РотаТек®

General characteristics. Structure:

Active ingredient: live reassortant of human and bull rotaviruses: not less than 2.2×106 IE * reassortant of G1, not less than 2.8×106 IE * reassortant of G2, not less than 2.2×106 IE * reassortant of G3, not less than 2×106 IE * reassortant of G4, not less than 2.3×106 IE * reassortant of P1A[8].

Excipients: sucrose, sodium hydroxide, citrate sodium a dihydrate, dihydrophosphate sodium a dihydrate, polysorbate 80, culture medium - 15% (in the volume relation).

Pharmacological properties:

Pharmacodynamics. The live peroral pentavalent vaccine containing five live reassortantny strains of a rotavirus (bull and human). On a surface of four vaccinal reassortant of a rotavirus one of outside VP7 core proteins (serotypes of G1, G2, G3, or G4) of a human parent strain of a rotavirus and protein VP4 (P7[5] serotype) of a bull parent strain of a rotavirus are expressed (protein VP4 is responsible for a rotavirus attachment to a surface of cells). On a surface of the fifth reassortant of a virus protein VP4 (P1A[8] serotype) of a human parent strain of a rotavirus and outside VP7 core protein (G6 serotype) of a bull parent strain of a rotavirus is expressed.

Each of reassortant is grown up separately on culture of cells of Vero by standard cultural methods without use of antifungal drugs and cleared, and then reassortant everything are together placed in the buffered stabilizing solution.

In the intertwined cellular line of Vero and at all stages of receiving a vaccine there is no contamination by foreign agents, including tsirkovirusa of pigs.

^{The vaccine Rotatek®} does not contain tiomersat also other preservatives.

In a moderate climatic zone the rotavirusny gastroenteritis is a seasonal disease with increase in incidence (epidemics) in winter months. In the absence of treatment the rotavirusny gastroenteritis can lead to lethal dehydration.

Efficiency. According to clinical trials immunological efficacy ^{of Rotatek®} was shown concerning the gastroenteritis caused by rotaviruses of genotypes of G1P[8], G2P [4], G3P [8], G4P [8] and G9P [8].

Immunological efficacy ^{of Rotatek®} was studied in 2 parameters in placebo - a controlled research of efficiency and safety (REST).

1. At 5673 vaccinated children (2834 children) efficiency was measured in group of a vaccine as reduction of number of cases of the rotavirusny gastroenteritis caused by G genotypes entering a vaccine (G1-G4) which developed after 14 days after receiving the third dose of a vaccine and throughout the first full rotavirusny season after vaccination.

2. At 68038 vaccinated children (34035 children) efficiency of protection was measured in group of a vaccine as reduction of number of cases of hospitalization and requests for acute management concerning a rotavirusny gastroenteritis, since 14 in the afternoon after receiving the third dose of a vaccine.

Results of these researches are presented in tables:

* Heavy degree was determined as result "more than 16 of 24" by the validirovanny clinical system of calculation based on intensity and duration of symptoms (fever, vomiting, diarrhea, changes of behavior).
** Statistically significantly

* Statistically significantly

Reduction of number of cases of the rotavirusny gastroenteritis caused by G1-G4 genotypes during the second rotavirusny season after vaccination made 88% [95% of DI: 49.4; 98.7] for heavy degree of a disease and 62.6% [95% of DI: 44.3; 75.4] for a disease of any severity.

Efficiency against a rotavirus of genotypes G 2 P [4], G 3 P [8], G 4 P [8] and G 9 P [8] was calculated for smaller number of cases, than for G1. Efficiency against G2P[4] genotypes most likely is connected with existence of a reassortant of G2 as a part of a vaccine.

In the combined analysis of the research REST and other research of a phase 3 immunological efficacy against the rotavirusny gastroenteritis (any severity) caused by G1-, G2-, G3-and G4 serotypes made 61.5% [95% of DI: 14.2; 84.2] among the children who received the third dose of drug aged from 26 to 32 (inclusive) of weeks.

In Finland the expanded research (FES) in which during up to 3 years after vaccination observed group of 20736 children who were earlier participating in the research REST was conducted.

In the research REST it was reported about 403 cases of the rotavirusny gastroenteritis connected with genotypes of G1-G4 and G9 (20 cases in group of a vaccine and 383 in group of placebo). In the research FES 136 cases (9 in group of a vaccine and 127 in group of placebo) were noted in addition what made 31% and 25% respectively of the sum of cases for each group in the researches FES and REST.

On the basis of the integrated data of RESTI FES reduction of number of cases of hospitalization and requests for acute management concerning a rotavirusny gastroenteritis within 3 years after vaccination made 94.4% (95% of DI: 91.6; 96.2) for genotypes of G1-G4, 95.5% (95% of DI: 92.8; 97.2) for a genotype of G1, 81.9% (95% of DI: 16.1; 98) for a genotype of G2, 89. % (95% of DI: 53., 3; 98,7) for a genotype of G3, 83,4% (95% of DI: 51,2; 95,8) for G4 genotype, and 94,2% (95% of DI: 62,2; 99,9) for G9 genotype. Within the third year in group of a vaccine (3112 children) of requests for medical care concerning a rotavirusny gastroenteritis it was not recorded, and in group of placebo (3126 children) only 1 (not typed) case was noted.

In clinical trials it was confirmed that it is necessary to conduct a full course of vaccination (3 doses) for achievement of necessary level and duration of protection against a rotavirusny gastroenteritis. However the analysis of data showed that even before end of a full course of vaccination the number of cases of a rotavirusny gastroenteritis with such severity which would demand hospitalization or an urgent call of the doctor decreased (after about 14 days after introduction of the first dose).

Efficiency at premature children. In the research REST ^{the vaccine Rotatek®} was entered to about 1000 children who were born at duration of gestation from 25 to 36 weeks. Immunological efficacy ^{of Rotatek®} at this subgroup did not differ from subgroup of the children who were born in time.

Post-registration observation research on safety. In a large prospective post-registration observation research the risk of invagination of intestines and a disease of Kawasaki at 85150 children, the received one or more doses ^{of the vaccine Rotatek®} (17433 patsiyento-years of observation) was analyzed. Within 0-30 days after introduction of a vaccine there was no statistically significant difference in the frequency of development of invagination of intestines or a disease of Kawasaki in comparison with frequency in the general population. Besides, there was no statistically significant difference among these side effects at observation within 30 days after introduction ^{of the vaccine Rotatek®} in comparison with control group of the children receiving AKDS (62617 children, 12399 patsiyento-years of observations). It was reported about 6 confirmed intestines invagination cases at the children receiving ^{the vaccine Rotatek®}, 5 cases - at the children receiving AKDS (relative risk 0.8; 95% of DI: 0.22; 3.52). One confirmed case of a disease of Kawasaki was reported at the children receiving ^{the vaccine Rotatek®}, one case - at the children receiving AKDS (relative risk 0.7; 95% of DI: 0.01; 55, 56). Thus, any additional risk connected with safety, rather general profile of safety was not recorded.

Data of researches on efficiency at the level of population. In a post-registration observation research in the USA population immunological efficacy ^{of Rotatek®} concerning reduction of number of cases of hospitalization and requests for acute management concerning a rotavirusny gastroenteritis was studied, using the national database. According to this research cases of the request for the health insurance without active involvement of observed children were estimated, data were not collected directly at parents or children. Cases of a rotavirusny gastroenteritis identified, using special diagnostic codes. These 33140 children, vaccinated by 3 doses ^{of the drug Rotatek®}, and 26167 children vaccinated by AKDS were analyzed. Observation was made within 2 rotavirusny seasons, since the moment no later than 14 days after receiving the third dose or since the beginning of every season, and until the end of every season. Immunological efficacy against a gastroenteritis made 100% [95% of DI: 87; 100] for cases of hospitalization and urgent addresses to the doctor and 96% [95% of DI: 76; 100] for out-patient cases. Immunological efficacy (on number of hospitalization and requests for acute management) against a gastroenteritis of any etiology (rotavirusny or another) made 59% [95% of DI: 47; 68].

According to the observation research of children under 2 years in the northwest of France in which 4864 children who received at least one dose ^{of the vaccine Rotatek®} participated the full course of vaccination was received by 47,1% of children. From all children with symptoms of a gastroenteritis it was taken kcal for the analysis on the maintenance of a rotavirus. From 1895 children who received all 3 doses of a vaccine 1 child with the confirmed gastroenteritis case was hospitalized. Among 2102 not vaccinated children of such cases there were 47. Not corrected immunological efficacy ^{of Rotatek®} on prevention of hospitalization concerning a rotavirusny gastroenteritis among children up to 2 years made 98% [95% of DI: 83; 100].

Immunogenicity. The mechanism of a host defense of an organism up to the end is not studied ^{by the vaccine Rotatek®} from the gastroenteritis caused by rotaviruses. The interrelation between the maintenance of antibodies to rotaviruses after vaccination by rotavirusny vaccines and degree of protection against a rotavirusny gastroenteritis is not established. According to clinical trials of a phase 3 after carrying out the full course of vaccination consisting of three doses ^{of the drug Rotatek®}, at 92.5-100% vaccinated in serum substantial increase of level anti-ротавирусного IgA is observed. The vaccine causes an immune response, i.e. formation of serumal neutralized antibodies, to five core proteins of the rotaviruses of the person which are contained in reassortant of a vaccine (G1, G 2, G, 3, G 4 and R1A [8]).

Indications to use:

— active immunization of children aged from 6 up to 32 weeks for the purpose of prevention of the gastroenteritis caused by rotaviruses of serotypes of G1, G2, G3, G4 and serotypes of G containing P1A[8] (for example, G9).

Route of administration and doses:

The vaccine Rotatek® is accepted inside. It is not intended for injections.

Scheme of vaccination. The course of vaccination consists of three doses of the drug Rotatek® with an interval between introductions from 4 to 10 weeks.

The first dose of the drug Rotatek® is entered to children aged from 6 up to 12 weeks.

All three doses are recommended to be entered before achievement of 32 weeks by the child of age.

At introduction of an incomplete dose (for example, the child spat out or srygnut a part of a dose) it is not recommended to enter an additional dose as this mode of dosing was not studied in clinical trials. The remained doses should be entered according to the scheme of vaccination.

The vaccine Rotatek® can be applied at the premature children who were born at duration of gestation not less than 25 weeks. The vaccine should be entered to such children not earlier than in 6 weeks after the birth.

Rules of introduction of a vaccine. The vaccine Rotatek® represents liquid, ready to use. The vaccine can be applied regardless of meal or any liquid, including breast milk. The vaccine cannot be mixed with other solutions and vaccines in one capacity. The vaccine cannot be dissolved or parted. Not to use if external damages of a tuba are found and/or contents of a tuba look unusually.

Recommendations about preparation and performing vaccination. To take out one packaging from the refrigerator, to break off it and to get a plastic tuba. If the tuba with a vaccine is not placed in packaging from a foil, then it is necessary to begin with the second stage.

Holding a tuba vertically, a cap up, to knock on a cap to remove liquid from the dosing tip.

To puncture the dosing tip, having turned the screwing-up cap against the stop clockwise.

To turn a cap counterclockwise and to remove it.

To enter a dose, carefully squeezing out liquid in the child's mouth in the direction of the cheek interior until the tuba becomes empty (in a tip of a tuba there can be a liquid drop).

Features of use:

Use at pregnancy and feeding by a breast. The vaccine Rotatek® is intended only for the children given to pregnancy and/or during breastfeeding is not present.

Use for children. The vaccine Rotatek® is usually well transferred and has high performance on prevention of a rotavirusny gastroenteritis at use for children aged from 6 up to 32 weeks.

Efficiency and safety were not established at children aged 6 weeks are younger.

Special instructions. According to clinical trials the vaccinal virus was found in Calais in 8.9% of the vaccinated children only within 1 week after introduction of the first dose of a vaccine and only in 0.3% of children (1 case) after introduction of the 3rd dose. According to post-registration data transfer of a vaccinal virus to not vaccinated persons is possible. The vaccine Rotatek® has to be appointed with care to the children who are in close contact with people with an immunodeficiency (including with oncological diseases, immunokomprometirovanny or the people receiving immunosuppressive therapy). It is necessary to follow special hygienic rules at contact with a stake of the vaccinated child.

Data on efficiency and safety of use of the vaccine Rotatek® for children with komprometirovanny immunity, children with asymptomatic HIV infection or children to whom hemotransfusion was made or are entered immunoglobulins no more than in 42 days prior to introduction of a vaccine, no. It is improbable that asymptomatic HIV - the infection (HIV carriage) will influence safety and immunological efficacy of Rotatek®. Nevertheless, in connection with insufficiency of clinical data purpose of the vaccine Rotatek® at asymptomatic HIV infection is not recommended.

At children with heavy combined immunodeficience cases of the gastroenteritis caused by the rotavirus strains entering a vaccine were noted.

In clinical trial the vaccine Rotatek® was applied approximately at 1000 children born at the term of a gestation from 25 to 36 weeks, the first dose was entered on the 6th week after the birth. Immunological efficacy of Rotatek® at this subgroup did not differ from subgroup of the children who were born in time. However, among these there are 1000 children, 19 was born from 25 to 28 weeks of a gestation, 55-from 29 to 31 weeks in time, and the others - from 32 to 36 weeks.

According to clinical trials the risk of invagination of intestines in group of the patients receiving the vaccine Rotatek® was comparable to risk in group of placebo. However within 31 days after introduction of the first dose of the vaccine Rotatek® and, especially during the first 7 days, small increase in risk of emergence of invagination of intestines cannot be excluded. In this regard, it is necessary to watch closely for emergence of the symptoms characteristic of this disease: the acute pain in a stomach, pernicious vomiting, availability of blood in Calais, abdominal distention, fever, - and urgently to ask for medical care in case of their emergence.

The specified protection level after vaccination by the drug Rotatek® is provided at the complete course of vaccination consisting of 3 doses. As well as any other vaccine, Rotatek® cannot provide full protection of all vaccinated. The vaccine Rotatek® is effective only against a rotavirusny infection and does not protect from the gastroenteritis caused by other pathogenic microorganisms.

Clinical trials of efficiency of protection against a rotavirusny gastroenteritis were conducted in Europe, the USA, the countries of Latin America and Asia. During performing these clinical trials the most widespread genotype of a rotavirus was G1P[8] while other genotypes of G2P[4], G3P [8], G4P [8] and G9P [8] were found less often. Protection level which is provided by the vaccine Rotatek® against rotaviruses of other types and in other populations is unknown.

Data of clinical trials on use of the vaccine Rotatek® for prevention after contact with a sick rotavirusny gastroenteritis are absent.

At the decision on vaccination of the child with heavy degree of prematurity (pregnancy ≤28 weeks, but not less than 25 weeks) who especially have immaturity of a respiratory organs in the anamnesis it is necessary to consider the fact that the advantage of immunization against a rotavirusny infection at this group of patients is high, and it is not necessary neither to refuse vaccination, nor to postpone its date. However considering potential risk of an apnoea, it is preferable to do performing the first vaccination of the premature baby in the conditions of a hospital with an opportunity, medical observation of a condition of such patient during 48-72 h.

Since in production of the reassortant who are a part of the vaccine Rotatek® biological material of animal origin is used, in a vaccine small fragments of DNA of a tsirkovirus of pigs of 1 and 2 types (TsVS-1 and TsVS-2) are found, at the same time virus particles of TsVS-1 and/or TsVS-2 in a vaccine are absent. Ability of TsVS-1 and/or TsVS-2 to cause a disease in the person is not known.

РотаТек® it is necessary to enter as soon as possible after extraction from the refrigerator.

Drug can be used after withdrawal from the refrigerator during 48 h provided that it was stored at a temperature not above 25 °C. If packaging with a vaccine was not used during the specified time, it is subject to utilization.

Use in pediatrics. The vaccine Rotatek® is usually well transferred and has high performance on prevention of a rotavirusny gastroenteritis at use for children aged from 6 up to 32 weeks.

Efficiency and safety were not established at children aged 6 weeks are younger.

Influence on ability to driving of motor transport and to control of mechanisms. It is not applicable.

Side effects:

The vaccine is usually well transferred. At the children participating in three placebos - controlled clinical trials (6130 children in group of a vaccine, 5560 children in group of placebo), side effects of the drug Rotatek® within 42 days after vaccination with or without sharing of other vaccines for children were estimated. In general undesirable reactions were noted at 47% of the children receiving Rotatek® in comparison with 45.8% at group of placebo. A hyperthermia (temperature increase above 38 °C) (20.9%), diarrhea (17.6%) and vomiting (10.1%) were the most frequent undesirable phenomena.

Serious side reactions were estimated at all participants (36150 children in group of a vaccine, 35536 children in group of placebo) in 3 clinical trials within 42 days after reception of each dose. In general the frequency of serious undesirable reactions made 0.1% in group of a vaccine, 0.2% in group of placebo.

On the basis of the joint these 3 clinical trials (6130 children in troupe of a vaccine, 5560 children in group of placebo) undesirable reactions which frequency in group of a vaccine surpassed frequency in group of placebo for 0.2-2.5% are listed.

Determination of frequency of side reactions: very often (≥1/10), it is frequent ≥1/100, but <1/10), infrequently ≥1/1000, but <1/100), is rare ≥1/10 000, but <1/1000).

The side reactions allocated (*) were observed in the post-registration period, their frequency was established according to the corresponding clinical trials.

Infectious and parasitic diseases: often - upper respiratory tract infections; infrequently - a nasopharyngitis, average otitis.

From the alimentary system: very often - diarrhea, vomiting; infrequently - pain in upper parts of a stomach, a gematokheziya *; seldom - invagination кишечника*.

From skin and hypodermic fabrics: infrequently - rash; seldom - крапивница*.

From respiratory system: seldom - a bronchospasm.

General frustration: very often - a hyperthermia.

Additional information. The disease of Kawasaki was observed at 5 of 36150 children in group of a vaccine (<0.1%) and 1 of 35536 in group of placebo (<0.1%) with relative risk 4.9 [95%di:0.6; 239.1] (statistically it is not significant). Data of post-registration researches do not confirm increase in risk of developing of a disease of Kawasaki after vaccination with the drug Rotatek®.

The risk of invagination of intestines was estimated at placebo - a controlled research. At observation within 42 days after introduction of each dose 6 cases of invagination of intestines in the group receiving the vaccine Rotatek® (34 837 patients) and 5 cases in group of placebo (34 788 patients) were noted. Dependence of development of invagination of intestines on time after introduction of any of doses was not noted.

Data of post-registration researches do not confirm increase in risk of emergence of invagination of intestines after vaccination with the drug Rotatek®.

Special groups of patients. At children with heavy combined immunodeficience cases of the gastroenteritis caused by the rotavirus strains entering a vaccine were noted. There is a risk of development of an apnoea in the premature children (born on duration of gestation up to 28 weeks inclusive).

Interaction with other medicines:

Children can enter the vaccine Rotatek® along with any following antigens which are a part both the monovalent, and combined vaccines: a diphtherial anatoxin, tetanic anatoxin, the acellular pertussoid vaccine conjugated by a vaccine against Haemophilus influenzae type b inactivated by the poliomyelitic vaccine, a vaccine against a hepatitis B virus, the hexavalent vaccine (containing above-mentioned components), conjugated by a pneumococcal vaccine, a meningococcal vaccine of a serogroup of Page. Decrease in development of protective antibodys at simultaneous introduction of several vaccines and the vaccines Rotatek® was not noted.

Simultaneous introduction of a peroral poliovaktsina (OPV) and the vaccine Rotatek® did not influence the immune response caused by OPV, but reduced an immune response on Rotatek a little, however there are no data confirming decrease in degree of protection against severe forms of a rotavirusny gastroenteritis. The immune response on the vaccine Rotatek®ne changed at introduction of OPV in two weeks after introduction of the vaccine Rotatek®.

Contraindications:

— intestines invagination in the anamnesis;

— the inborn malformations of digestive tract contributing to intestines invagination;

— an immunodeficiency, suspicion on an immunodeficiency or a HIV carriage;

— the acute inflammatory processes which are followed by high temperature (in these cases vaccination is carried out after recovery or to remission stages). The infectious disease of easy severity should not serve as a cause of failure from vaccination;

— an acute form of diarrhea or vomiting (in these cases vaccination is carried out at a remission stage);

— intolerance of fructose, disturbance of absorption of a glyukozo-galaktozny complex, insufficiency of enzymes of invertase and (or) isomaltase;

— hypersensitivity to any component of the vaccine Rotatek®, and also on introduction of the vaccine Rotatek® in the anamnesis.

With care:

— at active gastrointestinal diseases, including chronic
diarrhea (lack of clinical data);

— at an arrest of development (lack of clinical data);

— at an immunokomprometirovanny state (for example, as a result of malignant new growths or immunodepressive therapy);

— at a transfusion of blood or products of blood, including immunoglobulins, less than in 42 days prior to the planned vaccination.

Overdose:

Several cases of overdose by the vaccine Rotatek® are known. There are no differences in a profile of the undesirable phenomena in comparison with use of drug in the recommended doses.

Storage conditions:

Drug should be stored in the unavailable to children, protected from light place at a temperature from 2 °C to 8 °C. A period of validity - 2 years.

Issue conditions:

According to the recipe

Packaging:

2 ml - tubas from polyethylene of low density of 4 ml (1) - packs cardboard
2 ml - tubas from polyethylene of low density of 4 ml (10) - packs cardboard.
2 ml - tubas from polyethylene of low density of 4 ml (1) - packagings individual of aluminum foil (1) - packs cardboard.
2 ml - tubas from polyethylene of low density of 4 ml (1) - packagings individual of aluminum foil (10) - packs cardboard.