Mutacol Berna

MUTACOL BERNA®

Berna Products

Cholera Vaccine Live Oral CVD 103-HgR

Cholera Prophylaxis

Action And Clinical Pharmacology: V. cholerae is the etiological agent of cholera, an acute diarrheal disease. This vaccine will not afford protection against species of vibrio other than 01 V. cholerae or against other bacteria that cause enteric disease. Mutacol Berna vaccine will not afford protection against 0139 V. cholerae.

There are less than 30 cases of cholera diagnosed per year in the U.S. while 8 cases were identified in Canada during 1995. All of these cases were contracted during travel outside of Canada. A small number of cholera cases have been contracted in the U.S. following the consumption of contaminated foodstuffs. No secondary spread of the disease was observed. Cholera is now considered to be endemic in most of Central and South America, sub-Saharan Africa and Southeast Asia. Antibiotics and oral rehydration solutions are used to treat cholera. Death associated with cholera among European or North American travelers is rare.

Upon ingestion, virulent strains of V. cholerae are able to pass through the stomach acid barrier and colonize the intestinal tract. V. cholerae present in the intestinal tract secrete cholera toxin which acts to stimulate fluid secretion, thereby resulting in the diarrhea characteristic of cholera. Possible mechanisms whereby disease may be prevented include evoking a local antibacterial and/or antitoxin immune response in the intestinal tract. Such local immunity may be induced by oral ingestion of a live attenuated strain of V. cholerae undergoing an aborted infection.

The ability of V. cholerae to cause disease and to induce a protective immune response is dependent upon colonization of the intestinal tract and secretion of cholera toxin. The V. cholerae CVD 103-HgR vaccine strain was attenuated by deletion of the enzymatically active portion of the cholera toxin molecule from the bacterial chromosome. The nonactive portion of the cholera toxin molecule is still synthesized. In addition, the insertion of a mercury-resistance marker into hlyA gene appears to have diminished the ability of CVD 103-HgR to colonize the intestinal tract. Oral administration of the V. cholerae CVD 103-HgR strain is able to elicit a local intestinal and serum antibody response which recognizes native cholera toxin and wild type V. cholerae. Due to the inability of V. cholerae CVD 103-HgR to synthesize active cholera toxin, disease symptoms normally associated with V. cholerae infection are absent.

The efficacy of CVD 103-HgR has been evaluated in a series of studies in which volunteers received either vaccine or placebo and subsequently ingested an amount of wild type V. cholerae sufficient to cause disease symptoms. The results of these studies are summarized in Table I.

The degree of protection was influenced by the biotype and serotype of the challenge strain. Immunization with V. cholerae CVD 103-HgR conferred complete protection against a challenge strain of the same biotype/serotype (Classical/Inaba). Protection was evident 8 days after immunization. An undiminished level of protection was maintained for up to 6 months postimmunization. A lower level of protection was observed when a challenge strain with a heterologous biotype and/or serotype was used. It should be noted that immunization with V. cholerae CVD 103-HgR conferred 94% protection against moderate to severe diarrhea (³2 L of total stool volume purged).

Additional challenge studies were performed with V. cholerae CVD 103, which is identical to V. cholerae CVD 103-HgR with the exception that it does not contain a mercury-resistance marker. The protection afforded following immunization with V. cholerae CVD 103 and challenge approximately 1 month later with a Classical/Inaba, Classical/Ogawa or El Tor/Inaba strain was 87%, 82% and 67%, respectively. While V. cholerae CVD 103-HgR is excreted in the stool at a lower rate than V. cholerae CVD 103, the level of protection conferred when identical challenge strains were used was comparable (100% versus 87% for V. cholerae CVD 103-HgR and V. cholerae CVD 103, respectively, against a Classical/Inaba challenge, and 62 vs 67% against an El Tor/Inaba challenge).

The efficacy of CVD 103-HgR vaccine strain has not been evaluated in cholera endemic areas. However, the above observations support the expectation that this vaccine will provide protection to recipients from noncholera endemic areas such as Canada who travel to cholera endemic areas.

Indications And Clinical Uses: For immunization of adults and children 2 years of age and older against disease caused by V. cholerae. Results from clinical studies indicate that adults and children 2 years of age and older may be protected against cholera following the oral ingestion of 1 dose of this vaccine. Immunization should be completed at least 1 week prior to potential exposure to V. cholerae.

Routine immunization against cholera is not recommended in Canada. Selective immunization against cholera is recommended for travelers to areas of the world with a risk of exposure to cholera and for travelers to countries requiring evidence of cholera vaccination for entry.

Not all recipients of Mutacol Berna Vaccine will be fully protected against cholera. Travelers should take all necessary precautions to avoid contact with or ingestion of potentially contaminated sources of food or water.

There is no evidence to support the use of cholera vaccine to control common source outbreaks or in the management of household contacts.

Mutacol Berna vaccine will not afford protection against enteric organisms other than V. cholerae. An optimal booster dose has not yet been established. However, it is recommended that a booster dose be taken every 6 months under conditions of repeated or continued exposure to cholera (see Dosage).

Cholera is present in many parts of the world. Travelers entering such areas are at risk of contracting cholera following the ingestion of contaminated food or water. Parenterally administered cholera vaccine has been shown to be effective at reducing the incidence of disease in such endemic areas. However, immunization with such vaccines is frequently accompanied by adverse reactions such as pain and/or swelling at the injection site, fever, malaise and headache.

Contra-Indications: Hypersensitivity to any component of the vaccine or the buffer.

Safety of Mutacol Berna vaccine has not been demonstrated in persons deficient in their ability to mount a humoral or cell-mediated immune response, due to either a congenital or acquired immunodeficient state including treatment with immunosuppressive or antimitotic drugs. The vaccine should not be administered to these persons regardless of the benefits.

Manufacturers’ Warnings In Clinical States: Mutacol Berna vaccine is not to be taken during an acute febrile illness or in the face of an acute gastrointestinal illness. Postpone taking the vaccine if persistent diarrhea or vomiting is occurring (see Precautions, General).

Phenylketonurics: Contains 17 mg of phenylalanine per double-chambered sachet. This is due to the fact that Mutacol Berna vaccine is sweetened by aspartame (a phenylalanine derivative).

Precautions: General: Mutacol Berna vaccine should not be administered to persons during an acute febrile illness or acute gastrointestinal illness. The vaccine should not be administered to individuals receiving sulfonamides or antibiotics since these agents may be active against the vaccine strain and prevent a sufficient degree of multiplication to occur. Antimalarial prophylaxis with chloroquine should begin no sooner than 1 week after administration of Mutacol Berna vaccine since concomitant use of this drug has been shown to decrease the immune response to the vaccine. The simultaneous administration of mefloquine or proguanil with Mutacol Berna vaccine has been shown not to significantly decrease the seroconversion rate. The concomitant administration of oral polio vaccine or yellow fever vaccine did not suppress the immune response elicited by Mutacol Berna vaccine. There is no reason to believe that simultaneous administration of parenteral vaccines or immunoglobulins with Mutacol Berna vaccine will decrease vaccine efficacy. The administration of Mutacol Berna vaccine and Vivotif Berna vaccine, enteric coated capsules, should be separated by at least 8 hours due to the fact that the buffer administered with Mutacol Berna vaccine may affect the transit of enteric coated capsules through the gastrointestinal tract.

Information for the Patient: Vaccine potency is dependent upon storage under refrigeration (between 2 and 8°C). The vaccine should be stored under refrigeration at all times. The vaccine should be ingested approximately 1 hour before a meal. It is essential that the buffer and vaccine be resuspended in cold or lukewarm water (temperature not to exceed body temperature, e.g., 37°C). Do not resuspend in milk, juice or in a carbonated beverage. It is essential that the buffer (Chamber A) and vaccine (Chamber B) be added to the liquid (approximately 100 mL) at the same time and mixed for 5 to 10 seconds to yield a homogeneous suspension. The reconstituted vaccine should be swallowed as soon after reconstitution and mixing as possible.

Phenylketonurics: Contains 17 mg of phenylalanine per double-chambered sachet. This is due to the fact that Mutacol Berna vaccine is sweetened by aspartame (a phenylalanine derivative).

Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies in animals with Mutacol Berna vaccine have not been performed as to carcinogenic potential, mutagenic potential or impairment of fertility.

Pregnancy: Animal reproduction studies have not been conducted with Mutacol Berna vaccine. It is not known whether Mutacol Berna vaccine can cause fetal harm when administered to pregnant women or can affect reproduction capacity. Mutacol Berna vaccine should be given to a pregnant woman only if clearly needed.

Lactation: There are no data to warrant the use of this product in nursing mothers. It is not known if Mutacol Berna vaccine is excreted in human milk.

Children: The safety of Mutacol Berna vaccine has not been established in children under 2 years of age. This product is therefore not recommended for use in children under 2 years of age.

Adverse Reactions: Several lots of Mutacol Berna vaccine have been evaluated in controlled clinical studies involving adults and children 2 to 9 years of age. Objectively monitored side effects, e.g., abdominal pain, diarrhea, nausea, vomiting, fever, headache and skin rash, did not appear at a statistically higher frequency in the vaccinated group as compared with a placebo group. Reported adverse reactions include nausea, abdominal cramps and diarrhea.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Mutacol Berna vaccine containing between 5´101´100viable vaccine organisms has been administered to several hundred adults and children 2 years of age and older. This dosage was, at a minimum, 5-fold higher than the currently recommended dose. Objectively monitored adverse reactions, e.g., abdominal pain, diarrhea, nausea, vomiting, fever, headache and skin rash, did not occur at a statistically higher rate among the vaccine recipients as compared with a placebo group.

Dosage And Administration: The sachet containing the buffer (Chamber A) and vaccine (Chamber B) should be inspected to ensure that the foil is intact. The vaccine is to be swallowed approximately 1 hour before a meal.

The vaccine is to be reconstituted in the following manner (see diagram on sachet). The sachet is to be folded along the solid black line and cut along the dotted line after ensuring that the contents have been displaced to the bottom to prevent spillage. The contents of both chambers are to be emptied simultaneously into 100 mL of cold or lukewarm water (temperature not to exceed body temperature, e.g., 37°C). Do not resuspend in milk, juice or in a carbonated beverage. Resuspend the sachet contents by gently mixing for 5 to 10 seconds. The vaccine should be swallowed as soon after mixing as possible. Not all recipients of Mutacol Berna vaccine will be fully protected against cholera.

Travelers should take all necessary precautions to avoid contact with or ingestion of potentially contaminated food or water.

Booster: The optimum booster schedule for Mutacol Berna vaccine has not been determined. Efficacy has been shown to persist for at least 6 months. Further, there is no experience with Mutacol Berna vaccine as a booster in persons previously immunized with parenteral cholera vaccine. Despite these limitations, it is recommended that a booster dose be given every 6 months under conditions of repeated or continued exposure to cholera.

Availability And Storage: Mutacol Berna vaccine is a live attenuated vaccine for oral administration. The vaccine contains the attenuated strain V. cholerae CVD 103-HgR and is manufactured by the Swiss Serum and Vaccine Institute Berne. The vaccine strain is grown under controlled conditions in a medium containing casamino acids, yeast extract and mineral salts. The bacteria are collected by filtration, mixed with a stabilizer containing sucrose, ascorbic acid and amino acids, and lyophilized. The lyophilized bacteria are mixed with lactose and aspartame and filled into 1 chamber of an aluminum foil sachet. Mutacol Berna vaccine is sweetened by aspartame (a phenylalanine derivative) and therefore contains 17 mg of phenylalanine. The other chamber of the sachet contains a sodium bicarbonate ascorbic acid buffer which serves to neutralize gastric acid.

The contents of the vaccine and buffer chamber are: Buffer Chamber (A): sodium bicarbonate 2.4 to 2.9 g; ascorbic acid 1.5 to 1.8 g; lactose 0.18 to 0.22 g. Vaccine Chamber (B): viable V. cholerae CVD 103-HgR 2-10´10colony-forming units; non-viable V. cholerae CVD 103-HgR 20-100´10bacterial cells; sucrose 1.4 to 30 mg; amino acid mixture 0.15 to 3 mg; ascorbic acid 0.06 to 1 mg; aspartame 20 to 30 mg; lactose 1.8 to 2.1 g. Packages of 1 single double-chambered aluminum foil sachet containing 1 dose of vaccine.

The contents of each chamber (chamber A and B) require simultaneous reconstitution prior to oral administration. Mutacol Berna is not stable when exposed to ambient temperatures. The vaccine should therefore be shipped and stored between 2 and 8°C. Each package of vaccine shows an expiration date. This expiration date is valid only if the product has been maintained at 2 to 8°C. Store in a dry place and protect from light.

MUTACOL BERNA® Berna Products Cholera Vaccine Live Oral CVD 103-HgR Cholera Prophylaxis

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