Influenza A Vaccine

Influenza A (H1N1) 2009 Monovalent Vaccine, for intramuscular injection, is a sterile, clear, colorless to slightly opalescent suspension with some sediment that resuspends upon shaking to form a homogeneous suspension. Influenza A (H1N1) 2009 Monovalent Vaccine is prepared from influenza virus propagated in the allantoic fluid of embryonated chicken eggs. Following harvest, the virus is purified in a sucrose density gradient using a continuous flow zonal centrifuge. The purified virus is inactivated with beta-propiolactone, and the virus particles are disrupted using sodium taurodeoxycholate to produce a "split virion". The disrupted virus is further purified and suspended in a phosphate buffered isotonic solution.

Influenza A (H1N1) 2009 Monovalent Vaccine is formulated to contain 15 mcg hemagglutinin (HA) per 0.5 mL dose of influenza A/California/7/2009 (H1N1)v-like virus.

Thimerosal, a mercury derivative, is not used in the manufacturing process for the single dose presentations; therefore these products contain no preservative. The multi-dose presentation contains thimerosal, added as a preservative; each 0.5 mL dose contains 24.5 mcg of mercury.

A single 0.5 mL dose of Influenza A (H1N1) 2009 Monovalent Vaccine contains sodium chloride (4.1 mg), monobasic sodium phosphate (80 mcg), dibasic sodium phosphate (300 mcg), monobasic potassium phosphate (20 mcg), potassium chloride (20 mcg), and calcium chloride (1.5 mcg). A single 0.25 mL dose of Influenza A (H1N1) 2009 Monovalent Vaccine contains half of these quantities. From the manufacturing process, each 0.5 mL dose may also contain residual amounts of sodium taurodeoxycholate (≤ 10 ppm), ovalbumin (≤ 1 mcg), neomycin sulfate (≤ 0.2 picograms [pg]), polymyxin B (≤ 0.03 pg), and beta-propiolactone (< 25 nanograms).

The rubber tip cap and plunger used for the preservative-free, single-dose syringes and the rubber stoppers used for the multi-dose vial contain no latex.

CSL's Influenza A (H1N1) 2009 Monovalent Vaccine and seasonal trivalent Influenza Virus Vaccine (AFLURIA) are manufactured by the same process. Data in this section were obtained in clinical studies conducted with AFLURIA.

Immunogenicity in the Adult and Geriatric Populations

Three randomized, controlled clinical studies of AFLURIA have evaluated the immune responses by measuring HI antibody titers to each virus strain in the vaccine. In these studies, post-vaccination immunogenicity was evaluated on sera obtained 21 days after administration of AFLURIA. No controlled clinical studies demonstrating a decrease in influenza disease after vaccination with AFLURIA have been performed.

The US study (Study 1) was a randomized, double-blinded, placebo-controlled, multicenter study in healthy subjects ages 18 to less than 65 years. A total of 1,357 subjects were vaccinated (1,089 subjects with AFLURIA and 268 with a thimerosal-containing placebo). Subjects receiving AFLURIA were vaccinated using either a single-dose (preservative-free) or multi-dose (one of three lots) formulation. The evaluable efficacy population consisted of 1,341 subjects (1,077 in the AFLURIA group and 264 in the placebo group) with complete serological data who had not received any contraindicated medications before the post-vaccination immunogenicity assessment. Among the evaluable efficacy population receiving AFLURIA, 37.5% were men and 62.5% were women. The mean age of the entire evaluable population receiving AFLURIA was 38 years; 73% were ages 18 to less than 50 years and 27% were ages 50 to less than 65 years. Additionally, 81% of AFLURIA recipients were White, 12% Black, and 6% Asian.

In Study 1, the following co-primary immunogenicity endpoints were assessed: 1) the lower bounds of the 2-sided 95% confidence intervals (CI) for the proportion of subjects with HI antibody titers of 1:40 or greater after vaccination, which should exceed 70% for each vaccine antigen strain; and 2) the lower bounds of the 2-sided 95% CI for rates of seroconversion (defined as a 4-fold increase in post-vaccination HI antibody titers from pre-vaccination titers of 1:10 or greater, or an increase in titers from less than 1:10 to 1:40 or greater), which should exceed 40% for each vaccine antigen strain.

In subjects ages 18 to less than 65 years, serum HI antibody responses to AFLURIA met the pre-specified co-primary endpoint criteria for all three virus strains (Table 5). Clinical lot-to-lot consistency was demonstrated for the single-dose (preservative-free) and multi-dose formulations of AFLURIA, showing that these formulations elicited similar immune responses.

The UK study (Study 2) was a randomized, controlled study that enrolled 275 healthy subjects ages 65 years and older. This study compared AFLURIA with a European-licensed trivalent inactivated influenza vaccine as an active control. The evaluable efficacy population consisted of 274 subjects (206 in the AFLURIA group and 68 in the control group). Among these subjects, 50% were men and 50% were women, with a mean age of 72 years (range: 65 to 93 years).

The co-primary immunogenicity endpoints for the seroconversion rate and the proportion of subjects with a minimum post-vaccination HI antibody titer of 1:40 are presented in Table 6.

A second UK study (Study 3) was a randomized, controlled study that enrolled 406 healthy subjects ages 18 years and older (stratified by age from 18 to less than 60 years and 60 years and older). This study compared AFLURIA with a European-licensed trivalent inactivated influenza vaccine as an active control. In a post-hoc analysis of different age ranges, among subjects ages 18 to less than 65 years receiving AFLURIA (146 subjects), 47% were men and 53% were women, with a mean age of 48 years for all subjects. Among subjects ages 65 years and older receiving AFLURIA (60 subjects), 53% were men and 47% were women, with a mean age of 71 years.

Analysis of serum HI antibody responses showed that the lower bound of the 95% CI for subjects with HI antibody titers of 1:40 or greater after vaccination exceeded 70% for each strain. HI antibody responses were lower in subjects, ages 65 years and older after administration of AFLURIA. Serum HI antibody responses to the active control were similar to those for AFLURIA in both age groups.

Immunogenicity in a Pediatric Population

An open-label, uncontrolled, multi-center study (Study 4) to evaluate the safety, tolerability and immunogenicity of AFLURIA in children 6 months to 9 years of age was conducted in Australia. The study subjects were subdivided into two groups dependent upon age at time of enrollment. A total of 298 subjects were enrolled, including 151 subjects, 6 months to less than 3 years (mean age 1.7 years with 51.0% females) and 147 subjects, 3 years to less than 9 years (mean age 5 years with 55.1% females).

Two doses of AFLURIA were administered to all subjects, with a 30 day interval between each dose. Children ages 6 months to less than 3 years received two 0.25 mL doses of AFLURIA. Children ages 3 years to less than 9 years were administered two 0.5 mL doses of AFLURIA. Sera for immunological assessment were taken 30 days (± 3) following each vaccination. Immunogenicity endpoints were the seroconversion rate and the proportion of subjects with a minimum post-vaccination HI antibody titer of 1:40. The results for each dose are presented in Table 7.

For both age groups, the vaccine met FDA acceptance criteria for immunogenicity developed for healthy adults for all three influenza strains following two doses. These criteria are: 1) that the lower bound of the 2-sided 95% CI for the seroconversion rate should be at least 40%; and 2) the lower bound of the 2-sided 95% CI for the proportion of subjects with a post-vaccination HI titer of ≥ 1:40 should be at least 70%.

The rubber tip cap and plunger used for the preservative-free, single-dose syringes and the rubber stoppers used for the multi-dose vial contain no latex.

Store refrigerated at 2–8°C (36–46°F). Do not freeze. Protect from light. Do not use Influenza A (H1N1) 2009 Monovalent Vaccine beyond the expiration date printed on the label.

Applies to influenza virus vaccine, h1n1, inactivated: intramuscular suspension

Along with its needed effects, influenza virus vaccine, h1n1, inactivated may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking influenza virus vaccine, h1n1, inactivated:

• Difficulty with moving
• fever
• general feeling of discomfort or illness
• joint pain
• muscle aching or cramping
• muscle pains or stiffness
• swollen joints
• unusual tiredness or weakness

• Back pain, sudden and severe
• black, tarry stools
• bleeding gums
• blindness
• blistering, peeling, or loosening of the skin
• blood in the urine or stools
• blue-yellow color blindness
• blurred vision
• body aches or pain
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• burning, tingling, numbness or pain in the hands, arms, feet, or legs
• chest pain
• chills
• congestion
• convulsions
• cough
• decreased vision
• diarrhea
• difficult or labored breathing
• difficulty with swallowing
• dizziness
• dryness or soreness of the throat
• eye pain
• fainting
• fast heartbeat
• feeling faint, dizzy, or lightheadedness
• feeling of warmth or heat
• flushing or redness of the skin, especially on the face and neck
• headache
• hives
• hoarseness
• itching
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• muscle weakness, sudden and progressing
• pain in the arms or legs
• pinpoint red spots on the skin
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• red skin lesions, often with a purple center
• redness of the face, neck, arms, and occasionally, upper chest
• redness, soreness, or itching skin
• runny nose
• sensation of pins and needles
• shortness of breath
• skin rash
• sneezing
• sore throat
• sores, ulcers, or white spots in the mouth or on the lips
• sores, welting, or blisters
• stabbing pain
• stuffy nose
• sweating
• swollen, painful, or tender lymph glands in the neck, armpit, or groin
• tender, swollen glands in the neck
• tightness in the chest
• trouble with swallowing
• unusual bleeding or bruising
• voice changes
• weakness of the muscles in your face
• wheezing

Some side effects of influenza virus vaccine, h1n1, inactivated may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at injection site

• Lack or loss of strength

Influenza virus vaccine, H1N1, inactivated is contraindicated in patients with a history of a hypersensitivity reaction to chicken or egg proteins or life-threatening reactions to previous influenza vaccinations

If Guillain-Barre syndrome (GBS) has occurred within six weeks of vaccination with influenza vaccine, the decision to give Influenza Virus Vaccine, H1N1, inactivated should be based on careful consideration of the benefits and risks.

Immunocompromised persons may have a reduced immune response to Influenza Virus Vaccine, H1N1, inactivated.

Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine.

The preferred sites for intramuscular injections are the anterolateral aspect of the thigh in infants or the deltoid muscle of the upper arm in toddlers and young children. In adults, the preferred site for intramuscular injection is the deltoid muscle.

It is important to note that influenza seasons vary in their timing and duration from year to year. In general, vaccination should begin soon after the vaccine becomes available and if possible, prior to October. However, vaccination should continue throughout the influenza season as long as vaccine is available.

Influenza virus vaccine, H1N1, inactivated has been assigned to pregnancy category C by the FDA. Animal studies have not been reported. There are no controlled data in human pregnancy. Influenza virus vaccine, H1N1, inactivated is only recommended during pregnancy when benefit outweighs risk.

There are no data on the excretion of influenza virus vaccine, H1N1, inactivated into human milk. The manufacturer recommends that caution by used when administering influenza virus vaccine, H1N1, inactivated to nursing women.