MenQuadfi^® (Solution) Instructions for Use

Marketing Authorization Holder

Sanofi Pasteur, Inc. (USA)

Manufactured By

Sanofi Pasteur, Inc. (USA)

Packaging and Quality Control Release

SANOFI PASTEUR, Inc. (USA)

Or

NANOLEK, LLC (Russia)

Contact Information

SANOFI RUSSIA JSC (Russia)

ATC Code

J07AH08 (Meningococcus A, C, Y, W-135 purified polysaccharide antigens tetravalent conjugated)

Active Substance

Polysaccharide vaccine for prevention of meningococcal infection of serogroups A, C, W, Y conjugated (Grouping Name)

Dosage Forms

	MenQuadfi®	Solution for intramuscular administration 1 dose (0.5 ml): vial 1 or 10 pcs.
		Solution for intramuscular administration 1 dose (0.5 ml): vial 1 or 5 pcs.

Dosage Form, Packaging, and Composition

Solution for i/m administration colorless, transparent.

Excipients : sodium chloride, sodium acetate, water for injections.

0.5 ml (1 dose) – borosilicate glass vials (type I) capacity 2 ml (1) – cardboard packs.
0.5 ml (1 dose) – borosilicate glass vials (type I) capacity 2 ml (5) – cardboard packs.
0.5 ml (1 dose) – borosilicate glass vials (type I) capacity 2 ml (10) – cardboard packs.

Clinical-Pharmacological Group

Vaccine for the prevention of meningococcal infections of serogroups A, C, W, Y, polysaccharide, conjugated

Pharmacotherapeutic Group

Vaccines; bacterial vaccines; vaccines against meningococcal infection

Pharmacological Action

Mechanism of action

Antibodies to meningococcal capsular polysaccharides protect against the development of infection caused by meningococci through complement-mediated bactericidal activity.

The MenQuadfi^® vaccine induces the production of bactericidal antibodies specific to the capsular polysaccharides of Neisseria meningitidis serogroups A, C, W and Y.

Immunogenicity

The immunogenicity of the MenQuadfi^® vaccine in infants aged from 6 weeks to 12 months during primary vaccination was evaluated in 2 pivotal studies, in which primary vaccination consisted of administration of 1 or 3 doses (depending on the age at first dose administration) in the first year of life and a booster dose was administered in the second year of life.

The immunogenicity of a single booster dose of MenQuadfi^® was evaluated in one pivotal study (subjects aged from 15 to 55 years inclusive) and in four additional studies: in two – in children aged from 3 to 5 years after primary vaccination at the age of 12 to 23 months, in one – in adolescents and adults 3 to 6 years after primary vaccination and in one – in elderly subjects 3 years, 5 years and 6 to 7 years after primary vaccination at the age of 56 years and older. Additionally, within the framework of these studies, clinical information is available on the persistence of the immune response for at least 3 to 7 years after vaccination with MenQuadfi^®.

The primary immunogenicity analysis was performed by measuring serum bactericidal activity (SBA) using human serum as a source of exogenous complement (hSBA). Data obtained using rabbit complement (rSBA) are presented for clinical trial participants from all age groups and generally follow the trend observed with human complement (hSBA).

Children aged from 6 weeks to 12 months inclusive

Immunogenicity in infants under one year of age starting vaccination at the age of 6 weeks to 6 months

The study compared the immunogenicity of a primary vaccination series consisting of 3 doses of MenQuadfi^® vaccine (administered at 2, 4, and 6 months of age) and a booster dose (administered at 12-18 months of age) compared with the meningococcal serogroups A, C, W and Y vaccine conjugated with CRM protein (MenACWY-CRM) 30 days after the 3rd dose and the booster dose.

The proportion of participants with hSBA titer ≥1:8 (seroresponse), seroprotection rate and GMT are presented in Table 1.

Non-inferiority of the MenQuadfi^® vaccine compared to the MenACWY-CRM vaccine was demonstrated based on seroresponse rates after the third dose for all four serogroups.

Non-inferiority of the MenQuadfi^® vaccine compared to the MenACWY-CRM vaccine was demonstrated based on seroresponse rates after the booster dose for all four serogroups

Table 1. Comparison of bactericidal antibody levels on day 30 after vaccination with MenQuadfi^® and MenACWY-CRM simultaneously with routine pediatric vaccines at 2, 4, 6 and 12-18 months of age

N – number of participants included in the full analysis set for antibody persistence assessment (FAS3) with valid serology results. The number of participants varies by time point and serogroup.

^$ after primary dose = Day 30 of first clinical trial.

^# before booster dose = Day 0 of second clinical trial.

95% CI for the proportion rate calculated using the exact binomial method

Immune response to booster vaccination

A separate study evaluated the comparative immunogenicity of a booster dose of MenQuadfi^® vaccine and a booster dose of MenACWY-DT vaccine in subjects aged 15 years and older who had previously been vaccinated with a quadrivalent meningococcal conjugate vaccine (MenACWY-CRM [11.3%] or MenACWY-DT [86.3%]) at the age of 4 to 10 years inclusive.

Baseline proportions of subjects with seroprotection (% of subjects with hSBA titer ≥1:8) and GMT were similar for serogroups A, C, W and Y.

Table 16. Comparison of bactericidal antibody levels on day 30 after booster vaccination with MenQuadfi^® and MenACWY-DT in subjects aged 15 years and older, previously vaccinated with MenACWY-CRM or MenACWY-DT vaccine at the age of 4 to 10 years inclusive

N – number of subjects included in the analysis of the per-protocol population who completed the study and had valid serology results.

95% CI for the proportion rate calculated using the exact binomial method.

* Achievement of non-inferiority criterion

Preclinical safety data

According to the results of a study of reproductive and ontogenetic toxicity in female rabbits obtained in preclinical safety studies, no specific risks for humans were identified.

When the MenQuadfi^® vaccine was administered to female rabbits (two standard human doses before conception and three doses during pregnancy), no effect on mating ability, female fertility, or potential teratogenic effects or effects on prenatal and postnatal fetal development were found.

Pharmacokinetics

Pharmacokinetic studies have not been conducted.

Indications

• Primary vaccination and revaccination for the prevention of invasive forms of meningococcal infection caused by Neisseria meningitidis serogroups A, C, W and Y, in persons aged 6 weeks and older.

ICD codes

Dosage Regimen

For vaccination, one dose of 0.5 ml is administered.

Children

The safety and efficacy of the MenQuadfi^® vaccine have been established in persons aged 6 weeks to 17 years. Data from a number of studies indicate that the MenQuadfi^® vaccine can be administered to preterm infants.

The safety of the MenQuadfi^® vaccine was assessed in 237 preterm infants: no differences in adverse reactions after administration of the MenQuadfi^® vaccine between preterm infants and full-term infants were found (see section “Adverse Reactions”.). In addition, the immune response to the MenQuadfi^® vaccine, assessed in 61-71 preterm infants, was comparable to that in full-term infants (see section “Pharmacological Action”).

Preterm infants whose clinical condition is satisfactory should be immunized with full doses of the vaccine at the same chronological age and according to the same schedule as full-term infants, regardless of birth weight.

Method of administration

The vaccine is administered intramuscularly only.

Recommended injection sites: deltoid muscle area, or anterolateral thigh depending on age and presence of sufficient muscle mass.

Intramuscular injections in children under 12 months of age are given only in the upper outer (anterolateral) surface of the middle part of the thigh.

Special precautions for the destruction of used medicinal product or waste generated after the use of the medicinal product, and other manipulations with the product

Before use, the vial with the vaccine should be visually inspected for the presence of foreign particles and/or abnormal coloration. In any of these cases, the vaccine should not be used.

The flip-off plastic cap should be removed, and using a suitable syringe and needle, 0.5 ml of solution should be withdrawn, ensuring the absence of air bubbles before administration.

All remaining medicinal product and waste should be destroyed in accordance with established procedures.

The method of administration is given above.

Adverse Reactions

The safety of the MenQuadfi^® vaccine in persons starting vaccination at the age of 6 weeks to 12 months was evaluated in 6 studies in which participants received at least one dose of MenQuadfi^® vaccine simultaneously with vaccines for routine childhood immunization (N = 6060) or simultaneously with MenB vaccine (N = 314). Vaccines for routine childhood immunization included the following vaccines: DTaP-IPV/Hib, or DTaP-IPV-HepB, or DTaP-IPV-HepB-Hib, or DTaP-IPV-HepB/Hib; Hib vaccine; PCV13 or PCV10; rotavirus vaccine; hepatitis B vaccine; measles vaccine; measles, mumps and rubella (MMR) vaccine; varicella (chickenpox) vaccine; hepatitis A vaccine.

These studies evaluated the safety of primary vaccination consisting of 1, 2 or 3 doses of MenQuadfi^® vaccine in the first year of life followed by a booster dose in the second year of life (at the age of 12 months and older).

The most frequent adverse reactions within 7 days after immunization with MenQuadfi^® vaccine in children aged 6 weeks to 12 months were irritability (74.6%) and injection site pain (64.6%). These adverse reactions were mostly mild or moderate in severity.

Two studies also included 222 preterm infants (gestational age less than 37 weeks) who received at least one dose of MenQuadfi^® vaccine. No differences in the frequency and severity of solicited adverse reactions after any vaccination between preterm infants and full-term infants were found.

The safety of a single dose of MenQuadfi^® vaccine was evaluated in persons aged 12 months and older in seven randomized, multicenter, pivotal clinical trials with active control. In these studies, 6308 participants were included in the safety analysis, receiving either primary immunization (n=5 906) or a booster dose (n=402) of MenQuadfi^® vaccine. The age composition of the 6308 participants was as follows: 1389 children in the 2nd year of life (from 12 to 23 months inclusive), 498 children aged 2 to 9 years inclusive, 2289 children and adolescents aged 10 to 17 years inclusive, 1684 persons aged 18 to 55 years inclusive, 199 persons aged 56 to 64 years inclusive, and 249 elderly persons aged 65 years and older. Of these, 392 children and adolescents aged 10 to 17 years inclusive were immunized with MenQuadfi^® vaccine together with Tdap and HPV vaccines, and 589 children aged 12 to 23 months inclusive received MenQuadfi^® vaccine together with MMR+V (n=189), DTaP-IPV-HepB-Hib (n=200) or PCV-13 (n=200) vaccines.

The most frequently reported adverse reactions within 7 days after immunization with a single dose of MenQuadfi^® without co-administration with other vaccines in children in the second year of life were irritability (36.7%) and injection site tenderness (30.6%), and in persons aged 2 years and older – injection site pain (38.7%) and myalgia (30.5%). These adverse reactions were mostly mild to moderate in intensity.

The incidence of adverse reactions following a booster dose of MenQuadfi^® in adolescents and adults aged 15 years and older was comparable to that observed in adolescents and adults primarily immunized with MenQuadfi^®.

No difference was identified in adverse reactions when MenQuadfi^® was administered concomitantly with routine pediatric vaccines compared to the administration of other meningococcal vaccines in children aged 6 to 12 months.

In children aged 12 to 23 months, the incidence of adverse reactions observed within 7 days after administration of MMR+V vaccines with or without MenQuadfi^® was comparable to that after administration of DTaP-IPV-HepB-Hib vaccine with or without MenQuadfi^®. The overall incidence of adverse reactions in children aged 12 to 23 months who received PCV-13 concomitantly with MenQuadfi^® was higher (36.5%) than in children who received only PCV-13 (17.2%).

Children and adolescents aged 10 to 17 years received either MenQuadfi^® alone (N=171) or MenQuadfi^® concomitantly with Tdap-IPV and the first dose of 9vHPV (N=116). The most frequently reported local adverse reaction was injection site pain, which was reported more frequently when MenQuadfi^® was co-administered with Tdap-IPV and 9vHPV vaccines (83.6%) than when MenQuadfi^® was administered alone (67.3%). Overall, the frequency and intensity of adverse events were comparable between the two groups.

As part of a clinical study, the safety of a booster dose of MenQuadfi^® administered alone or concomitantly with a vaccine for the prevention of meningococcal disease caused by Neisseria meningitidis serogroup B (MenB recombinant (rDNA) subunit adsorbed) was evaluated in children aged 12-13 months who had previously received a dose of MenQuadfi^® at 3 months or a dose of MenB vaccine at 2 and 4 months.

The most frequent injection site reaction after any administration of MenQuadfi^®, both when co-administered with MenB recombinant (rDNA) subunit adsorbed and when administered alone, was redness. Participants who received MenQuadfi^® concomitantly with MenB recombinant (rDNA) subunit adsorbed had a higher incidence of MenQuadfi^® injection site tenderness compared to those who received it alone.

Following administration of MenB recombinant (rDNA) subunit adsorbed, higher rates of injection site swelling were observed in participants who received it alone or concomitantly with MenQuadfi^® compared to those who received only MenQuadfi^®.

The most frequent systemic reaction after any administration of MenQuadfi^®, both when co-administered with MenB recombinant (rDNA) subunit adsorbed and when administered alone, was irritability. Unusual crying and drowsiness were observed more frequently in children who received MenB recombinant (rDNA) subunit adsorbed alone or concomitantly with MenQuadfi^® compared to participants who received only MenQuadfi^®.

As part of an additional clinical study, adolescents and adults aged 13 to 26 years, 3-6 years after primary immunization with MenQuadfi^®, received MenQuadfi^® concomitantly with a vaccine for the prevention of meningococcal disease caused by Neisseria meningitidis serogroup B (MenB recombinant adsorbed or recombinant (rDNA) subunit adsorbed).

The incidence of systemic adverse reactions within 7 days after vaccination was generally higher when MenQuadfi^® was co-administered with MenB recombinant adsorbed or recombinant (rDNA) subunit adsorbed than when MenQuadfi^® was used alone.

The most frequently reported adverse reaction was mild myalgia, which was observed more frequently in adolescents and adults who received MenQuadfi^® and MenB vaccines simultaneously than in those who received only MenQuadfi^®.

The most frequently reported local adverse reaction was injection site pain, which was reported more frequently when MenQuadfi^® was co-administered with MenB vaccines than when MenQuadfi^® was administered alone.

Below are summary data on the frequency of adverse reactions reported after vaccination with MenQuadfi^® in various groups of individuals.

The adverse reactions listed below are categorized according to the following frequency definitions: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Frequency not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 17. Frequency of adverse reactions following administration of any dose of MenQuadfi^® in children initiating vaccination at the age of 6 weeks to 12 months concomitantly with routine pediatric vaccination

* Observed at a frequency of < 0.1% in 1 child aged 12 to 18 months.

** Observed at a frequency of < 0.1% in 3 or more children who experienced the event.

***Petechiae occurred at a frequency of < 0.1% in 1 child during the period from 6 weeks to less than 12 months.

Table 18. Frequency of adverse reactions in children aged 12 to 23 months inclusive

Table 19. Frequency of adverse reactions in individuals aged 2 years and older without co-administration with other vaccines, observed after administration of MenQuadfi^®

Children and adolescents

The safety profile of MenQuadfi^® in children and adolescents aged 2 to 17 years inclusive is generally comparable to that in adults. Redness and swelling at the injection site were reported more frequently in children aged 2 to 9 years inclusive (category ‘Very common’) than in older age groups.

When co-administered with routine pediatric vaccines, the safety profile of MenQuadfi^® when used as a booster dose in the second year of life was similar to its safety profile in children aged 6 weeks to 12 months. Adverse reactions were generally comparable after administration of MenQuadfi^® to children aged 12 to 23 months as a booster dose or as a single dose for primary immunization.

In children in the second year of life, injection site redness and swelling (category ‘Very common’), vomiting (category ‘Common’), and diarrhea (category ‘Common’) were reported more frequently than in older age groups. Table 13 lists adverse reactions with a frequency of ‘Very common’ or ‘Common’ that were also observed in clinical studies in children in the second year of life after vaccination with MenQuadfi^®.

Individuals aged 56 years and older

Overall, within 7 days after immunization with a single dose of MenQuadfi^®, individuals aged 56 years and older experienced the same general disorders and administration site reactions as adults aged 18 to 55 years inclusive, but with a lower frequency, except for injection site pruritus, which was observed more frequently (category ‘Common’) in individuals aged 56 years and older. These adverse reactions were mostly mild to moderate in intensity.

Post-marketing data

Frequency not known: hypersensitivity reactions, including anaphylactic reactions, seizures with or without fever.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after authorization of the medicinal product to ensure continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to the active substances, to any of the excipients of the vaccine, or a severe allergic reaction following previous administration of this vaccine or a vaccine containing the same components;
• As with other vaccines, administration of MenQuadfi^® to persons with acute severe febrile illnesses should be postponed until recovery.

Use in Pregnancy and Lactation

Pregnancy

Data on the use of MenQuadfi^® in pregnant women are limited.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

MenQuadfi^® should be used during pregnancy only if the expected benefit of vaccination for the pregnant woman outweighs the potential risks, including those to the fetus.

Breast-feeding

Data on the possible passage of MenQuadfi^® components into breast milk are not available. MenQuadfi^® should be used during breast-feeding if the expected benefit of vaccination for the pregnant woman outweighs the potential risks.

Fertility

In a conducted study of reproductive toxicity and the effect of MenQuadfi^® on fetal development in rabbits, no data were obtained on the negative effect of the vaccine on female fertility or their ability to mate. Studies on the effect of the vaccine on male rabbit fertility have not been conducted.

Pediatric Use

MenQuadfi^® is used in children from the age of 6 weeks.

Geriatric Use

Overall, within 7 days after immunization with a single dose of MenQuadfi^®, individuals aged 56 years and older experienced the same general disorders and administration site reactions as adults aged 18 to 55 years inclusive, but with a lower frequency, except for injection site pruritus, which was observed more frequently (category ‘Common’) in individuals aged 56 years and older. These adverse reactions were mostly mild to moderate in intensity.

Special Precautions

MenQuadfi^® must not be administered subcutaneously, intravascularly, or intradermally.

Prior to vaccination, medical history (especially regarding previous vaccination and possible occurrence of adverse reactions) should be reviewed and a clinical examination performed.

Hypersensitivity

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.

Syncope

Syncope (fainting) and other psychogenic reactions related to stress in response to the injection procedure can occur following, or even before, any vaccination. Measures should be taken to prevent fainting and injury from falling due to loss of consciousness.

Thrombocytopenia and bleeding disorders

MenQuadfi^® should be administered with caution to individuals with thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injection, unless the potential benefit outweighs the risk of complications from vaccine administration.

Protection against infectious diseases

MenQuadfi^® is intended to provide protection against infection caused by Neisseria meningitidis serogroups A, C, W, and Y. This vaccine does not provide protection against infection caused by other serogroups of Neisseria meningitidis.

As with other vaccines, a protective immune response may not be elicited in all vaccinated individuals.

Immunodeficiency

In patients receiving immunosuppressive therapy or in patients with immunodeficiencies, the immune response following vaccination with MenQuadfi^® may be reduced (see section “Drug Interactions”).

Patients with hereditary complement deficiency (e.g., deficiency of C5 or C3 components), as well as patients receiving drugs that inhibit the activation of terminal complement components (e.g., eculizumab), are at increased risk of developing invasive forms of infection caused by Neisseria meningitidis serogroups A, C, W, and Y, even if they develop antibodies as a result of vaccination with MenQuadfi^®. Data in immunocompromised patients are not available.

Tetanus immunization

Despite the content of tetanus toxoid in the vaccine, immunization with MenQuadfi^® does not replace routine tetanus vaccination.

Concomitant administration of MenQuadfi^® and a vaccine containing tetanus toxoid does not reduce the immune response to tetanus toxoid and does not affect safety.

Effect on ability to drive and use machines

MenQuadfi^® has no or negligible influence on the ability to drive and use machines.

However, some adverse reactions may temporarily affect the ability to drive or use machines.

Overdose

Overdose is unlikely considering the vaccine presentation in a single-dose vial. In case of overdose, monitoring of vital functions is recommended, and symptomatic treatment may be considered.

Drug Interactions

MenQuadfi^® must not be mixed with any other vaccine in the same vial.

In case of concomitant administration, the products should be administered at different injection sites, preferably contralaterally, using separate syringes.

Clinical studies in children aged 6 weeks to 23 months inclusive have confirmed the possibility of concomitant administration of MenQuadfi^® with the following vaccines: measles, mumps, and rubella (MMR) vaccine; varicella (V) vaccine; diphtheria, tetanus, pertussis (acellular component) (DTaP) vaccine, including combinations with hepatitis B (HepB) vaccine, inactivated poliovirus (IPV) vaccine, or Haemophilus influenzae type b (Hib) vaccine (i.e., for example, with such vaccines as DTaP-IPV-HepB-Hib or DTaP-IPV/Hib); concomitantly with 13-valent pneumococcal polysaccharide conjugate vaccine (PCV-13) and rotavirus vaccine.

No effect on the immune response was observed when MenQuadfi^® was administered concomitantly with a vaccine for the prevention of meningococcal disease caused by serogroup B (MenB).

Clinical studies in children and adolescents aged 10 to 17 years inclusive have confirmed the possibility of concomitant administration of MenQuadfi^® with diphtheria (reduced antigen content), tetanus, pertussis (acellular, reduced antigen content) vaccine, adsorbed (Tdap) or Tdap-IPV, as well as quadrivalent human papillomavirus recombinant vaccine, adsorbed (HPV) or nine-valent human papillomavirus (9vHPV) vaccine. However, concomitant administration of these vaccines may affect the immune response to some of the antigens.

In clinical studies involving children and adolescents aged 10 to 17 years inclusive, who had not been previously vaccinated against meningococcal infection, the co-administration of the DTaP vaccine with the MenQuadfi^® vaccine and for HPV prevention resulted in an immune response to pertussis toxoid (PT) that was non-inferior in effectiveness, and lower antibody titers to filamentous hemagglutinin (FHA), pertactin (PRN), and fimbrial agglutinogens (FIM) compared to the co-administration of the DTP vaccine and for HPV prevention (the immune response was assessed after the full completion of HPV vaccination). The clinical consequences of the immune response to pertussis toxoid, which are also observed as a result of co-administration with other quadrivalent meningococcal conjugate vaccines, are unknown.

A clinical study evaluated the humoral response to a booster dose of MenQuadfi^® when administered alone or simultaneously with vaccines for the prevention of meningococcal disease caused by Neisseria meningitidis serogroup B (MenB recombinant adsorbed or recombinant (rDNA) subunit adsorbed), in adolescents and adults aged 13 to 26 years who had received the primary immunization series with MenQuadfi^® 3-6 years earlier. Co-administration of the MenQuadfi^® vaccine and MenB vaccines showed no effect on the immune response against serogroups A, C, Y, and W.

The simultaneous administration of the MenQuadfi^® vaccine and other vaccines not listed above has not been studied. In accordance with national recommendations, the simultaneous administration of an unlimited number of vaccines (except for BCG) using different syringes and in different anatomical areas of the body is permitted. Administration of vaccines within the same calendar day is considered simultaneous.

If separate administration (not on the same calendar day) of the MenQuadfi^® vaccine and other vaccines is necessary, any interval between administrations is acceptable, since the MenQuadfi^® vaccine is inactivated.

Concomitant use with immunosuppressive drugs

In patients receiving immunosuppressive therapy, the immune response following vaccination may be reduced.

Incompatibility

In the absence of compatibility study results, the MenQuadfi^® vaccine should not be mixed with other medicinal products in the same syringe.

Storage Conditions

The drug should be stored out of the reach of children, in a refrigerator (at a temperature from 2°C (35.6°F) to 8°C (46.4°F)). Do not freeze.

Shelf Life

The shelf life is 48 months.

The chemical and physical stability of the vaccine has been confirmed following a single temperature excursion up to 25°C (77°F) for 72 hours.

Dispensing Status

The vaccine is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.