Hepatitis A vaccine, inactivated

Dosage Forms And Strengths

Suspension for injection available in four presentations:

• 0.5-mL pediatric dose in single-dose vials and prefilled syringes
• 1-mL adult dose in single-dose vials and prefilled syringes

 [See DESCRIPTION for listing of vaccine components and Storage and Handling]

Storage And Handling

VAQTA is available in single-dose vials and prefilled Luer Lock syringes.

25U/0.5 mL in single-dose vials and prefilled Luer Lock syringes.

NDC 0006-4831-41 – box of ten 0.5-mL single dose vials.
NDC 0006-4095-09 – carton of six 0.5-mL prefilled single-dose Luer Lock syringes with tip caps.

50U/1-mL in single-dose vials and prefilled Luer Lock syringes.

NDC 0006-4841-00 – 1-mL single dose vial.
NDC 0006-4841-41 – box of ten 1-mL single dose vials.
NDC 0006-4096-09 – carton of six 1-mL prefilled single-dose Luer Lock syringes with tip caps.

Store vaccine at 2-8°C (36-46°F).

DO NOT FREEZE since freezing destroys potency.

Manuf. and Dist. by : Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

Dosage Forms & Strengths

injection

• 50 units/mL (Vaqta adult dose)
• 1440 ELISA units/mL (Havrix adult dose)

Hepatitis A Immunization

Indicated as active immunization against hepatitis A virus (HAV) for any person seeking protection, and persons with the following risks: men who have sex with men, IV or non-IV illicit drug abusers, chronic liver disease, international travelers, close contact with an international adoptee, persons working with HAV-infected primates or HAV in lab setting

2-dose vaccination series: 1 mL IM; separate the 2 doses by 6-18 months (ACIP guidelines); Havrix labeling states separating the dose by 6-12 months

Additional Information

Up-to-date vaccination schedules available at http://www.cdc.gov/vaccines/default.htm

Dosage Forms & Strengths

injection

• 25 units/0.5 mL (Vaqta pediatric dose)
• 720 ELISA units/0.5mL (Havrix pediatric dose)

Hepatitis A Immunization

Indicated as routine vaccination for children at least 12 months of age (ACIP guidelines)

<12 months: Not indicated

Routine vaccination (2-dose series): 0.5 mL IM initiated at aged 12 through 23 months; separate the 2 doses by 6-18 months (ACIP guidelines); Havrix labeling states separating the dose by 6-12 months

Children who have received 1 dose before age 24 months, should receive a second dose 6-18 months after the first dose

Catch up schedule

• For any person ≥2 yr who has not already received hepatitis A vaccine series, give 2 doses separated by 6-18 months if immunity against hepatitis A virus infection is desired
• Minimum interval between the 2-dose series is 6 months

Contraindications

Documented hypersensitivity

Cautions

First dose at least 2 wk before exposure to HAV

Current exposure to HAV: may co-administer IG

Hepatitis is a serious disease caused by a virus. Hepatitis A is spread through contact with the stool (bowel movements) of a person infected with the hepatitis A virus. This usually occurs by eating food or drinking water that has become contaminated as a result of handling by an infected person.

Hepatitis causes inflammation of the liver, vomiting, and jaundice (yellowing of the skin or eyes). Hepatitis can lead to liver cancer, cirrhosis, or death.

The hepatitis A adult vaccine is used to help prevent this disease in adults. The vaccine works by exposing you to a small amount of the virus, which causes the body to develop immunity to the disease. This vaccine will not treat an active infection that has already developed in the body.

Vaccination with hepatitis A adult vaccine is recommended for all adults who travel in certain areas of the world where hepatitis A is a common disease.

Other risk factors for hepatitis include: being a homosexual male; having chronic liver disease; using intravenous (IV) drugs; receiving treatment for hemophilia or other bleeding disorders; working in a research laboratory or around animals (especially monkeys) where you may be exposed to the hepatitis A virus; or being in an area where there has been an outbreak of hepatitis A.

Like any vaccine, the hepatitis A vaccine may not provide protection from disease in every person.

Contact your doctor if you will miss a hepatitis A vaccine dose or if you get behind schedule. The next dose should be given as soon as possible. There is no need to start over.

Be sure to receive all recommended doses of this vaccine. If you do not receive the full series of vaccines, you may not be fully protected against the disease.

There are no restrictions on food, beverages, or activity before or after receiving this vaccine, unless your doctor has told you otherwise.

Your doctor or pharmacist may have information about this vaccine written for health professionals that you may read. You may also find additional information from your local health department or the Centers for Disease Control and Prevention.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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Hepatitis A vaccine will not protect you against infection with hepatitis B, C, and E, or other viruses that affect the liver. It may also not protect you from hepatitis A if you are already infected with the virus, even if you do not yet show symptoms.

You should not receive this vaccine if you have ever had a life-threatening allergic reaction to any vaccine containing hepatitis A, or if you have received cancer chemotherapy or radiation treatment in the past 3 months.

Before receiving this vaccine, tell your doctor if you have:

• a bleeding or blood clotting disorder such as hemophilia or easy bruising;
• a history of seizures;
• a neurologic disorder or disease affecting the brain;
• an allergy to latex rubber;
• a weak immune system caused by disease, bone marrow transplant, or by using certain medicines or receiving cancer treatments; or
• if you are taking a blood thinner such as warfarin (Coumadin).

You can still receive a vaccine if you have a cold or fever. In the case of a more severe illness with a fever or any type of infection, wait until you get better before receiving this vaccine.

Before receiving the hepatitis A vaccine, tell your doctor if you are pregnant.

It is not known if hepatitis A vaccine passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

VAQTA * [Hepatitis A Vaccine, Inactivated] is an inactivated whole virus vaccine derived from hepatitis A virus (HAV) grown in cell culture in human MRC-5 diploid fibroblasts. It contains inactivated virus of a strain which was originally derived by further serial passage of a proven attenuated strain. The virus is grown, harvested, purified by a combination of physical and high performance liquid chromatographic techniques developed at the Merck Research Laboratories, formalin inactivated, and then adsorbed onto amorphous aluminum hydroxyphosphate sulfate. One milliliter of the vaccine contains approximately 50 units (U) of hepatitis A virus antigen, which is purified and formulated without a preservative. Within the limits of current assay variability, the 50U dose of VAQTA contains less than 0.1 mcg of a non-viral protein, less than 4 × 10 -6 mcg of DNA, less than 10 -4 mcg of bovine albumin, and less than 0.8 mcg of formaldehyde. Other process chemical residuals are less than 10 parts per billion (ppb).

VAQTA is a sterile suspension for intramuscular injection.

VAQTA is supplied in two formulations:

Pediatric/Adolescent Formulation: each 0.5 mL dose contains approximately 25U of hepatitis A virus antigen adsorbed onto approximately 0.225 mg of aluminum provided as amorphous aluminum hydroxyphosphate sulfate, and 35 mcg of sodium borate as a pH stabilizer, in 0.9% sodium chloride.

Adult Formulation: each 1 mL dose contains approximately 50U of hepatitis A virus antigen adsorbed onto approximately 0.45 mg of aluminum provided as amorphous aluminum hydroxyphosphate sulfate, and 70 mcg of sodium borate as a pH stabilizer, in 0.9% sodium chloride.

Hepatitis A Disease

Hepatitis A virus is one of several hepatitis viruses that cause a systemic infection with pathology in the liver. The incubation period ranges from approximately 20 to 50 days. While the course of the disease is generally benign and does not result in chronic hepatitis, infection with hepatitis A virus remains an important cause of morbidity and occasional fulminant hepatitis and death.

Hepatitis A is transmitted most often by the fecal-oral route, with infection occurring primarily within private households. Common-source outbreaks due to contaminated food and water supplies have occurred following consumption of certain foods such as raw shellfish, and uncooked foods prepared by an infected food-handler or otherwise contaminated prior to ingestion (salads, sandwiches, frozen raspberries, etc.). Bloodborne transmission, while uncommon, is possible via blood transfusion, contaminated blood products, or from needles shared with an infected viremic individual. Sexual transmission has also been reported.

The disease burden due to hepatitis A in the United States has been estimated to be approximately 143,000 infections per year, of which 75,800 result in clinical hepatitis A disease, 11,400 hospitalizations, and 80 deaths due to fulminant hepatitis. Worldwide, it has been estimated that 1.4 million cases are reported annually. The clinical manifestations of hepatitis A infection often pass unrecognized in children </=2 years of age whereas overt hepatitis A develops in the majority of infected older children and adults. Symptoms and signs of hepatitis A infection are similar to those associated with other types of viral hepatitis and include anorexia, nausea, fever/chills, jaundice, dark urine, light-colored stools, abdominal pain, malaise, and fatigue.

Clinical Trials

Clinical trials conducted worldwide with several formulations of the vaccine in 9421 healthy individuals ranging from 2 to 85 years of age have demonstrated that VAQTA is highly immunogenic and generally well tolerated.

Protection from hepatitis A disease has been shown to be related to the presence of antibody; an anamnestic antibody response occurs in healthy individuals with a history of infection who are subsequently re-exposed to hepatitis A virus. Similarly, protection after vaccination with VAQTA has been associated with the onset of serconversion (>/=10 mIU/mL of hepatitis A antibody, measured by a modification of the HAVAB ** radioimmunoassay [RIA] ) and with an anamnestic antibody response following booster vaccination with VAQTA.

Post-marketing Safety Study

In a post-marketing short-term safety surveillance study, conducted at a large health maintenance organization in the United States, a total of 42,110 individuals >/=2 years of age received 1 or 2 doses of VAQTA (13,735 children/adolescent and 28,375 adult subjects). Safety was passively monitored by electronic search of the automated medical records database for emergency room and outpatient visits, hospitalizations, and deaths. Medical charts were reviewed when indicated. There was no serious, vaccine-related, adverse event identified among the 42,110 vaccine recipients in this study. Diarrhea/gastroenteritis, resulting in outpatient visits, was determined by the investigator to be the only vaccine-related nonserious adverse event in the study. There was no vaccine-related, adverse event identified that had not been reported in earlier clinical trials with VAQTA. (See ADVERSE REACTIONS , Post-marketing Safety Study .)

Immunology

In combined clinical studies, 97% of 1230 healthy children and adolescents 2 through 18 years of age seroconverted with a geometric mean titer (GMT) of 43 mIU/mL within 4 weeks after a single ~25U/0.5 mL intramuscular dose of VAQTA. Similarly, 95% of 1411 adults >/=19 years of age seroconverted with a GMT of 37 mIU/mL within 4 weeks after a single ~50U/1.0 mL intramuscular dose of VAQTA. Furthermore, at 2 weeks post-vaccination, 69% (n=744) of adults seroconverted with a GMT of 16 mIU/mL after a single dose of VAQTA. Immune memory was demonstrated by an anamnestic antibody response in individuals who received either a ~25U/0.5 mL or ~50U/1.0 mL booster dose (see Persistence ).

A ~50U/1.0 mL intramuscular dose of VAQTA also was evaluated at four weeks post primary dose in healthy adolescents (18 years of age); 94% of 17 adolescents seroconverted with a GMT of 40 mIU/mL. In individuals 18 years of age, the GMT following a ~50 U/1.0 mL booster dose was greater than the GMT following a ~25U/0.5 mL booster dose. Both doses were immunogenic and were generally well tolerated. (See DOSAGE AND ADMINISTRATION .)

While a study evaluating VAQTA alone in a post-exposure setting has not been conducted, the concurrent use of VAQTA (~50U) and immune globulin (IG, 0.06 mL/kg) was evaluated in a clinical study involving healthy adults 18 to 39 years of age. Table 1 provides seroconversion rates and GMT at 4 and 24 weeks after the first dose in each treatment group and at one month after a booster dose of VAQTA (administered at 24 weeks).

Efficacy

A very high degree of protection has been demonstrated after a single dose of VAQTA in children and adolescents. The protective efficacy, immunogenicity and safety of VAQTA were evaluated in a randomized, double-blind, placebo-controlled study involving 1037 susceptible healthy children and adolescents 2 through 16 years of age in a U.S. community with recurrent outbreaks of hepatitis A (The Monroe Efficacy Study). Each child received an intramuscular dose of VAQTA (~25U) or placebo. Among those individuals who were initially seronegative (by modified HAVAB), seroconversion was achieved in >99% of vaccine recipients within 4 weeks after vaccination. The onset of seroconversion following a single dose of VAQTA was shown to parallel the onset of protection against clinical hepatitis A disease.

Because of the long incubation period of the disease (approximately 20 to 50 days, or longer in children), the primary endpoint was based on clinically confirmed cases *** of hepatitis A occurring >/=50 days after vaccination in order to exclude any children incubating the infection before vaccination. In subjects who were initially seronegative, the protective efficacy of a single dose of VAQTA was observed to be 100% with 21 cases of clinically confirmed hepatitis A occurring in the placebo group and none in the vaccine group (p<0.001). A secondary endpoint was pre-defined as the number of clinically confirmed cases of hepatitis A >/=30 days. With this secondary endpoint, 28 cases of clinically confirmed hepatitis A occurred in the placebo group while none occurrred in the vaccine group >/=30 days after vaccination. In addition, it was observed in this trial that no cases of clinically confirmed hepatitis A occurred in the vaccine group after day 16. **/*  Following demonstration of protection with a single dose and termination of the study, a booster dose was administered to a subset of vaccinees 6, 12, or 18 months after the primary dose.

Persistence

The total duration of the protective effect of VAQTA in healthy vaccinees is unknown at present. However, seropositivity was shown to persist up to 18 months after a single ~25U dose in a cohort of 35 out of 39 children and adolescents who participated in The Monroe Efficacy Study; 95% of this cohort responded anamnestically following a booster at 18 months. To date, no cases of clinically confirmed hepatitis A disease >/=50 days after vaccination have occurred in those vaccinees from The Monroe Efficacy Study monitored for up to 6 years.

The effectiveness of VAQTA for use in community outbreak control has been demonstrated by the fact that, although cases of imported infection have occurred, the study community has remained free of outbreaks. In contrast, three nearby sister communities to Monroe have continued to experience outbreaks.

In adults, seropositivity has been shown to persist up to 18 months after a single ~50U dose. Persistence of immunologic memory was demonstrated with an anamnestic antibody response to a booster dose of ~25U given 6 to 18 months after the primary dose in children and adolescents (Table 2), and to a booster dose of ~50U given 6 to 18 months after the primary dose to adults (Table 3).

In a clinical study involving healthy children and adolescents who received two doses (~25U) of VAQTA, detectable levels of anti-HAV antibodies (>/=10 mIU/mL) were present in 100% of subjects for up to 6 years postvaccination. In subjects who received VAQTA at 0 and 6 months, the GMT was 819 mIU/mL (n=175) at 2.5 to 3.5 years and 505 mIU/mL (n=174) at 5 to 6 years postvaccination. In subjects who received VAQTA at 0 and 12 months, the GMT was 2224 mIU/mL (n=49) at 2.5 to 3.5 years and 1191 mIU/mL (n=47) at 5 to 6 years postvaccination. In subjects who received VAQTA at 0 and 18 months, the GMT was 2501 mIU/mL (n=53) at 2.5 to 3.5 years and 1500 mIU/mL (n=53) at 5 to 6 years postvaccination.

In studies of healthy adults who received two doses (~50U) of VAQTA at 0 and 6 months, the hepatitis A antibody response to date has been shown to persist up to 6 years. Detectable levels of anti-HAV antibodies (>/=10 mIU/mL) were present in 100% (378/378) of subjects with a GMT of 1734 mIU/mL at 1 year, 99.2% (252/254) of subjects with a GMT of 687 mIU/mL at 2 to 3 years, 99.1% (219/221) of subjects with a GMT of 605 mIU/mL at 4 years, and 99.4% (170/171) of subjects with a GMT of 684 mIU/mL at 6 years postvaccination.

Studies in healthy children, adolescents and adults are ongoing to evaluate longer-term antibody persistence and the need, if any, for additional booster doses.

Interchangeability of the Booster Dose

A clinical study in 537 healthy adults, 18 to 83 years of age, evaluated the immune response to a booster dose of VAQTA and HAVRIX **/**  (hepatitis A vaccine, inactivated) given at 6 or 12 months following an initial dose of HAVRIX. When VAQTA was given as a booster dose following HAVRIX, the vaccine produced an adequate immune response (see Table 4) and was generally well tolerated. (See DOSAGE AND ADMINISTRATION , Interchangability of the Booster Dose .)

**/** Registered trademark of SmithKline Beecham

Use With Other Vaccines

A controlled clinical study was conducted with 240 healthy adults, 18 to 54 years of age, who were randomized to receive either VAQTA, typhoid and yellow fever vaccines concomitantly at separate injection sites, typhoid and yellow fever vaccines concomitantly at separate injection sites, or VAQTA alone. The seropositivity rate for hepatitis A when VAQTA, typhoid and yellow fever vaccines were administered concomitantly was generally similar to when VAQTA was given alone. The antibody response rates for typhoid and yellow fever were adequate when typhoid and yellow fever vaccines were administered concomitantly with and without VAQTA. The GMTs for hepatitis A when VAQTA, typhoid and yellow fever vaccines were administered concomitantly were reduced when compared to VAQTA alone. Following receipt of the booster dose of VAQTA, the GMTs for hepatitis A in these two groups were observed to be comparable. The concomitant administration of these three vaccines at separate injection sites was generally well tolerated. (See INDICATIONS AND USAGE , Use With Other Vaccines and DOSAGE AND ADMINISTRATION , Use With Other Vaccines .)