Vivotif
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Vivotif®
2 QUALITATIVE AND QUALITATIVE COMPOSITION
The composition in terms of active ingredients is as follows:
- Salmonella enterica serovar Typhi (abbr. S. Typhi) Ty21a not less than 2 x 109 viable cells
Quantities expressed per capsule.
3 PHARMACEUTICAL FORM
Enteric-coated capsule, for oral administration to humans.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
For active oral immunisation against typhoid fever in children aged 6 years and over, adults and elderly.
4.2 Posology and method of administration
Posology
Children aged 6 years and above, adults and elderly: One capsule is to be taken on day 1. The second capsule should be taken on day 3 and the third capsule on day 5.
Unless the immunisation schedule of 3 vaccine capsules is completed, an optimal immune response may not be achieved.
Even after three doses, not all recipients of Vivotif will be fully protected against typhoid fever. Therefore, travellers should take all necessary precautions to avoid contact with or ingestion of potentially contaminated food or water.
Protection against typhoid fever commences approximately 7-10 days after ingesting the third dose of vaccine.
Under conditions of repeated or continuous exposure to S. Typhi protection persists for at least 3 years.
In the case of travel from a non-endemic area to an area where typhoid fever is endemic, an annual booster consisting of three doses is recommended.
Children under 6years: Safety and efficacy have not been established in children under 6 years of age.
Method of administration
The blister containing the vaccine capsules should be inspected to ensure that the foil seal and capsules are intact.
The capsule should be taken approximately one hour before a meal with a cold or lukewarm (temperature not to exceed body temperature, e.g. 37°C [98.6°F]) drink on alternate days, e.g. days 1, 3 and 5. The vaccine capsule should not be chewed and should be swallowed as soon as possible after placing in the mouth.
4.3 Contraindications
Vivotif must not be administered:
- To persons known to be hypersensitive to any component of the vaccine or the enteric-coated capsule (see section 6.1).
- To persons with congenital or acquired immune deficiency (including patients receiving immunosuppressive or antimitotic drugs).
- During an acute febrile illness or during an acute gastrointestinal illness. Vaccination should be postponed until after recovery.
4.4 Special warnings and precautions for use
None known
4.5 Interaction with other medicinal products and other forms of interaction
The vaccination with Vivotif should be avoided during and for at least three days before and after antibiotic or sulphonamide treatment, due to possible inhibition of the growth of the vaccine organisms and potential attenuation of the immune response.
Combination with malaria prophylaxis
Limited data are available regarding the concomitant use of anti-malaria prophylaxis (For more detailed information see section 5.1). If prophylaxis with antimalarials is planned, it is recommended to complete first the Vivotif vaccination and then start the malaria prophylaxis after an interval of at least three days between the last Vivotif dose and the start of malaria prophylaxis.
Vivotif may be administered concomitantly with live attenuated parenteral vaccines and oral polio vaccine.
4.6 Fertility, pregnancy and lactation
Animal reproduction studies have not been conducted with Vivotif. It is not known whether Vivotif can cause foetal harm when administered to pregnant women or can affect reproduction capacity. The Vivotif capsule coating contains dibutyl phthalate (DBP), which at high doses was shown to have reproductive and developmental toxicity in animals (see preclinical safety data). Vivotif should be given to a pregnant woman only if clearly needed.
There are no data regarding administration of Vivotif to nursing mothers. It is not known if Vivotif is excreted in human milk. It is also not known to which extent the inactive ingredient DBP may be excreted with breast-milk. Vivotif should be administered during lactation only if clearly needed.
4.7 Effects on ability to drive and use machines
None known.
4.8 Undesirable effects
The following adverse reactions were reported commonly (<1/10 but >1/100) in clinical studies:
Gastrointestinal disorders
Abdominal pain, nausea, diarrhoea, vomiting
General disorders and administration site conditions Fever, influenza-like illness
Nervous system disorders Headache
Skin and subcutaneous tissue disorders Rash
The following additional adverse reactions have been reported very rarely (approximately <1/10,000) during post-marketing surveillance:
Skin reactions such as dermatitis, exanthema, pruritus, urticaria.
Anaphylaxis.
Asthenia, malaise, tiredness, shivering, influenza-like illness Paraesthesiae, dizziness.
Arthralgia, myalgia, back pain
Decreased appetite, flatulence, abdominal distension
4.9 Overdose
Doses five-fold higher than the recommended dose do not produce vomiting, abdominal distress or fever. However overdosing can increase the possibility of shedding the S. Typhi Ty21a organisms in the faeces. An optimal immune response cannot be guaranteed in case several capsules are taken at the same time.
5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties
As a result of irreversible changes in cell wall biosynthesis, the Ty21a strain is devoid of pathogenicity but is able to elicit an immune response against S. Typhi.
Excretion of the vaccine strain after administering doses approximately 50 times greater than those in the present vaccine was assessed by taking stool or rectal swabs daily for 7 days following the last dose of vaccine. The rate of excretion of the vaccine strain in the stools was low, and the vaccine strain could not be recovered from small bowel aspirates one or more days after vaccination. Sera for determination of antibodies to O, H and Vi antigens were obtained prior to vaccination and biweekly for 8 weeks. Fourfold or greater responses in titre of O antibody only were observed. There was no correlation between faecal excretion of the strain Ty21a organisms and seroconversion with respect to titre of any of the antibodies tested.
The interference between malarial prophylaxis and Vivotif has been investigated in several clinical studies and has revealed the following effects:
Chloroquine:
In a study with 21 subjects, chloroquine administered in alternate days (evening of days 0, 2,
4, 6, etc...) with Vivotif (morning of days 1, 3, 5; dose: 1 x 109 CFU) did not impair the immune response to Vivotif. In another study with 30 subjects, concomitant administration of chloroquine (prophylactic dose, 250 mg, weekly) with Vivotif (given as liquid formulation; dose: 5 x 109 CFU first dose concomitant with CVD103-HgR (cholera vaccine (live, oral))) did not impair the immune response to Vivotif.
Mefloquine:
Mefloquine (prophylactic dose, 250 mg) administered the day before the first dose of Vivotif (12 hour before Vivotif) inhibited the multiplication of the vaccine strain.
Concomitant administration of mefloquine at prophylactic doses and schedule (250 mg weekly) with Vivotif (as liquid formulation; first dose concomitant with CVD103-HgR (cholera vaccine (live, oral))) did not exert a significant negative effect on the combined serum anti-S. Typhi IgG or IgA antibody response. However, the IgG response was somewhat lower in the group that received mefloquine.
The two studies have differences in design (e.g. different interval between mefloquine and Vivotif administration with oral live attenuated cholera vaccine) that could partially explain the different conclusions. However, taken together the data do not exclude the potential influence of mefloquine on the immune response after vaccination with Vivotif.
Proguanil:
In a study with 30 subjects, concomitant daily administration of proguanil (200 mg daily) with Vivotif (as liquid formulation; dose: 5 x 109 CFU; first dose concomitant with CVD103-HgR (cholera vaccine (live, oral))) affects the immune response to Vivotif.
Pyrimethamine/Sulfadoxin:
In a study with 21 subjects, antecedent administration (evening, day 0) of pyrimethamine/sulfadoxin did not impair the immune response to vaccination with Vivotif (morning of days 1, 3, 5; dose: 1 x 109 CFU).
Atovaquone/proguanil:
In a study with 165 subjects, the combination atovaquone/proguanil (daily doses depending on body weight of the subjects: 62.5 mg/25 mg; 125 mg/ 50 mg and 187.5 mg/75 mg) did not interfere with the immunogenicity of Vivotif (as liquid formulation; dose: 5 x 109 CFU).
5.2 Pharmacokinetic properties
Not applicable.
5.3 Preclinical safety data
In experimental animal studies, dibutyl phthalate (DBP) in high doses had an influence on the reproductive system and development such as testicular development, decreased anogenital distance as a sign of feminisation in male offspring and the weight of the offspring.
The Vivotif capsule coating contains a maximum of 8 mg of DBP, which exceeds the Permitted Daily Exposure (PDE) of 0.01 mg/kg/day for children and for adults. However, the risks related to exposure with DBP are outweighed by the benefits of protection from typhoid fever.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
The excipients contained in the preparation are as follows:
Sucrose (Saccharose) Ph. Eur Ascorbic acid (E300) Ph. Eur Casein hydrolysate HSE
(Hy-Case SF Sheffield)
Lactose anhydrous NF/USP, Ph. Eur
Magnesium stearate (E470) Ph. Eur.
Inactivated S. typhi Ty21a bacteria HSE
Capsule:
Gelatin
Titanium dioxide (white) (E171)
Titanium dioxide (red) (E171)
Erythrosine red No.3 (E127)
Ferric oxide (yellow) (E172)
Ferric oxide (red) (E172)
Capsule coating:
HydroxypropyImethyl-cellulose- phthalate
(HP-MCP) - 50
Ethylene glycol
Dibutyl phthalate
Diethyl phthalate
6.2 Incompatibilities
None known.
6.3 Shelf life
In blister packs: 18 months from date of packing, unopened, at 2-8°C. After opening blister: not applicable.
6.4 Special precautions for storage
Store at 2-8°C. Protect from light
6.5 Nature and contents of container
Blister packs (PVC/PE/PVDC 250/30/90). Each blister pack contains 3 capsules.
6.6 Special precautions for disposal
No special instructions.
7 MARKETING AUTHORISATION HOLDER
PaxVax Ltd.
1 Victoria Square Birmingham B1 1BD UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 43552/0002
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
23/06/2009
10 DATE OF REVISION OF THE TEXT
03/10/2016