Vaccine Information: Vaxchora (Page 2 of 4)

7 DRUG INTERACTIONS

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 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VAXCHORA during pregnancy. To enroll in or obtain information about the registry, please call PaxVax at 1-800-533-5899.

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 and adolescents younger than 18 years.

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)].

11 DESCRIPTION

VAXCHORA (Cholera Vaccine, Live, Oral) is a live, attenuated bacterial vaccine suspension for oral administration containing the V. cholerae strain CVD 103-HgR. CVD 103-HgR was constructed from the serogroup O1 classical Inaba strain 569B by deleting the catalytic domain sequence of both copies of the ctxA gene, which prevents the synthesis of active cholera toxin (CT). This attenuated strain remains able to synthesize the immunogenic non-toxic B subunit of CT (encoded by the ctxB gene). In addition, a marker was inserted into the hemolysin gene locus (hlyA) to enable differentiation of the vaccine strain from wild type V. cholerae O1.

The vaccine strain is grown in fermentors under controlled conditions in medium containing casamino acids, yeast extract, mineral salts, and an anti-foaming agent. The bacteria are concentrated by ultrafiltration before addition of a stabilization solution containing ascorbic acid (an antioxidant), Hy-Case SF (hydrolyzed casein [a protein derived from cow's milk], a cryoprotectant), and sucrose (a cryoprotectant). The stabilized bacteria are lyophilized, milled, and blended with anhydrous lactose (a bulking agent). The active component blend is filled into packets.

The buffer component is manufactured by blending together sodium bicarbonate (a gastric acid neutralizer), sodium carbonate (a buffer), ascorbic acid (a buffer and water chlorine neutralizer), and anhydrous lactose (a manufacturing flow aid). The buffer component blend is filled into packets. One buffer component packet and one active component packet are packaged into individual single dose cartons for distribution.

After reconstitution, VAXCHORA contains 4 x 108 to 2 x 109 colony forming units (CFU) of live attenuated V. cholerae CVD 103-HgR. The resulting suspension should be slightly cloudy and may contain white particulates. The active and buffer ingredients are shown in Table 2.

Table 2: Vaccine Composition

*
CFU=colony forming units.
mg=milligrams.
g=grams.

Ingredient

Quantity/packet

Active Component Packet

V. cholerae CVD 103-HgR

4 x 108 to 2 x 109 CFU *

Sucrose

≤165.37 mg

Hy-Case SF (hydrolyzed casein)

≤17.11 mg

Ascorbic acid

≤8.55 mg

Anhydrous lactose

≤2.09 g

Buffer Component Packet

Sodium bicarbonate

2.16-2.41 g

Sodium carbonate

0.24-0.49 g

Ascorbic acid

1.50-1.80 g

Anhydrous lactose

0.18-0.22 g

12 CLINICAL PHARMACOLOGY

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 NONCLINICAL TOXICOLOGY

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 CLINICAL STUDIES

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 3).

Table 3: Vaccine Efficacy in the Prevention of Moderate to Severe Diarrhea Following Challenge with V. cholerae O1 El Tor Inaba at 10 Days and 3 Months Post-Vaccination (Intent-to-Treat Population)

Combined Placebo *
VAXCHORA VAXCHORA 10 Day or 3 Month
10 Day Challenge * 3 Month Challenge * Challenge
Parameter N=35 § N=33 § N=66 §
*
Data are derived from Study 2 (NCT01895855).
Combined placebo group comprised of all placebo recipients who were challenged at either 10 days (N=33) or 3 months (N=33) following vaccination.
Challenge strain was V. cholerae O1 El Tor Inaba N16961.
§
N=number of subjects challenged in each group.
Moderate or severe diarrhea (≥ 3 liters of diarrhea) within 10 days after challenge.
#
Vaccine Efficacy=[(Attack Rate in Placebo Group -- Attack Rate in Vaccine Group)/Attack Rate in Placebo Group] x 100.
Þ
Pre-specified criteria for success were that the lower bound of the two-sided 95% confidence interval for vaccine efficacy must be ≥30% in both the 10 Day and 3 Month challenge groups.
ß
CI=confidence interval.

Number of Subjects with

2 (5.7%)

4 (12.1%)

39 (59.1%)

Moderate or Severe

Diarrhea (Attack Rate)

Vaccine Efficacy %#Þ

90.3%

79.5%

[95% CI ß]

[62.7%, 100.0%]

[49.9%, 100.0%]

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