disease (including AIDS).
•
If your child has a family history of congenital or hereditary immunodeficiency, unless the
immune competence of your child is demonstrated.
•
If your child has active untreated tuberculosis.
•
If your child has any illness with fever higher than 38.5°C; however, low-grade fever itself is
not a reason to delay vaccination.
•
If your child is pregnant (in addition, pregnancy should be avoided for 3 months after
vaccination, see
Pregnancy and breast-feeding
).
47
Take special care with ProQuad
If the person to be vaccinated has experienced any of the following, talk to the doctor or pharmacist
before ProQuad is given:
•
If your child has had an allergic reaction to eggs or anything that contained egg.
•
If your child has a history or family history of allergies or of convulsions (fits).
•
If your child has had a side effect after vaccination with measles, mumps, or rubella (in a single
vaccine or combined vaccine, such as the measles, mumps, and rubella vaccine manufactured
by Merck & Co., Inc. or ProQuad) that involved easy bruising or bleeding for longer than usual.
•
If your child has infection with Human Immunodeficiency Virus (HIV) but does not show
symptoms of HIV disease. However, vaccination may be less effective than for uninfected
persons (see
Do not use ProQuad
).
Once vaccinated, your child should attempt to avoid for up to 6 weeks following vaccination,
whenever possible, close association with the following individuals:
•
Individuals with a lowered resistance to diseases.
•
Pregnant women who have either not had chickenpox or have not been vaccinated against
chickenpox.
•
Newborn infants of mothers who have either not had chickenpox or have not been vaccinated
against chickenpox.
Tell your doctor if there is anyone who falls into one of the categories above and is expected to be in
contact with your vaccinated child.
As with other vaccines, ProQuad may not completely protect all persons who are vaccinated. Also, if
the person to be vaccinated has already been exposed to the measles, mumps, rubella, or varicella
virus but is not yet ill, ProQuad may not be able to prevent the illness from appearing.
Using other medicines and other vaccines
ProQuad may be given with Prevenar and/or hepatitis A vaccine at the same visit at a separate
injection site (e.g. the other arm or leg).
The doctor may delay vaccination for at least 3 months following blood or plasma transfusions, or
administration of immune globulin (IG), or varicella zoster immune globulin (VZIG). After
vaccination with ProQuad, IG or VZIG should not be given for 1 month, unless your doctor tells you
otherwise.
If a tuberculin test is to be performed, it should be done either any time before, simultaneously with,
or 4 to 6 weeks after vaccination with ProQuad.
Tell the doctor if your child has recently received a vaccine or if one is scheduled to be given in the
near future. The doctor will determine when ProQuad may be given.
The use of salicylates (for example, acetylsalicylic acid, a substance present in many medicines used
to relieve pain and lower fever) should be avoided for 6 weeks following vaccination with ProQuad.
Please tell your doctor or pharmacist if your child is taking or has recently taken any other medicines
(or other vaccines) including medicines obtained without a prescription.
48
Pregnancy and breast-feeding
ProQuad should not be given to pregnant females. Females of child-bearing age should take the
necessary precautions to avoid pregnancy for 3 months, or according to doctor’s recommendation,
after they have been given the vaccine.
Persons who are breast-feeding or who intend to breast-feed should tell the doctor. The doctor will
decide if ProQuad should be given.
Ask your doctor or pharmacist for advice before taking any medicine.
Important information about some of the ingredients of ProQuad
ProQuad contains sorbitol. If you have been told by your doctor that you or your child has an
intolerance to some sugars, inform your doctor before you or your child takes this vaccine.
3.
HOW TO USE ProQuad
ProQuad should be injected under the skin in the upper arm or in the outer thigh.
ProQuad is not to be injected directly into any blood vessel.
ProQuad is given by injection to persons from 12 months of age. The appropriate time and number of
injections will be determined by your doctor using appropriate official recommendations.
Reconstitution instructions intended for medical and healthcare professionals are included at
the end of the leaflet
If you forget to take ProQuad
Your doctor will decide when to give the missed dose.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, ProQuad can cause side effects, although not everybody gets them.
The most common side effects reported with the use of ProQuad were: injection site complaints
including pain/tenderness/soreness, redness, swelling or bruising; fever (38.9°C or higher);
irritability; rash (including measles-like rash, varicella-like rash, viral exanthema, and injection site
rash); upper respiratory infection; vomiting and diarrhoea.
Other less common side effects have been reported following administration of ProQuad and some of
these were serious. These included: allergic reactions (hives); seizures with a fever; cough and
bronchiolitis (difficulty breathing with or without cough); and unsteadiness with walking.
Other side effects have been reported with the use of either measles, mumps, and rubella vaccine
manufactured by Merck & Co., Inc., the monovalent components of the measles, mumps, and rubella
vaccine produced by Merck & Co., Inc., or Varicella Vaccine live (Oka/Merck): unusual bleeding or
bruising under the skin, swelling of the testicles; tingling of the skin, herpes zoster (shingles);
inflammation of the brain (encephalitis); severe skin disorders; skin infection; stroke; seizures without
a fever; joint pain and/or swelling (which could be transient or chronic); and inflammation of the lung
(pneumonia/pneumonitis).
49
The doctor has a more complete list of side effects for ProQuad and for the vaccine components for
ProQuad (the measles, mumps, and rubella vaccine manufactured by Merck & Co., Inc. and Varicella
Vaccine live (Oka/Merck)).
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist. If the condition persists or worsens, seek medical attention.
5.
HOW TO STORE ProQuad
Keep out of the reach and sight of children.
Store and transport refrigerated (2°C-8°C).
Keep the vial in the outer carton in order to protect from light.
Do not use ProQuad after the expiry date which is stated on the outer carton after EXP.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help protect the environment.
6.
FURTHER INFORMATION
What ProQuad contains
After reconstitution, one dose (0.5 ml) contains:
The active substances are:
Measles virus
1
Enders’ Edmonston strain (live, attenuated)..................not less than 3.00 log
10
CCID
50
*
Mumps virus
1
Jeryl Lynn™ (Level B) strain (live, attenuated).............not less than 4.30 log
10
CCID
50
*
Rubella virus
2
Wistar RA 27/3 strain (live, attenuated).........................not less than 3.00 log
10
CCID
50
*
Varicella virus
3
Oka/Merck strain (live, attenuated) .............................not less than 3.99 log
10
PFU**
*50% cell culture infectious dose
** plaque-forming units
(
1
) Produced in chick embryo cells.
(
2
) Produced in human diploid lung (WI-38) fibroblasts.
(
3
) Produced in human diploid cells (MRC-5).
The other ingredients are:
Powder
Sucrose, hydrolysed gelatin, urea, sodium chloride, sorbitol, monosodium glutamate, sodium
phosphate, sodium bicarbonate, potassium phosphate, potassium chloride, medium 199 with Hanks’
Salts, MEM, neomycin, phenol red, hydrochloric acid and sodium hydroxide.
Solvent
Water for injections.
What ProQuad looks like and contents of the pack
The vaccine is a powder for suspension for injection contained in a single-dose vial, which should be
mixed with solvent provided with the vial of powder.
50
ProQuad is available in pack of 1 and pack of 10. Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder: Sanofi Pasteur MSD SNC, 8 rue Jonas Salk, F-69007 Lyon, France
Manufacturer Responsible for Batch Release: Merck Sharp and Dohme, B.V., Waarderweg, 39, 2031
BN Haarlem, The Netherlands
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
België Belgique/Belgien:
Sanofi Pasteur MSD, Tél/Tel: +32.2.726.95.84
България:
Мерк Шарп и Доум България ЕООД тел. + 359 2 819 3740
Česká republika:
Merck Sharp & Dohme IDEA, Inc., org. sl., Tel.: +420.233.010.111
Danmark:
Sanofi Pasteur MSD, Tlf: +45 23 32 69 29
Deutschland:
Sanofi Pasteur MSD GmbH, Tel: +49.6224.5940
Eesti:
Merck Sharp & Dohme OÜ, Tel: +372.613.9750
Ελλάδα:
ΒΙΑΝΕΞ Α.Ε., Τηλ: +30.210.8009111
España:
Sanofi Pasteur MSD S.A., Tel: +34.91.371.78.00
France:
Sanofi Pasteur MSD SNC, Tél: +33.4.37.28.40.00
Ireland:
Sanofi Pasteur MSD Ltd, Tel: +3531.468.5600
Ísland:
Sanofi Pasteur MSD, Sími: +32.2.726.95.84
Italia:
Sanofi Pasteur MSD Spa, Tel: +39.06.664.092.11
Kύπρος:
Merck Sharp & Dohme (Middle East) Limited., Τηλ: +357 22866700
Latvija:
SIA Merck Sharp & Dohme Latvija, Tel: +371.67364.224
Lietuva:
UAB Merck Sharp & Dohme, Tel.: +370.5.2780.247
Luxembourg/Luxemburg:
Sanofi Pasteur MSD, Tél: +32.2.726.95.84
Magyarország:
MSD Magyarország Kft, Tel.: + 36.1.888.5300
Malta:
Merck Sharp & Dohme (Middle East) Limited., Tel: +357 22866700
Nederland:
Sanofi Pasteur MSD, Tel: +31.23.567.96.00
Norge:
Sanofi Pasteur MSD, Tlf: +47.67.50.50.20
Österreich:
Sanofi Pasteur MSD GmbH, Tel: +43.1.866.70.22.202
Polska:
MSD Polska Sp. z o.o., Tel.: +48.22.549.51.00
Portugal:
Sanofi Pasteur MSD, SA, Tel: +351.21.470.45.50
România
: Merck Sharp & Dohme Romania S.R.L. Tel: + 4021 529 29 00
Slovenija:
Merck Sharp & Dohme, inovativna zdravila d.o.o., Tel: +386.1.520.4201
Slovenská republika:
Merck Sharp & Dohme IDEA, Inc., Tel: +421.2.58282010
Suomi/Finland:
Sanofi Pasteur MSD, Puh/Tel: +358.9.565.88.30
Sverige:
Sanofi Pasteur MSD, Tel: +46.8.564.888.60
United Kingdom:
Sanofi Pasteur MSD Ltd, Tel: +44.1.628.785.291
This leaflet was last approved in:
---------------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only:
Reconstitution instructions
Before mixing with the solvent, the powder vaccine is a white to pale yellow compact crystalline
cake. When completely mixed, the vaccine is a clear pale yellow to light pink liquid.
51
Withdraw the entire volume of solvent into a syringe. 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 minimize loss
of potency. Discard if reconstituted vaccine is not used within 30 minutes.
Do not use the reconstituted vaccine if you notice any particulate matter or if the appearance of the
vaccine differs from that described above.
Any unused product or waste material should be disposed of in accordance with local requirements.
See also section 3 HOW TO USE ProQuad.
52
PACKAGE LEAFLET: INFORMATION FOR THE USER
ProQuad
Powder and solvent for suspension for injection in a pre-filled syringe
Measles, mumps, rubella and varicella vaccine (live)
Read all of this leaflet before your child is vaccinated.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or your pharmacist.
-
This vaccine has been prescribed for your child. Do not pass it on to others.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What ProQuad is and what it is used for
2.
Before you use ProQuad
3.
How to use ProQuad
4.
Possible side effects
5.
How to store ProQuad
6.
Further information
1.
WHAT ProQuad IS AND WHAT IT IS USED FOR
ProQuad is a vaccine containing measles, mumps, rubella, and varicella (chickenpox) viruses that
have been weakened. When a person is given the vaccine, the immune system (the body’s natural
defences) will make antibodies against the measles, mumps, rubella, and varicella viruses. The
antibodies help protect against diseases caused by these viruses.
ProQuad is given to help protect your child against measles, mumps, rubella, and varicella
(chickenpox). The vaccine may be administered to persons from 12 months of age.
Although ProQuad contains live viruses, they are too weak to cause measles, mumps, rubella, or
varicella (chickenpox) in healthy people.
2.
BEFORE YOU USE ProQuad
Do not use ProQuad
•
If your child is allergic (hypersensitive) to any of the components of ProQuad (including
neomycin or any of the ingredients listed under
“other ingredients”-see
section 6, Further
information
).
•
If your child has a blood disorder or any type of cancer that affects the immune system.
•
If your child is receiving treatment or taking medications that may weaken the immune system
(except low-dose corticosteroid therapy for asthma or replacement therapy).
•
If your child has a weakened immune system because of a disease (including AIDS).
•
If your child has a family history of congenital or hereditary immunodeficiency, unless the
immune competence of your child is demonstrated.
•
If your child has active untreated tuberculosis.
•
If your child has any illness with fever higher than 38.5°C; however, low-grade fever itself is
not a reason to delay vaccination.
•
If your child is pregnant (in addition, pregnancy should be avoided for 3 months after
vaccination, see
Pregnancy and breast-feeding
).
53
Take special care with ProQuad
If the person to be vaccinated has experienced any of the following, talk to the doctor or pharmacist
before ProQuad is given:
•
If your child has had an allergic reaction to eggs or anything that contained egg.
•
If your child has a history or family history of allergies or of convulsions (fits).
•
If your child has had a side effect after vaccination with measles, mumps, or rubella (in a single
vaccine or combined vaccine, such as the measles, mumps, and rubella vaccine manufactured
by Merck & Co., Inc. or ProQuad) that involved easy bruising or bleeding for longer than usual.
•
If your child has infection with Human Immunodeficiency Virus (HIV) but does not show
symptoms of HIV disease. However, vaccination may be less effective than for uninfected
persons (see
Do not use ProQuad
).
Once vaccinated, your child should attempt to avoid for up to 6 weeks following vaccination,
whenever possible, close association with the following individuals:
•
Individuals with a lowered resistance to diseases.
•
Pregnant women who have either not had chickenpox or have not been vaccinated against
chickenpox.
•
Newborn infants of mothers who have either not had chickenpox or have not been vaccinated
against chickenpox.
Tell your doctor if there is anyone who falls into one of the categories above and is expected to be in
contact with your vaccinated child.
As with other vaccines, ProQuad may not completely protect all persons who are vaccinated. Also, if
the person to be vaccinated has already been exposed to the measles, mumps, rubella, or varicella
virus but is not yet ill, ProQuad may not be able to prevent the illness from appearing.
Using other medicines and other vaccines
ProQuad may be given with Prevenar and/or hepatitis A vaccine at the same visit at a separate
injection site (e.g. the other arm or leg).
The doctor may delay vaccination for at least 3 months following blood or plasma transfusions, or
administration of immune globulin (IG), or varicella zoster immune globulin (VZIG). After
vaccination with ProQuad, IG or VZIG should not be given for 1 month, unless your doctor tells you
otherwise.
If a tuberculin test is to be performed, it should be done either any time before, simultaneously with,
or 4 to 6 weeks after vaccination with ProQuad.
Tell the doctor if your child has recently received a vaccine or if one is scheduled to be given in the
near future. The doctor will determine when ProQuad may be given.
The use of salicylates (for example, acetylsalicylic acid, a substance present in many medicines used
to relieve pain and lower fever) should be avoided for 6 weeks following vaccination with ProQuad.
Please tell your doctor or pharmacist if your child is taking or has recently taken any other medicines
(or other vaccines) including medicines obtained without a prescription.
54
Pregnancy and breast-feeding
ProQuad should not be given to pregnant females. Females of child-bearing age should take the
necessary precautions to avoid pregnancy for 3 months, or according to doctor’s recommendation,
after they have been given the vaccine.
Persons who are breast-feeding or who intend to breast-feed should tell the doctor. The doctor will
decide if ProQuad should be given.
Ask your doctor or pharmacist for advice before taking any medicine.
Important information about some of the ingredients of ProQuad
ProQuad contains sorbitol. If you have been told by your doctor that you or your child has an
intolerance to some sugars, inform your doctor before you or your child takes this vaccine.
3.
HOW TO USE ProQuad
ProQuad should be injected under the skin in the upper arm or in the outer thigh.
ProQuad is not to be injected directly into any blood vessel.
ProQuad is given by injection to persons from 12 months of age. The appropriate time and number of
injections will be determined by your doctor using appropriate official recommendations.
Reconstitution instructions intended for medical and healthcare professionals are included at
the end of the leaflet
If you forget to take ProQuad
Your doctor will decide when to give the missed dose.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, ProQuad can cause side effects, although not everybody gets them.
The most common side effects reported with the use of ProQuad were: injection site complaints
including pain/tenderness/soreness, redness, swelling or bruising; fever (38.9°C or higher);
irritability; rash (including measles-like rash, varicella-like rash, viral exanthema, and injection site
rash); upper respiratory infection; vomiting and diarrhoea.
Other less common side effects have been reported following administration of ProQuad and some of
these were serious. These included: allergic reactions (hives); seizures with a fever; cough and
bronchiolitis (difficulty breathing with or without cough); and unsteadiness with walking.
Other side effects have been reported with the use of either measles, mumps, and rubella vaccine
manufactured by Merck & Co., Inc., the monovalent components of the measles, mumps, and rubella
vaccine produced by Merck & Co., Inc., or Varicella Vaccine live (Oka/Merck): unusual bleeding or
bruising under the skin, swelling of the testicles; tingling of the skin, herpes zoster (shingles);
inflammation of the brain (encephalitis); severe skin disorders; skin infection; stroke; seizures without
a fever; joint pain and/or swelling (which could be transient or chronic); and inflammation of the lung
(pneumonia/pneumonitis).
55
The doctor has a more complete list of side effects for ProQuad and for the vaccine components for
ProQuad (the measles, mumps, and rubella vaccine manufactured by Merck & Co., Inc. and Varicella
Vaccine live (Oka/Merck)).
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist. If the condition persists or worsens, seek medical attention.
5.
HOW TO STORE ProQuad
Keep out of the reach and sight of children.
Store and transport refrigerated (2°C-8°C).
Keep the vial in the outer carton in order to protect from light.
Do not use ProQuad after the expiry date which is stated on the outer carton after EXP.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help protect the environment.
6.
FURTHER INFORMATION
What ProQuad contains
After reconstitution, one dose (0.5 ml) contains:
The active substances are:
Measles virus
1
Enders’ Edmonston strain (live, attenuated)........ not less than 3.00 log
10
CCID
50
*
Mumps virus
1
Jeryl Lynn™ (Level B) strain (live, attenuated)... not less than 4.30 log
10
CCID
50
*
Rubella virus
2
Wistar RA 27/3 strain (live, attenuated)............... not less than 3.00 log
10
CCID
50
*
Varicella virus
3
Oka/Merck strain (live, attenuated) ................... not less than 3.99 log
10
PFU**
*50% cell culture infectious dose
**plaque-forming units
(
1
) Produced in chick embryo cells.
(
2
) Produced in human diploid lung (WI-38) fibroblasts.
(
3
) Produced in human diploid cells (MRC-5).
The other ingredients are:
Powder
Sucrose, hydrolysed gelatin, urea, sodium chloride, sorbitol, monosodium glutamate, sodium
phosphate, sodium bicarbonate, potassium phosphate, potassium chloride, medium 199 with Hanks’
Salts, MEM, neomycin, phenol red, hydrochloric acid and sodium hydroxide.
Solvent
Water for injections.
What ProQuad looks like and contents of the pack
The vaccine is a powder for suspension for injection contained in a single-dose vial, which should be
mixed with solvent provided with the vial of powder.
56
ProQuad is available in pack of 1, 10 and 20. Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder: Sanofi Pasteur MSD SNC, 8 rue Jonas Salk, F-69007 Lyon, France
Manufacturer Responsible for Batch Release: Merck Sharp and Dohme, B.V., Waarderweg, 39, 2031
BN Haarlem, The Netherlands
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder.
België Belgique/Belgien:
Sanofi Pasteur MSD, Tél/Tel: +32.2.726.95.84
България:
Мерк Шарп и Доум България ЕООД тел. + 359 2 819 3740
Česká republika:
Merck Sharp & Dohme IDEA, Inc., org. sl.,Tel.: +420.233.010.111
Danmark:
Sanofi Pasteur MSD, Tlf: +45 23 32 69 29
Deutschland:
Sanofi Pasteur MSD GmbH, Tel: +49.6224.5940
Eesti:
Merck Sharp & Dohme OÜ, Tel: +372.613.9750
Ελλάδα:
ΒΙΑΝΕΞ Α.Ε., Τηλ: +30.210.8009111
España:
Sanofi Pasteur MSD S.A., Tel: +34.91.371.78.00
France:
Sanofi Pasteur MSD SNC, Tél: +33.4.37.28.40.00
Ireland:
Sanofi Pasteur MSD Ltd, Tel: +3531. 468.5600
Ísland:
Sanofi Pasteur MSD, Sími: +32.2.726.95.84
Italia:
Sanofi Pasteur MSD Spa, Tel: +39.06.664.092.11
Kύπρος:
Merck Sharp & Dohme (Middle East) Limited., Τηλ: +357 22866700
Latvija:
SIA Merck Sharp & Dohme Latvija, Tel: +371.67364.224
Lietuva:
UAB Merck Sharp & Dohme, Tel.: +370.5.2780.247
Luxembourg/Luxemburg:
Sanofi Pasteur MSD, Tél: +32.2.726.95.84
Magyarország:
MSD Magyarország Kft, Tel.: + 36.1.888.5300
Malta:
Merck Sharp & Dohme (Middle East) Limited., Tel: +357 22866700
Nederland:
Sanofi Pasteur MSD, Tel: +31. 23.567.96.00
Norge:
Sanofi Pasteur MSD, Tlf: +47. 67.50.50.20
Österreich:
Sanofi Pasteur MSD GmbH, Tel: +43.1.866.70.22.202
Polska:
MSD Polska Sp. z o.o., Tel.: +48.22.549.51.00
Portugal:
Sanofi Pasteur MSD, SA, Tel: +351.21.470.45.50
România
: Merck Sharp & Dohme Romania S.R.L. Tel: + 4021 529 29 00
Slovenija:
Merck Sharp & Dohme, inovativna zdravila d.o.o., Tel: +386.1.520.4201
Slovenská republika:
Merck Sharp & Dohme IDEA, Inc., Tel: +421.2.58282010
Suomi/Finland:
Sanofi Pasteur MSD, Puh/Tel: +358.9.565.88.30
Sverige:
Sanofi Pasteur MSD, Tel: +46.8.564.888.60
United Kingdom:
Sanofi Pasteur MSD Ltd, Tel: +44.1.628.785.291
This leaflet was last approved in:
---------------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only:
Reconstitution instructions
Before mixing with the solvent, the powder vaccine is a white to pale yellow compact crystalline
cake. When completely mixed, the vaccine is a clear pale yellow to light pink liquid.
57
.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 minimize loss
of potency. Discard if reconstituted vaccine is not used within 30 minutes.
Do not use the reconstituted vaccine if you notice any particulate matter or if the appearance of the
vaccine differs from that described above.
Any unused product or waste material should be disposed of in accordance with local requirements.
See also section 3 HOW TO USE ProQuad.
58
Source: European Medicines Agency
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