4.1. Therapeutic indications

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.

4.2. Posology and method of administration

Posology

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 below 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 within 6 months for children aged 2 to below 6 years. No clinical efficacy data has been generated on repeat booster dosing. However, immunological and duration of protection data suggest that if up to 2 years have elapsed since the last vaccination for adults and up to 6 months for children aged 2 to below 6 years a single booster dose should be given. If more than 2 years have elapsed since the last vaccination (more than 6 months for children aged 2 to below 6 years) 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 suspension should be mixed with the buffer (sodium hydrogen carbonate) solution. The sodium hydrogen carbonate is supplied as effervescent powder, which should be dissolved in a glass of cool water (approx. 150 ml). Chlorinated water can be used. The suspension should then be mixed with the buffer 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 1 hour after administration of Dukoral.

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

4.3. Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 or to formaldehyde.

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

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.

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 vaccines 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 additionally to standard protective measures to avoid cholera.

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

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 administration of Dukoral.

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.

4.6. Fertility, pregnancy and lactation

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.

During a mass-vaccination campaign conducted in Zanzibar, 196 pregnant women had received at least one dose of Dukoral. There was no statistically significant evidence of a harmful effect of Dukoral exposure during pregnancy.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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 from the available data).

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

Metabolism and nutrition disorder

Rare

Loss of /or poor appetite

Very rare

Dehydration

Nervous system disorders

Uncommon

Headache

Rare

Dizziness

Very rare

Drowsiness, insomnia, fainting, reduced sense of taste

Respiratory, thoracic and mediastinal disorders

Rare

Respiratory symptoms (including rhinitis and cough)

Gastrointestinal disorders

Uncommon

Diarrhoea, abdominal cramps, abdominal pain, stomach/abdominal gurgling (gas), abdominal discomfort

Rare

Vomiting, nausea

Very rare

Sore throat, dyspepsia

Skin and subcutaneous tissue disorders

Very rare

Sweating, rash

Musculoskeletal and connective tissue disorders

Very rare

Joint pain

General disorders and administration site conditions

Rare

Fever, malaise

Very rare

Fatigue, shivers

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-like syndrome, asthenia, chills

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 he Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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