4.1. Therapeutic indications

M-M-RvaxPro is indicated for simultaneous vaccination against measles, mumps and rubella in individuals from 12 months of age (see section 4.2).

M-M-RvaxPro can be administered to infants from 9 months of age under special circumstances (see sections 4.2, 4.4 and 5.1).

For use in measles outbreaks, or for post-exposure vaccination, or, for use in previously unvaccinated individuals older than 9 months who are in contact with susceptible pregnant women, and persons likely to be susceptible to mumps and rubella, see section 5.1.

M-M-RvaxPro is to be used on the basis of official recommendations.

4.2. Posology and method of administration

Posology

• Individuals 12 months of age or older:

Individuals 12 months or older should receive one dose at an elected date. A second dose may be administered at least 4 weeks after the first dose in accordance with official recommendation. The second dose is intended for individuals who did not respond to the first dose for any reason.

• Infants between 9 and 12 months of age:

Immunogenicity and safety data show that M-M-RvaxPro can be administered to infants between 9 and 12 months of age, in accordance with official recommendations or when an early protection is considered necessary (e.g., day-care, outbreak situations, or travel to a region with high prevalence of measles). Such infants should be revaccinated at 12 to 15 months of age. An additional dose with a measles-containing vaccine should be considered according to official recommendations (see sections 4.4 and 5.1).

• Infants below 9 months of age:

No data on the efficacy and safety of M-M-RvaxPro for use in children below 9 months of age are currently available.

Method of administration

The vaccine is to be injected intramuscularly (IM) or subcutaneously (SC).

The preferred injection sites are the anterolateral area of the thigh in younger children and the deltoid area in older children, adolescents, and adults.

The vaccine should be administered subcutaneously in patients with thrombocytopenia or any coagulation disorder.

For precautions to be taken before handling or administering the medicinal product, and for instructions on reconstitution of the medicinal product before administration, see section 6.6.

DO NOT INJECT INTRAVASCULARLY.

4.3. Contraindications

Hypersensitivity to any measles, mumps, or rubella vaccine, or to any of the excipients listed in section 6.1, including neomycin (see sections 2 and 4.4).

Pregnancy. Furthermore, pregnancy should be avoided for 1 month following vaccination (see section 4.6).

Vaccination should be postponed during any illness with fever > 38.5 °C.

Active untreated tuberculosis. Children under treatment for tuberculosis have not experienced exacerbation of the disease when immunised with live measles virus vaccine. No studies have been reported to date on the effect of measles virus vaccines on children with untreated tuberculosis.

Blood dyscrasias, leukaemia, lymphomas of any type, or other malignant neoplasms affecting the haematopoietic and lymphatic systems.

Current immunosuppressive therapy (including high doses of corticosteroids). M-M-RvaxPro is not contraindicated in individuals who are receiving topical or low-dose parenteral corticosteroids (e.g., for asthma prophylaxis or replacement therapy).

Severe humoral or cellular (primary or acquired) immunodeficiency, e.g., severe combined immunodeficiency, agammaglobulinemia and AIDS or symptomatic HIV infection or an age-specific CD4+ T-lymphocyte percentage in children below 12 months: CD4+ < 25%; children between 12-35 months: CD4+ < 20%; children between 36-59 months: CD4+ < 15% (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.

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

As with all injectable vaccines, appropriate medical treatment should always be readily available in case of rare anaphylactic reactions following the administration of the vaccine (see section 4.8).

Adults and adolescents with a history of allergies may potentially be at increased risk of anaphylaxis or anaphylactoid reactions. Close monitoring is recommended following vaccination for the early signs of such reactions.

Since 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 administration of M-M-RvaxPro 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).

Infants from 9 to 12 months of age vaccinated with a measles-containing vaccine during measles outbreaks or for other reasons may fail to respond to the vaccine due to the presence of circulating antibodies of maternal origin and/or immaturity of the immune system (see sections 4.2 and 5.1).

Thrombocytopenia

This vaccine should be given subcutaneously to individuals with thrombocytopenia or any coagulation disorder because bleeding may occur following an intramuscular administration in these individuals.

Individuals with current thrombocytopenia may develop more severe thrombocytopenia following vaccination. In addition, individuals who experienced thrombocytopenia with the first dose of M-M-RvaxPro (or its component vaccines) 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 in such cases (see section 4.8).

Other

Vaccination may be considered in patients with selected immune deficiencies where the benefits outweigh the risks (asymptomatic HIV patients, IgG subclass deficiencies, congenital neutropenia, chronic granulomatous disease, and complement deficiency diseases).

Immunocompromised patients who have no contraindication for this vaccination (see section 4.3) may not respond as well as immunocompetent patients; therefore, some of these patients may acquire measles, mumps, or rubella in case of contact, despite appropriate vaccine administration. These patients should be monitored carefully for signs of measles, parotitis, and rubella.

Vaccination with M-M-RvaxPro may not result in protection in all vaccinees.

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 vaccinees to susceptible contacts.

Sodium

This medicinal product contains less than 1 mmol sodium (23 milligrams) per dose, that is to say essentially 'sodium-free'.

Potassium

This medicinal product contains less than 1 mmol potassium (39 milligrams) per dose, that is to say essentially 'potassium-free'.

Sorbitol (E 420)

This medicinal product contains 14.5 milligrams of sorbitol per dose. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.

Interference with laboratory tests: see section 4.5.

4.5. Interaction with other medicinal products and other forms of interaction

Immune globulin

Immune globulin (Ig) is not to be given concomitantly with M-M-RvaxPro.

Administration of immune globulins concomitantly with M-M-RvaxPro may interfere with the expected immune response. Vaccination should be deferred for at least 3 months following blood or plasma transfusions, or administration of human immune serum globulin.

Administration of measles, mumps, or rubella antibody-containing blood products, including immune globulin preparations, should be avoided within 1 month after a dose of M-M-RvaxPro unless considered to be essential.

Laboratory tests

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 4 to 6 weeks after vaccination with M-M-RvaxPro.

Concomitant administration with other vaccines

M-M-RvaxPro can be given concomitantly with a pneumococcal conjugate vaccine.

Published clinical data support concomitant administration of the previous formulation of the measles, mumps and rubella vaccine manufactured by Merck Sharp & Dohme LLC, Rahway, NJ 07065, USA (herein after MSD) with other childhood vaccinations, including DTaP (or DTwP), IPV (or OPV), HIB (Haemophilus influenzae type b), HIB-HBV (Haemophilus influenzae type b with Hepatitis B vaccine), and VAR (varicella).

Based on clinical studies with the quadrivalent measles, mumps, rubella and varicella vaccine and with the previous formulation of the combined measles, mumps and rubella vaccine manufactured by MSD, M-M-RvaxPro can be given concomitantly with a hepatitis A vaccine. In these clinical studies, it was demonstrated that the immune responses were unaffected and that the overall safety profiles of the administered vaccines were similar.

Since M-M-RvaxPro has been shown to have safety and immunogenicity profiles similar to the previous formulation of the combined measles, mumps and rubella vaccine manufactured by MSD, experience with this vaccine can be considered.

M-M-RvaxPro should be given concomitantly at separate injection sites, or one month before or after administration of other live virus vaccines.

4.6. Fertility, pregnancy and lactation

Pregnancy

Pregnant women should not be vaccinated with M-M-RvaxPro.

Studies have not been conducted with M-M-RvaxPro in pregnant women.

In a review of more than 3,500 susceptible women who were unknowingly in early stages of pregnancy when vaccinated with a rubella-containing vaccine, no cases of congenital rubella syndrome were reported. Subsequent post-marketing surveillance identified congenital rubella syndrome associated with a rubella vaccine strain following inadvertent vaccination of a pregnant woman with a measles, mumps and rubella vaccine.

Foetal damage has not been documented when measles or mumps vaccines have been given to pregnant women.

Inadvertent vaccination of unknowingly pregnant women with measles-, mumps-, or rubella-containing vaccines should not be a reason for termination of pregnancy.

Pregnancy should be avoided for 1 month following vaccination. Women who intend to become pregnant should be advised to delay.

Breast-feeding

Studies have shown that breast-feeding postpartum women vaccinated with live attenuated rubella vaccines 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. It is not known whether measles or mumps vaccine virus is secreted in human milk; therefore, caution should be exercised when M-M-RvaxPro is administered to a breast-feeding woman.

Fertility

M-M-RvaxPro has not been evaluated in fertility studies.

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. M-M-RvaxPro is expected to have no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

a. Summary of the safety profile

In clinical trials, M-M-RvaxPro was administered to 1,965 children (see section 5.1), and the general safety profile was comparable to the previous formulation of the measles, mumps and rubella vaccine manufactured by MSD.

In a clinical trial, 752 children received M-M-RvaxPro, either intramuscularly or subcutaneously. The general safety profile of either administration routes were comparable, although injection site reactions were less frequent in the IM group (15.8%) compared with the SC group (25.8%).

All adverse reactions were evaluated in 1,940 children. Among these children, the vaccine-related adverse reactions, summarised in section b, were observed in individuals following vaccination with M-M-RvaxPro (excluding isolated reports with frequency < 0.2%).

In comparison to the first dose, a second dose of M-M-RvaxPro is not associated with an increase in the incidence and severity of clinical symptoms including those suggestive of hypersensitivity reaction.

Additionally, other adverse reactions reported with post-marketing use of M-M-RvaxPro and/or in clinical studies and post-marketing use of previous formulations of monovalent and of the combined measles, mumps and rubella vaccines manufactured by MSD without regard to causality or frequency are available and are summarised in section b. The frequency of these adverse events is qualified as "not known" when it cannot be estimated based on the available data. These data were reported based on more than 400 million doses distributed worldwide.

The most common adverse reactions reported with the use of M-M-RvaxPro were: fever (38.5 °C or higher); injection site reactions including pain, swelling and erythema.

b. Tabulated list of adverse reactions

Adverse reactions are ranked under headings of frequency using the following convention:

[Very common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Not known (cannot be estimated from the available data)]

Adverse reactions

Frequency

Infections and infestations

Nasopharyngitis, Upper respiratory tract infection or Viral infection

Uncommon

Aseptic meningitis†, Atypical measles, Epididymitis, Orchitis, Otitis media, Parotitis, Rhinitis, Subacute sclerosing panencephalitis†

Not known

Blood and the lymphatic system disorders

Regional lymphadenopathy, Thrombocytopenia

Not known

Immune system disorders

Anaphylactoid reaction, Anaphylaxis and related phenomenon such as Angioneurotic oedema, Facial oedema, and Peripheral oedema

Not known

Psychiatric disorders

Crying

Uncommon

Irritability

Not known

Nervous system disorders

Afebrile convulsions or seizures, Ataxia, Dizziness, Encephalitis†, Encephalopathy†, Febrile convulsion (in children), Guillain-Barre syndrome, Headache, Measles inclusion body encephalitis (MIBE) (see section 4.3), Ocular palsies, Optic neuritis, Paraesthesia, Polyneuritis, Polyneuropathy, Retrobulbar neuritis, Syncope

Not known

Eye disorders

Conjunctivitis, Retinitis

Not known

Ear and labyrinth disorders

Nerve deafness

Not known

Respiratory, thoracic and mediastinal disorders

Rhinorrhoea

Uncommon

Bronchial spasm, Cough, Pneumonia, Pneumonitis (see section 4.3), Sore throat

Not known

Gastrointestinal disorders

Diarrhoea or Vomiting

Uncommon

Nausea

Not known

Skin and subcutaneous tissue disorders

Rash morbilliform or other Rash

Common

Urticaria

Uncommon

Panniculitis, Pruritus, Purpura, Skin induration, Stevens-Johnson syndrome, Skin granuloma (associated with vaccine derived rubella virus)

Not known

Musculoskeletal, connective tissue and bone disorders

Arthritis† and/or Arthralgia† (usually transient and rarely chronic), Myalgia

Not known

General disorders and administration site conditions

Fever (38.5 °C or higher), Injection site erythema, Injection site pain, and Injection site swelling

Very common

Injection site bruising

Common

Injection site rash

Uncommon

Burning and/or Stinging of short duration at the injection site, Malaise, Papillitis, Peripheral oedema, Swelling, Tenderness, Vesicles at the injection site, Wheal and Flare at the injection site

Not known

Vascular disorders

Vasculitis

Not known

† see section c

c. Description of selected adverse reactions

Aseptic meningitis

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.

Encephalitis and Encephalopathy

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 (see section 4.3); disseminated mumps and rubella vaccine virus infection has also been reported.

Subacute sclerosing panencephalitis

There is no evidence that measles vaccine can cause subacute sclerosing panencephalitis (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 unrecognised 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 suggest that the overall effect of measles vaccine has been to protect against SSPE by preventing measles with its inherent risk of SSPE.

Arthralgia and/or arthritis

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 sex, being greatest in adult females and least in prepubertal children. Following vaccination in children, reactions in joints are generally uncommon (0-3%) and of brief duration. In women, incidence rates for arthritis and arthralgia are generally higher than those seen in children (12-20%), and the reactions tend to be more marked and of longer duration. Symptoms may persist for a matter of months or on rare occasions for years. In adolescent girls, the reactions appear to be intermediate in incidence between those seen in children and adult women. Even in older women (35-45 years), these reactions are generally well tolerated and rarely interfere with normal activities.

Chronic arthritis

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Administration of a higher than recommended dose of M-M-RvaxPro was reported rarely and the adverse reaction profile was comparable to that observed with the recommended dose of M-M-RvaxPro.