DUKORAL suspension and effervescent granules for oral suspension

Cholera vaccine (inactivated, oral)

Each dose of vaccine suspension (3 ml) contains:

− A total of 1x10¹¹ bacteria of the following strains:

− Recombinant cholera toxin B subunit (rCTB) 1 mg

(produced in V. cholerae O1 Inaba, classical biotype strain 213.)

* Bacterial count before inactivation.

Excipients:

Sodium dihydrogen phosphate monohydrate 1.7 mg, disodium hydrogen phosphate dihydrate 9.4 mg, sodium chloride 26 mg, sodium hydrogen carbonate 3600 mg, sodium carbonate anhydrous 400 mg, saccharin sodium 30 mg, sodium citrate 6 mg.

One dose contains approximately 1.1 g sodium.

For a full list of excipients, see section 6.1.

Suspension and effervescent granules for oral suspension.

The suspension, supplied in a vial is whitish. The effervescent granules, supplied in a sachet, are white.

DUKORAL is indicated for active immunisation against disease caused by Vibrio cholerae serogroup O1 in adults and children from 2 years of age who will be visiting endemic/epidemic areas.

The use of DUKORAL should be determined on the basis of official recommendations taking into consideration the variability of epidemiology and the risk of contracting disease in different geographical areas and travelling conditions.

DUKORAL should not replace standard protective measures. In the event of diarrhoea measures of rehydration should be instituted.

Primary vaccination schedule

The standard primary course of vaccination with DUKORAL against cholera consists of 2 doses for adults and children from 6 years of age. Children 2 to 6 years of age should receive 3 doses. Doses are to be administered at intervals of at least one week. If more than 6 weeks have elapsed between doses, the primary immunisation course should be re-started.

Immunisation should be completed at least 1 week prior to potential exposure to V. cholerae O1.

Booster dose

For continuous protection against cholera a single booster dose is recommended within 2 years for adults and children from 6 years of age, and after 6 months for children aged 2 to 6 years. No clinical efficacy data has been generated on repeat booster dosing. However, immunological data suggest that if up to 2 years have elapsed since the last vaccination a single booster dose should be given. If more than 2 years have elapsed since the last vaccination the primary course should be repeated.

Children less than 2 years

DUKORAL has been given to children between 1 and 2 years of age in safety and immunogenicity studies, but the protective efficacy has not been studied in this age group. Therefore, DUKORAL is not recommended to be used in children less than 2 years of age.

Elderly

There are only very limited data on protective efficacy of the vaccine in subjects aged 65 years and more.

Method of administration

The vaccine is intended for oral use. Before ingestion, the vaccine suspension should be mixed with a sodium hydrogen carbonate solution. The sodium hydrogen carbonate is supplied as effervescent granules, which should be dissolved in a glass of cool water (approx. 150 ml). The vaccine suspension should then be mixed with the sodium hydrogen carbonate solution and drunk within 2 hours. Food and drink should be avoided 1 hour before and 1 hour after vaccination. Oral administration of other medicinal products should be avoided within 1 hour before and after administration of DUKORAL.

Children 2 to 6 years of age: half of the sodium hydrogen carbonate solution is poured away and the remaining part (approx. 75 ml) is mixed with the entire contents of the vaccine vial.

Hypersensitivity to the active substances, to any of the excipients or to formaldehyde.

Administration of DUKORAL should be postponed for subjects suffering from acute gastrointestinal illness or acute febrile illness.

No clinical data on protective efficacy of DUKORAL against cholera after administration of booster doses are available.

DUKORAL confers protection specific to Vibrio cholerae serogroup O1. Immunisation does not protect against V. cholerae serogroup O139 or other species of Vibrio.

In subjects infected with HIV, limited data are available on immunogenicity and safety of the vaccine. Vaccine protective efficacy has not been studied. Immunisation of HIV infected subjects could result in transient increases of viral load. DUKORAL may not induce protective antibody levels in subjects with advanced HIV disease. However, an effectiveness study in a population with high HIV prevalence showed similar protection as in other populations.

Antibody response in vaccinees with endogenous or iatrogenic immunosuppression may be insufficient.

Formaldehyde is used during the manufacturing process and trace amounts may be present in the final product. Caution should be taken in subjects with known hypersensitivity to formaldehyde.

DUKORAL contains approximately 1.1 g sodium per dose, which should be taken into consideration by patients on a controlled sodium diet.

The vaccine does not provide complete protection and it is important to adhere to standard protective measures to avoid cholera.

The vaccine is acid labile. Food and/or drink will increase acid production in the stomach and the effect of the vaccine may be impaired. Consequently, food and drink should be avoided 1 hour before and 1 hour after vaccination.

Oral administration of other vaccines and medicinal products should be avoided 1 hour before and 1 hour after vaccination.

Preliminary results from a clinical study including a limited number of volunteers showed no interaction with the antibody response to DUKORAL when a live oral vaccine (enterocapsules) against typhoid was given simultaneously with DUKORAL. The immune response to live typhoid vaccine was not investigated in this study. Similarly, a yellow fever vaccine was given concomitantly with DUKORAL, and there was no interaction observed with the immune response to the yellow fever vaccine. The immune responses to DUKORAL were not studied. No other vaccines/ medicinal products, including oral polio vaccine and antimalarials, have been given simultaneously with DUKORAL in clinical studies.

No animal data on reproduction toxicity are available. Following careful benefit/risk assessment the vaccine may be administered during pregnancy and to breast-feeding women although no specific clinical studies have been performed to address this issue.

There is no evidence of an effect on the ability to drive and use machines.

The safety of DUKORAL was assessed in clinical trials, including both adults and children from 2 years of age, conducted in endemic and non-endemic countries for cholera and enterotoxigenic Escherichia coli (ETEC) producing heat-labile enterotoxin (LT). Over 94,000 doses of DUKORAL were administered during the clinical trials. Evaluation of safety varied between trials with respect to mode of surveillance, definition of symptoms and time of follow-up. In the majority of studies adverse events were assessed by passive surveillance. The most frequently reported adverse reactions, such as gastrointestinal symptoms including abdominal pain, diarrhoea, loose stools, nausea and vomiting, occurred at similar frequencies in vaccine and placebo groups.

Frequency classification: 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), not known (cannot be estimated form the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Metabolism and nutrition disorder

Nervous system disorders

Respiratory, thoracic and mediastinal disorders

Gastrointestinal disorders

Skin and subcutaneous tissue disorders

Musculoskeletal and connective tissue disorders

General disorders and administration site conditions

Adverse reactions from post-marketing surveillance

Additional adverse reactions reported during post-marketing surveillance are listed below.

Infections and infestations: Gastroenteritis

Blood and lymphatic system disorders: Lymphadenitis

Nervous system disorders: Paraesthesia

Vascular disorders: Hypertension

Respiratory, thoracic and mediastinal disorders: Dyspnoea, increased sputum

Gastrointestinal disorders: Flatulence

Skin and subcutaneous tissue disorders: Urticaria, angioedema, pruritus

General disorders and administration site conditions: Pain, flu-syndrome, asthenia, chills

Data on overdose are extremely limited. Adverse reactions reported are consistent with those seen after the recommended dosing.

Pharmacotherapeutic group: Bacterial vaccines, ATC-code: J07AE01

Mechanism of action

The vaccine contains killed whole V. cholerae O1 bacteria and the recombinant non-toxic B-subunit of the cholera toxin (CTB). Bacterial strains of both Inaba and Ogawa serotypes and of El Tor and Classical biotypes are included in the vaccine. DUKORAL is taken orally with bicarbonate buffer, which protects the antigens from the gastric acid. The vaccine acts by inducing antibodies against both the bacterial components and CTB. The antibacterial intestinal antibodies prevent the bacteria from attaching to the intestinal wall thereby impeding colonisation of V. cholerae O1. The anti-toxin intestinal antibodies prevent the cholera toxin from binding to the intestinal mucosal surface thereby preventing the toxin-mediated diarrhoeal symptoms.

The heat-labile toxin (LT) of enterotoxigenic E. coli (ETEC ) is structurally, functionally and immunologically similar to CTB. The two toxins cross-react immunologically.

Efficacy against cholera

Efficacy against cholera was assessed in three randomised double-blind placebo-controlled clinical trials conducted in Bangladesh (endemic region) and in Peru (non-endemic region). The number of patients enrolled, dosage regimens and follow-up periods are shown in the following table.

In the Bangladesh field trial, protective efficacy of DUKORAL in the overall population was 85% (95%CI: 56, 95, per-protocol analysis) for the initial 6 months of follow-up. Duration of vaccine protection differed by age, lasting for 6 months in children and for 2 years in adults (see table below). An exploratory analysis suggested that 2 vaccine doses seemed as effective as 3 doses in adults.

Table: Protective efficacy against cholera in the Bangladesh study (per-protocol analysis)

In the second trial, conducted in Peru and enrolling military recruits, the short-term protective efficacy against cholera after 2 vaccine doses was 85% (95%CI: 36, 97, per-protocol analysis). The third study, a field trial conducted in Peru, failed to show any protective efficacy against cholera during the first year. Following a booster dose 10-12 months after primary immunisation, the protective efficacy during the second year was 60.5% (95%CI: 28,79).

Protective efficacy of DUKORAL against cholera has not been studied following repeated booster vaccination.

Immunogenicity

No established immunological correlates of protection against cholera after oral vaccination have been identified. There is a poor correlation between serum antibody responses, including vibriocidal antibody response, and protection. Locally produced secretory IgA antibodies in the intestine probably mediate protective immunity.

The vaccine induced intestinal antitoxin IgA responses in 70100% of vaccinated subjects. Serum vibriocidal antibodies against the bacterial components were seen in 3555% of vaccinated subjects and antitoxic antibodies in 7887% of vaccinated subjects. A booster dose elicited an anamnestic response indicative of an immune memory. The duration of the immunological memory was estimated to last for at least 2 years in adults.

Not applicable.

No preclinical safety testing with the vaccine has been conducted.

Suspension:

Sodium dihydrogen phosphate monohydrate

Disodium hydrogen phosphate dihydrate

Sodium chloride

Water for injections

Effervescent granules:

Sodium hydrogen carbonate

Citric acid

Sodium carbonate, anhydrous

Saccharin sodium

Sodium citrate

Raspberry flavour

DUKORAL should only be mixed with the supplied effervescent granules dissolved in water. In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

3 years.

After the effervescent granules have been dissolved in water and the vaccine suspension has been added, the mixture should be drunk within 2 hours.

Store in a refrigerator (2°C – 8°C).

Do not freeze.

The vaccine suspension is filled in a volume of 3 ml in vials (type I glass) with a rubber stopper (bromobutyl rubber) and a screw cap.

The effervescent granules are filled in an amount of 5.6 g in sachets with an inner layer of polyester/LD-polyethylene and an outer layer of aluminium/LD-polyethylene.

Each dose of vaccine is supplied with one sachet of effervescent granules.

Pack sizes: 1x1 dose, 2x1 dose, 20x1 dose

Not all pack sizes may be marketed.

The effervescent granules should be dissolved in approximately 150 ml of cool water. The vaccine vial should be shaken and the vaccine suspension should then be added to the sodium hydrogen carbonate solution and mixed well to obtain a colourless slightly opalescent solution.

Children 2 to 6 years of age: half of the sodium hydrogen carbonate solution is poured away and the remaining part (approx. 75 ml) is mixed with the entire contents of the vaccine vial.

Any unused product or waste material should be disposed of in accordance with local requirements.

Crucell Sweden AB

S-105 21 Stockholm

Sweden

EU/1/03/263/001-003

Date of first authorisation: 28 April 2004

Date of latest renewal: 25 March 2009

03/2009