1.1 Limitations of Use

The effectiveness of VAXCHORA has not been established in persons living in cholera-affected areas.

The effectiveness of VAXCHORA has not been established in persons who have pre-existing immunity due to previous exposure to V. cholerae or receipt of a cholera vaccine.

VAXCHORA has not been shown to protect against disease caused by V. cholerae serogroup O139 or other non-O1 serogroups.

2.1 Dose and Schedule

Administer a single oral dose of VAXCHORA a minimum of 10 days before potential exposure to cholera.

The safety and effectiveness of revaccination with VAXCHORA have not been established.

2.2 Restrictions on Eating and Drinking

Instruct recipients to avoid eating or drinking for 60 minutes before and after oral ingestion of VAXCHORA.

2.3 Preparation, Reconstitution and Administration

Prepare and administer VAXCHORA in a healthcare setting equipped to dispose of medical waste [see Disposal Instructions (2.4)].

1.

Remove the carton from the refrigerator [see Storage and Handling (16.2)]. Locate the 2 packets: the buffer component (Packet 1) and the active component (Packet 2).

2.

Pour 100 milliliters (mL) of cold or room temperature (41°F-72°F; 5°C-22°C) bottled water (purified, spring, or sparkling [carbonated]) into a clean, disposable cup. Do not use tap/faucet water, or any non-purified bottled water, other beverages, or liquids.

3.

Use scissors to cut the top off the buffer component packet.

4.

Empty buffer component packet contents into cup. Effervescence will occur.

5.

Using a disposable stirrer, stir until the buffer component completely dissolves. For children 2 through 5 years of age, discard half of the buffer solution after mixing.

6.

Use scissors to cut the top off the active component packet.

7.

Empty the active component packet contents (lyophilized V. cholerae CVD 103-HgR) into the cup containing the buffer solution.

8.

Stir for at least 30 seconds and until active component disperses to form a slightly cloudy suspension that may contain some white particulates.
If desired, no more than 4 g (1 teaspoon) of sucrose (table sugar) or no more than 1 g (1/4 teaspoon) of non-flavored stevia sweeteners may be added and stirred into the suspension. Do not add any other sweeteners or medicinal flavorings as this can reduce the effectiveness of the vaccine.

9.

Consume VAXCHORA within 30 minutes, if sucrose or non-flavored stevia are added. Consume VAXCHORA within 4 hours of reconstitution, if sucrose and non-flavored stevia have not been added, at room temperature around 70 °F (21°C).
The recipient should drink the full contents of the cup. Some residue may remain in the cup and should be discarded with the cup.

NOTE: If the packets are reconstituted in the improper order, the vaccine must be discarded [see Disposal Instructions (2.4)].

2.4 Disposal Instructions

Dispose of the cup, packets, and stirrer according to standard procedures for medical waste.

Inactivate any spilled vaccine and clean any non-disposable equipment used in the preparation of VAXCHORA with 70% isopropyl alcohol or 10% bleach solution.

5.1 Altered Immunocompetence

The safety and effectiveness of VAXCHORA have not been established in immunocompromised persons [see Immunocompromised Individuals (8.6)].

5.2 Shedding and Transmission

VAXCHORA may be shed in the stool of recipients for at least 7 days. There is a potential for transmission of the vaccine strain to non-vaccinated close contacts (e.g., household contacts) [see Pharmacodynamics (12.2)]. Use caution when considering whether to administer VAXCHORA to individuals with immunocompromised close contacts.

6.1 Clinical Trials Experience

Trials in Adults

The safety of VAXCHORA was evaluated in four randomized, placebo-controlled, multicenter clinical trials. A total of 3235 adults 18 through 64 years of age received one dose of VAXCHORA and 562 received placebo [physiologic saline (N=551) or lactose (N=11)]. Overall, the mean age was 32.5 years; 53.8% of trial participants were female; 67.1% were White, 27.3% were Black or African American, 1.8% were Asian, 1.7% were multiracial, 1.3% were other, 0.6% were American Indian or Alaskan Native and 0.3% were Native Hawaiian or Pacific Islander. There were 9.3% Hispanic or Latino participants.

Solicited Adverse Reactions

Adults 18 through 45 years of age received VAXCHORA in a multi-center, double-blind, randomized (8:1), placebo-controlled trial conducted in the United States and Australia (Study 1). The safety analysis set included 2789 VAXCHORA recipients. Solicited adverse reactions were recorded daily for 7 days following vaccination. Table 1 presents the frequency and severity of solicited adverse reactions observed within 7 days following receipt of VAXCHORA or placebo in Study 1.

Grading scales are defined as follows:

Tiredness, Headache, Abdominal Pain, Nausea, Lack of Appetite: Mild = no interference with activity, Moderate = Some interference with activity, Severe = significant, prevents daily activity, Potentially Life Threatening = emergency room (ER) visit or hospitalization.

Vomiting: Mild = 1-2 episodes/24 hours, Moderate = >2 episodes/24 hours, Severe = requires intravenous hydration, Potentially Life Threatening = ER visit or hospitalization for hypotensive shock.

Diarrhea: Mild = 4 loose stools/24 hours, Moderate = 5 loose stools/24 hours, Severe = ≥6 loose stools /24 hours, Potentially Life Threatening = ER visit or hospitalization.

Fever: Mild = 38.0-38.4ºC/100.4-101.1ºF, Moderate = 38.5-38.9ºC/101.2-102.0ºF, Severe = 39.0‑40.0ºC/102.1-104.0ºF, Potentially Life Threatening = >40.0 ºC/104.0 ºF.

Serious Adverse Events

In a pooled analysis of the four clinical studies, 0.6% (20/3235) of VAXCHORA recipients and 0.5% (3/562) of placebo recipients reported a serious adverse event within 6 months post-vaccination. None of these events were considered to be related to vaccination.

Pediatric Trial

The safety of VAXCHORA in children was evaluated in one randomized, placebo-controlled, multicenter clinical trial. A total of 468 children 2 through 17 years of age received one dose of VAXCHORA and 75 received placebo (physiologic saline). The mean age was 9.0 years; 51.6% were male; 59.5% were White, 31.3% were Black, 7.7% were multiracial, 0.9% were Asian, and 0.6% were American Indian/Alaskan Native. There were 8.7% Hispanic or Latino participants.

Solicited Adverse Reactions

Children 2 through 17 years of age received VAXCHORA in a multi-center, double-blind, randomized (6:1), placebo-controlled trial conducted in the United States (Study 5). Randomization was stratified by age, and children were enrolled in three separate age cohorts: 12 to < 18 years (Cohort 1), 6 to < 12 years (Cohort 2), and 2 to < 6 years (Cohort 3). The safety analysis set included 468 VAXCHORA recipients and 75 placebo recipients. Solicited adverse reactions were recorded daily for 7 days following vaccination. Table 2 presents the frequency and severity of solicited adverse reactions observed within 7 days following receipt of VAXCHORA or placebo in Study 5 for the 3 study cohorts.

Pediatric Grading scales are defined as follows:

Tiredness, Headache, Abdominal Pain, Nausea, Lack of Appetite: Mild = no interference with activity, Moderate = Some interference with activity, Severe = significant, prevents daily activity, Potentially Life Threatening = emergency room (ER) visit or hospitalization.

Vomiting: Mild = 1-2 episodes/24 hours, Moderate = >2 episodes/24 hours, Severe = requires intravenous hydration, Potentially Life Threatening = ER visit or hospitalization for hypotensive shock.

Diarrhea: Mild = 4 loose stools/24 hours, Moderate = 5 loose stools/24 hours, Severe = ≥6 loose stools /24 hours, Potentially Life Threatening = ER visit or hospitalization.

Fever: Mild = 38.0-38.4ºC/100.4-101.1ºF, Moderate = 38.5-38.9ºC/101.2-102.0ºF, Severe = 39.0‑40.0ºC/102.1-104.0ºF, Potentially Life Threatening = >40.0 ºC/104.0 ºF.

In total, 13.2% of VAXCHORA recipients reported an unsolicited adverse event that was considered related to study treatment, compared to 9.3% for placebo recipients.

The most frequent unsolicited adverse event for VAXCHORA was loose stool in Cohort 1 (13.9%), Cohort 2 (11.5%) and Cohort 3 (5.5%).

Serious Adverse Events

In Study 5, 0.2% (1/468) of VAXCHORA recipients and 1.3% (1/75) of placebo recipients reported a serious adverse event within 6 months post-vaccination. None of these events were considered to be related to vaccination.

7.1 Food and Drink

Avoid food or drink for 60 minutes before and after vaccine administration [see Restrictions on Eating and Drinking (2.2)].

7.2 Concomitant Vaccines or Medications

Vaccines

No data are available on concomitant administration of VAXCHORA with other vaccines.

Antibiotics

Avoid concomitant administration of VAXCHORA with systemic antibiotics since these agents may be active against the vaccine strain and prevent a sufficient degree of multiplication to occur in order to induce a protective immune response. Do not administer VAXCHORA to patients who have received oral or parenteral antibiotics within 14 days prior to vaccination.

Antimalarial Prophylaxis

Data from a study with a similar product indicate that the immune responses to VAXCHORA may be diminished when VAXCHORA is administered concomitantly with chloroquine. Administer VAXCHORA at least 10 days before beginning antimalarial prophylaxis with chloroquine.

7.3 Immunosuppressive Treatments

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to VAXCHORA [see Use in Specific Populations (8.6)].

8.1 Pregnancy

Risk Summary

VAXCHORA is not absorbed systemically following oral administration, and maternal use is not expected to result in fetal exposure to the drug.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Maternal cholera disease is associated with adverse pregnancy outcomes including fetal death.

Fetal/neonatal adverse reactions

The vaccine strain may be shed in the stool of the vaccinated mother for at least 7 days, with a potential for transmission of the vaccine strain from mother to infant during vaginal delivery.

8.2 Lactation

Risk Summary

VAXCHORA is not absorbed systemically by the mother following oral administration, and breastfeeding is not expected to result in exposure of the child to VAXCHORA.

8.4 Pediatric Use

The safety and effectiveness of VAXCHORA have not been established in children younger than 2 years of age.

8.5 Geriatric Use

The safety and effectiveness of VAXCHORA have not been established in adults 65 years of age or older.

8.6 Immunocompromised Individuals

The safety and effectiveness of VAXCHORA have not been established in immunocompromised individuals. The immunologic response to VAXCHORA may be diminished in immunocompromised individuals [see Drug Interactions (7.3)].

12.1 Mechanism of Action

VAXCHORA contains live attenuated cholera bacteria that replicate in the gastrointestinal tract of the recipient. Immune mechanisms conferring protection against cholera following receipt of VAXCHORA have not been determined. However, rises in serum vibriocidal antibody 10 days after vaccination with VAXCHORA were associated with protection in a human challenge study (Study 2) [see Immunogenicity (14.2)].

12.2 Pharmacodynamics

Shedding of the vaccine strain was evaluated in the first 7 days post-vaccination in a study of 53 healthy adult vaccine recipients (Study 3). VAXCHORA was shed in the stools of 11.3% [95% CI 4.3%, 23.0%] of vaccine recipients on any day through 7 days post-vaccination. During the 7 days post-vaccination, the proportion of subjects shedding was highest on day 7 (7.5% [95% CI 2.1%, 18.2%]). The duration of shedding of the vaccine strain is unknown.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

VAXCHORA has not been evaluated for the potential to cause carcinogenicity or genotoxicity, or to impair fertility.

14.1 Efficacy Against V. cholerae Challenge

Study 2 was a randomized, double-blind, saline placebo-controlled V. cholerae challenge study conducted in the US. Subjects 18 through 45 years of age (N=197) with no prior history of cholera infection or travel to a cholera-endemic area in the previous 5 years were randomized according to a 1:1 ratio to receive one dose of VAXCHORA or placebo. In order to identify the subset of subjects to be challenged, an unblinded statistician prepared four randomly ordered lists of subjects per site, one list each for vaccine recipients with blood type O, vaccine recipients with non-O blood types, placebo recipients with blood type O, and placebo recipients with non-O blood types. This was done to maintain a minimum of 60% blood group O subjects in each treatment group. Individuals with type O blood are less likely to be infected with V. cholerae, but are at risk for developing severe cholera if infected. Each site was provided with a blinded version of the four lists specific to its site and advised on the number of subjects from each list to challenge. In the event that a subject was determined to be ineligible for challenge, the site was instructed to select the next subject from the same list as the ineligible subject.

The challenges were split into 2 cohorts for 10 day and 3 month challenges. Subjects were admitted to an inpatient unit. Subjects had nothing by mouth from midnight before ingestion of the challenge strain, except for water, and had nothing by mouth for 90 minutes after ingestion of the challenge strain. Approximately 1 minute prior to challenge, subjects ingested 120 mL sodium bicarbonate (NaHCO3) buffer. The oral challenge consisted of 1 x 105 CFU live wild type V. cholerae El Tor Inaba N16961 in 30 mL NaHCO3 buffer at 10 days or 3 months post-vaccination. The co-primary objectives were to demonstrate the efficacy of a single dose of VAXCHORA in the prevention of moderate to severe diarrhea following challenge at 10 days and 3 months post-vaccination. Moderate to severe diarrhea was defined as cumulative diarrheal purge ≥ 3 liters (L) within 10 days after challenge. Diarrheal stool was defined as ≥ 2 unformed stools (takes shape of container) collected during a 48 hour period ≥ 200 grams (g) or a single unformed stool ≥ 300 g. Subjects were instructed to collect every stool from the time of challenge until discharge from the inpatient unit. Nursing staff or study personnel inspected all stool, graded the consistency of the stool and calculated the total weight of diarrheal stool per day. Weight of stool was converted to volume using the formula 1 g=1 mL. VAXCHORA recipients challenged at 10 days post-vaccination and VAXCHORA recipients challenged at 3 months post-vaccination were compared with a pooled group of placebo (saline) recipients challenged at 10 days or 3 months post-vaccination.

Of the 95 VAXCHORA recipients, 68 were challenged; 35 were challenged at 10 days post-vaccination and 33 were challenged at 3 months post-vaccination. Of the 102 placebo recipients, 66 were challenged; 33 were challenged at 10 days post-vaccination and 33 at 3 months post-vaccination. Among all randomized subjects, the mean age was 31.0 years. Overall, the mean age of the challenge population was 31.4 years. More males were in the vaccine group (71.6%) compared to the placebo group (54.9%). The majority of randomized subjects were Black (67.5%), 29.4% were White, 0.5% were American Indian/Alaskan Native, 0.5% were Asian, and 2.0% were other. There were 4.6% Hispanic or Latino participants. Overall 50.3% had blood type O. Among subjects selected for either challenge cohort, more males were challenged in the vaccine group (76.5%) compared to the placebo group (57.6%). The majority (70.9%) of the challenge population were Black, 25.4% were White, 0.7% were American Indian/Alaskan Native, 0.7% were Asian, and 2.2% were other. There were 3.7% Hispanic or Latino participants. Overall, 56.0% of challenged subjects had blood type O.

Vaccine efficacy against the occurrence of moderate to severe diarrhea at 10 days post-vaccination was 90.3% [95% CI 62.7%, 100.0%] and at 3 months post-vaccination was 79.5% [95% CI 49.9%, 100.0%] (Table 4).

14.2 Immunogenicity

Vibriocidal Antibody Against the Vaccine Strain (classical Inaba)

A vibriocidal antibody assay was used to measure serum levels of neutralizing antibodies against the vaccine strain.

Study 2 was a randomized, double-blind, saline placebo-controlled V. cholerae challenge study conducted in adults 18 through 45 years of age. In the subset of subjects challenged in Study 2, 91% [95% CI 82%, 97%] of vaccinees seroconverted prior to challenge and 9% developed moderate to severe cholera following challenge, while 2% of placebo recipients seroconverted prior to challenge and 59% developed moderate to severe cholera following challenge. Seroconversion was defined as a ≥ 4-fold rise in serum vibriocidal antibody from baseline to 10 days post-vaccination. Based on the observed association between seroconversion and protection from V. cholerae disease, seroconversion rate at 10 days post-vaccination was used to evaluate response to vaccination in other age groups.

Study 1 was a randomized, double-blind, saline placebo-controlled safety and immunogenicity study conducted in the US and Australia. A total of 3146 subjects 18 through 45 years of age not previously exposed to cholera were randomized 8:1 to receive one dose of VAXCHORA or placebo. The mean age was 29.9 years; 45.2% were male; 68.3% were White, 25.6% were Black, 2.0% were Asian, 1.9% were multiracial, 1.4% were other, 0.4% were American Indian/Alaskan Native, and 0.3% were Native Hawaiian/Pacific Islander. There were 10.0% Hispanic or Latino participants.

In this study, classical Inaba vibriocidal antibody seroconversion rates were 93.5% [95% CI 92.5%, 94.4%] in vaccine recipients and 4% [95% CI 2%, 7%] in placebo recipients at 10 days post-vaccination.

Study 4 was a randomized, double-blind, placebo-controlled safety and immunogenicity study conducted in the US. A total of 398 subjects 46 through 64 years of age with no prior history of cholera infection or travel to a cholera-endemic area in the previous 5 years were randomized 3:1 to receive one dose of VAXCHORA or placebo. Overall, the mean age of the randomized population was 53.8 years; 45.7% were male; 74.9% were White, 21.9% were Black, 1.8% were American Indian/Alaskan Native, 0.5% were Asian, 0.5% were multiracial, 0.3% were Native Hawaiian/Pacific Islander, and 0.3% were other. There were 7.5% Hispanic or Latino participants.

Vibriocidal antibody seroconversion rates at 10 days post-vaccination for the classical Inaba strain among 46 through 64-year-old subjects in Study 4 were compared to those in 18 through 45-year-old subjects in Study 1. VAXCHORA recipients from Study 1 were in the same age group as those in Study 2, the V. cholerae challenge study.

Adults 46 through 64 years were shown to have a non-inferior rate of classical Inaba vibriocidal antibody seroconversion at 10 days post-vaccination compared to adults 18 through 45 years of age (Table 5).

Vibriocidal Antibody Against Classical Ogawa, El Tor Inaba and El Tor Ogawa

V. cholerae serogroup O1 consists of four major subtypes: classical Inaba, classical Ogawa, El Tor Inaba and El Tor Ogawa. Serum vibriocidal antibody against the three types of V. cholerae not contained in the vaccine, namely classical Ogawa, El Tor Inaba and El Tor Ogawa, was also measured in Study 2 and Study 4. The percentages of vaccine recipients who seroconverted against each of the 4 major biotype/serotypes of V. cholerae serogroup O1 at 10 days post- vaccination (71.4% to 91.4%) are shown in Table 6.

Pediatric Trial - Vibriocidal Antibody Against the Vaccine Strain (classical Inaba)

The effectiveness of VAXCHORA for the pediatric population 2 through 17 years of age was demonstrated following comparison of the immune response to V. cholerae in children and adolescents to the immune response in adults following Vaxchora (immunobridging).

Study 5 was a randomized, double-blind, saline placebo-controlled safety and immunogenicity study conducted in the US. A total of 550 subjects 2 through 17 years of age not previously exposed to cholera were randomized 6:1 to receive one dose of VAXCHORA (1 x 109 CFU/dose) or placebo. Randomization was stratified by age into 3 age cohorts:

•

Cohort 1: 12 to <18 years of age

•

Cohort 2: 6 to <12 years of age

•

Cohort 3: 2 to <6 years of age

In this study, classical Inaba vibriocidal antibody seroconversion rates at 10-days post-vaccination in children 2 through 17 years of age were compared to seroconversion rates in adults 18 through 45 years of age.

Immunobridging results for VAXCHORA, at 10 days post-vaccination, are shown in Table 7. The rate of seroconversion among pediatric placebo recipients was 1.5% [95% CI 0.3%, 8.0%] at 10 days post-vaccination.

16.1 How Supplied

VAXCHORA is supplied as shown in Table 8. The contents of both packets are reconstituted with bottled water (purified, spring, or sparkling [carbonated]), to form one oral dose of the vaccine.

16.2 Storage and Handling

Store VAXCHORA buffer component and active component packets refrigerated at 36°F to 46°F (2°C to 8°C).

Protect from light and moisture.

Packages may be stored at 48°F to 77°F (9°C to 25°C) for no more than 5 days prior to reconstitution.