4.1. Therapeutic indications

Priorix-Tetra is indicated for active immunisation of individuals from the age of 11 months against measles, mumps, rubella and varicella.

Use in infants aged 9-10 months could be considered under special circumstances. See section 4.2.

Note: The use of Priorix-Tetra should be based on official recommendations.

4.2. Posology and method of administration

Posology

Individuals from 11 months of age

Individuals aged from 11 months should receive two doses (each of 0.5 ml) of Priorix-Tetra. The age at which individuals may receive Priorix-Tetra should reflect applicable official recommendations*, which vary according to the epidemiology of these diseases.

The dose interval should preferably* be between 6 weeks and 3 months. When the first dose is administered at 11 months of age, the second dose should be administered within 3 months. Under no circumstances should the dose interval be less than 4 weeks. See section 5.1.

Alternatively, and in accordance with applicable official recommendations*:

- A single dose of Priorix-Tetra may be administered to individuals who have already received a single dose of another measles, mumps and rubella (MMR) vaccine and/or a single dose of another varicella vaccine,

- A single dose of Priorix-Tetra may be administered followed by a single dose of another measles, mumps and rubella (MMR) vaccine and/or a single dose of another varicella vaccine.

* 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 vaccines.

Children from 9 to 10 months of age

In case an epidemiological situation requires vaccinating infants less than 11 months of age, the first dose of Priorix-Tetra can be given as from 9 months of age. A second dose of Priorix-Tetra should be given three months after the first dose (see section 5.1).

Method of administration

The vaccine is to be injected subcutaneously (SC) or intramuscularly (IM) in the deltoid region of the upper arm or in the higher anterolateral area of the thigh.

The vaccine should preferably be administered subcutaneously in subjects with thrombocytopenia or any coagulation disorder (see section 4.4).

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

As with other vaccines, the administration of Priorix-Tetra should be postponed in subjects suffering from acute severe febrile illness. However, the presence of a minor infection, such as a cold, should not result in the deferral of vaccination.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 or neomycin. A history of contact dermatitis to neomycin is not a contraindication. For egg allergy, see section 4.4.

Hypersensitivity after previous administration of measles, mumps, rubella and/or varicella vaccines.

Current immunosuppressive therapy (including high doses of corticosteroids). Priorix-Tetra 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).

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

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 and supervision should always be readily available in case of a rare anaphylactic event following the administration of the vaccine.

Alcohol and other disinfecting agents must be allowed to evaporate from the skin before injection of the vaccine since they can inactivate the attenuated viruses in the vaccine.

The measles and mumps components of the vaccine are produced in chick embryo cell culture and may therefore contain traces of egg protein. Persons with a history of anaphylactic, anaphylactoid, or other immediate reactions (e.g. generalised urticaria, swelling of the mouth and throat, difficulty breathing, hypotension, or shock) subsequent to egg ingestion may be at an enhanced risk of immediate-type hypersensitivity reactions after vaccination, although these types of reactions have been shown to be very rare. Individuals who have experienced anaphylaxis after egg ingestion should be vaccinated with extreme caution, with adequate treatment for anaphylaxis on hand should such a reaction occur.

Salicylates should be avoided for 6 weeks after each vaccination with Priorix-Tetra as Reye's Syndrome has been reported following the use of salicylates during natural varicella infection.

Limited protection against measles or varicella may be obtained by vaccination up to 72 hours after exposure to natural disease.

Febrile convulsions

There was an increased risk of fever and febrile convulsions 5 to 12 days after the first dose of Priorix-Tetra observed as compared to concomitant administration of MMR and varicella vaccines (see sections 4.8 and 5.1).

Vaccination of subjects with a personal or family history of convulsions (including febrile convulsions) should be considered with caution. For these subjects, alternative immunisation with separate MMR and varicella vaccines should be considered for the first dose (see section 4.2). In any case vaccinees should be monitored for fever during the risk period.

Fever rates are usually high after the first dose of measles-containing vaccines. There was no indication of an increased risk of fever after the second dose.

Immunocompromised patients

Vaccination may be considered in patients with selected immune deficiencies where the benefits outweigh the risks (e.g. asymptomatic HIV subjects, 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 subjects, therefore some of these patients may acquire measles, mumps, rubella or varicella in case of contact, despite appropriate vaccine administration. These patients should be monitored carefully for signs of measles, parotitis, rubella and varicella.

Transmission

Transmission of measles, mumps and rubella viruses from vaccinees to susceptible contacts has never been documented, although pharyngeal excretion of the rubella virus is known to occur about 7 to 28 days after vaccination with peak excretion around the 11th day.

Transmission of the Oka varicella vaccine virus has been shown to occur at a very low rate in seronegative contacts of vaccinees with rash. Transmission of the Oka varicella vaccine virus from a vaccinee who does not develop a rash to seronegative contacts cannot be excluded.

Vaccine recipients, even those who do not develop a varicella-like rash, 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 weighted against the risk of acquiring and transmitting wild-type varicella virus.

High-risk individuals susceptible to varicella include:

• Immunocompromised individuals (see sections 4.3 and 4.4)

• Pregnant women without documented positive history of varicella (chickenpox) or laboratory evidence of prior infection.

• Newborns of mothers without documented positive history of chickenpox or laboratory evidence of prior infection.

Priorix-Tetra should under no circumstances be administered intravascularly or intradermally.

Thrombocytopenia

Cases of worsening of thrombocytopenia and cases of recurrence of thrombocytopenia in subjects who suffered thrombocytopenia after the first dose have been reported following vaccination with live measles, mumps and rubella vaccines. In such cases, the risk-benefit of immunising with Priorix-Tetra should be carefully evaluated. These patients should be vaccinated with caution and preferably using the subcutaneous route.

Syncope (fainting) can occur following, or even before, any vaccination especially in adolescents as a psychogenic response to the needle injection. This can be accompanied by several neurological signs such as transient visual disturbance, paraesthesia and tonic-clonic limb movements during recovery. It is important that procedures are in place to avoid injury from faints.

As with any vaccine, a protective immune response may not be elicited in all vaccinees. As for other varicella vaccines, cases of varicella disease have been shown to occur in persons who have previously received Priorix-Tetra. These breakthrough cases are usually mild, with a fewer number of lesions and less fever as compared to cases in unvaccinated individuals.

Very few reports exist on disseminated varicella with internal organ involvement following vaccination with Oka varicella vaccine strain mainly in immunocompromised subjects.

Interference with serological testing (see section 4.5).

Encephalitis

Encephalitis has been reported during post-marketing use of live attenuated measles, mumps, rubella and varicella vaccines. In a few cases fatal outcomes have been observed, especially in patients who were immunocompromised (see section 4.3). Vaccinees/parents should be instructed to seek prompt medical attention if they/their child experience, after vaccination, symptoms suggestive of encephalitis such as loss or reduced levels of consciousness, convulsions or ataxia accompanied by fever and headache.

Excipients with known effect

Priorix-Tetra contains para-aminobenzoic acid. It may cause allergic reactions (possibly delayed), and exceptionally, bronchospasm.

The vaccine contains 583 micrograms of phenylalanine per dose. Phenylalanine may be harmful for individuals with phenylketonuria (PKU).

The vaccine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

The vaccine contains potassium, less than 1 mmol (39 mg) per dose, i.e. essentially 'potassium-free'.

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

Clinical studies have demonstrated that Priorix-Tetra can be given simultaneously with any of the following monovalent or combination vaccines [including hexavalent vaccines (DTPa-HBV-IPV/Hib)]: diphtheria-tetanus-acellular pertussis vaccine (DTPa), Haemophilus influenzae type b vaccine (Hib), inactivated polio vaccine (IPV), hepatitis B vaccine (HBV), meningococcal serogroup B vaccine (MenB), meningococcal serogroup C conjugate vaccine (MenC), meningococcal serogroups A, C, W-135 and Y conjugate vaccine (MenACWY) and 10-valent pneumococcal conjugate vaccine.

Due to an increased risk of fever, tenderness at the injection site, change in eating habits and irritability when Bexsero was co-administered with Priorix-Tetra, separate vaccinations can be considered when possible.

There are currently insufficient data to support the use of Priorix-Tetra with any other vaccines.

If Priorix-Tetra is to be given at the same time as another injectable vaccine, the vaccines should always be administered at different injection sites.

Serological testing

If tuberculin testing has to be done it should be carried out before or simultaneously with vaccination since it has been reported that combined measles, mumps and rubella vaccines may cause a temporary depression of tuberculin skin sensitivity. As this anergy may last up to a maximum of 6 weeks, tuberculin testing should not be performed within that period after vaccination to avoid false negative results.

In subjects who have received human gammaglobulins or a blood transfusion, vaccination should be delayed for at least three months because of the likelihood of vaccine failure due to passively acquired antibodies.

Vaccine recipients should avoid use of salicylates for 6 weeks after each vaccination with Priorix-Tetra (see section 4.4).

4.6. Fertility, pregnancy and lactation

Fertility

Priorix-Tetra has not been evaluated in fertility studies.

Pregnancy

Pregnant women should not be vaccinated with Priorix-Tetra.

Studies have not been conducted with Priorix-Tetra 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 (Wistar RA 27/3) following inadvertent vaccination of a pregnant woman with a measles, mumps and rubella vaccine.

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

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

Breast-feeding

Adequate human data on the use of Priorix-Tetra during lactation are not available.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

The safety profile presented below is based on data from clinical trials in which more than 6,700 doses of Priorix-Tetra were administered subcutaneously to more than 4,000 children from 9 to 27 months of age. Events were recorded for up to 42 days after vaccination.

The most common adverse reactions following Priorix-Tetra administration were pain and redness at the injection site as well as fever ≥38°C (rectal) or ≥37.5°C (axillary/oral).

Tabulated list of adverse reactions

Adverse reactions reported are listed according to the following frequency:

Very common:

Common:

Uncommon:

Rare:

Very rare:

(≥ 1/10)

(≥ 1/100 to < 1/10)

(≥ 1/1 000 to < 1/100)

(≥ 1/10 000 to < 1/1 000)

(< 1/10 000)

Clinical trial data

System Organ Class

Frequency

Adverse reactions

Infections and infestations

Uncommon

upper respiratory tract infection

Rare

otitis media

Blood and lymphatic system disorders

Uncommon

lymphadenopathy

Metabolism and nutrition disorders

Uncommon

anorexia

Psychiatric disorders

Common

irritability

Uncommon

crying, nervousness, insomnia

Nervous system disorders

Rare

febrile convulsions*

Respiratory, thoracic and mediastinal disorders

Uncommon

rhinitis

Rare

cough, bronchitis

Gastrointestinal disorders

Uncommon

parotid gland enlargement, diarrhoea, vomiting

Skin and subcutaneous tissue disorders

Common

rash

General disorders and administration site conditions

Very common

pain and redness at the injection site, fever (rectal ≥38°C - ≤39.5°C; axillary/oral: ≥37.5°C - ≤39°C)**

Common

swelling at the injection site, fever (rectal >39.5°C; axillary/oral >39°C)**

Uncommon

lethargy, malaise, fatigue

* The risk of febrile convulsions following the first dose vaccination of children aged 9 to 30 months with Priorix-Tetra compared with MMR or simultaneous, but separate MMR and varicella vaccination was assessed in a retrospective database analysis.

The study included 82 656 children immunized with MMRV, 149 259 with MMR and 39 203 with separate MMR and varicella vaccines.

Depending on the case definition used to identify febrile convulsions in the main risk period 5 to 12 days following the first dose, incidences of febrile convulsions were 2.18 (95% CI: 1.38; 3.45) or 6.19 (95% CI: 4.71; 8.13) per 10 000 subjects for the MMRV group and 0.49 (95% CI: 0.19; 1.25) or 2.55 (95% CI: 1.67; 3.89) per 10 000 subjects for the matched control cohorts.

These data suggest one additional case of febrile convulsion per 5 882 or 2 747 subjects vaccinated with Priorix-Tetra compared to matched control cohorts who received MMR or simultaneous, but separate MMR and varicella vaccination (attributable risk of 1.70 (95% CI: -1.86; 3.46) and 3.64 (95% CI: -6.11; 8.30) per 10 000 subjects, respectively) – see section 5.1.

**Following the administration of the first dose of the combined measles-mumps-rubella-varicella vaccine, higher incidences of fever (approximately 1.5 fold) were observed when compared to the concomitant administration of measles-mumps-rubella and varicella vaccines at separate injection sites.

No clinical studies with Priorix-Tetra (MMRV) have been conducted in subjects > 6 years of age. The safety profile of Priorix-Tetra in subjects > 6 years of age is extrapolated from the available data with GlaxoSmithKline's MMR vaccine (Priorix) and monovalent Oka varicella vaccine (Varilrix). The spectrum of adverse reactions such as fever, rash, injection site pain, injection site swelling and injection site redness in subjects > 6 years of age who received Priorix or Varilrix was comparable to that observed in children < 6 years of age who received Priorix-Tetra. In these clinical studies evidence has been obtained to conclude that the second dose of the MMR vaccine is better tolerated in terms of fever than the first dose, whereas reactogenicity of the varicella vaccine tends to remain similar irrespective of the dose applied. Injection site swelling is “commonly” reported in children who received Priorix-Tetra, while it is “very commonly” reported in Varilrix studies in adolescents and adults.

Post-marketing surveillance data

The following additional adverse reactions have been identified in rare occasions during post-marketing surveillance. Because they are reported voluntarily from a population of unknown size, a true estimate of frequency cannot be provided.

System Organ Class

Adverse reactions

Infections and infestations

meningitis, herpes zoster*, measles-like syndrome, mumps-like syndrome (including orchitis, epididymitis and parotitis)

Blood and lymphatic system disorders

thrombocytopenia, thrombocytopenic purpura

Immune system disorders

allergic reactions (including anaphylactic and anaphylactoid reactions)

Nervous system disorders

encephalitis*+, cerebellitis, cerebrovascular accident, Guillain Barré syndrome, transverse myelitis, peripheral neuritis, cerebellitis like symptoms (including transient gait disturbance and transient ataxia)

Vascular disorders

vasculitis

Skin and subcutaneous tissue disorders

erythema multiforme, varicella-like rash

Musculoskeletal and connective tissue disorders

arthralgia, arthritis

* These selected adverse reactions reported after vaccination are also a consequence of wild-type varicella infection. There is no indication of an increased risk of these adverse reactions following vaccination compared with wild-type disease.

+ see description of selected adverse reactions

Description of selected adverse reactions

Encephalitis has been observed following vaccination with live attenuated measles, mumps, rubella and varicella vaccines. Fatal outcome was reported in a few cases, especially in immunocompromised people (see section 4.4).

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

No case of overdose has been reported.