serious fix

Note from tss: This is what they want to put inside of you. Read this carefully. If you have questions, post them below the article.

———————– Page 1———————–

Novartis Vaccines and Diagnostics Limited BLA 1750

September 2009

Influenza A (H1N1) 2009 Monovalent Vaccine

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use Influenza A

(H1N1) 2009 Monovalent Vaccine safely and effectively. See full prescribing

information.

Influenza A (H1N1) 2009 Monovalent Vaccine

Manufactured by Novartis Vaccines and Diagnostics Ltd.

Suspension for Intramuscular Injection

INDICATIONS AND USAGE

• Influenza A (H1N1) 2009 Monovalent Vaccine is an inactivated influenza virus

vaccine indicated for active immunization of persons 4 years of age and older against

influenza disease caused by pandemic (H1N1) 2009 virus (1).

DOSAGE AND ADMINISTRATION

Based on currently available information the vaccination regimen is as follows:

• Children 4 through 9 years of age: Two 0.5-mL intramuscular injections

approximately 1 month apart (2.2)

• Children 10 through 17 years of age: A single 0.5-mL intramuscular injection (2.2)

• Adults 18 years of age and older: A single 0.5-mL intramuscular injection (2.2)

DOSAGE FORMS AND STRENGTHS

Influenza A (H1N1) 2009 Monovalent Vaccine, a sterile suspension for intramuscular

injection, is supplied in two presentations:

• Prefilled single dose syringe, 0.5-mL. Thimerosal, a mercury derivative used during

manufacture, is removed by subsequent purification steps to a trace amount (= 1 mcg

mercury per 0.5-mL dose) (3, 11)

• Multidose vial, 5-mL. Contains thimerosal, a mercury derivative (25 mcg mercury

per 0.5-mL dose). Thimerosal is added as preservative. (3,11)

CONTRAINDICATIONS

• History of systemic hypersensitivity reactions to egg proteins, or any other

component of Influenza A (H1N1) 2009 Monovalent Vaccine, or life-threatening

reactions to previous influenza vaccinations. (4, 11)

WARNINGS AND PRECAUTIONS

• If Guillain-Barré syndrome has occurred within 6 weeks of receipt of prior influenza

vaccine, the decision to give Influenza A (H1N1) 2009 Monovalent Vaccine should

be based on careful consideration of the potential benefits and risks. (5.1)

• Immunocompromised persons may have a reduced immune response to Influenza A

(H1N1) 2009 Monovalent Vaccine. (5.2)

ADVERSE REACTIONS

Adverse Reaction information is based on studies conducted with seasonal trivalent

Influenza Virus Vaccine manufactured by Novartis (FLUVIRIN).

Vial and Syringe leaflet text Page 1 of 20

———————– Page 2———————–

Novartis Vaccines and Diagnostics Limited BLA 1750

September 2009

The most frequently reported adverse reactions are mild hypersensitivity reactions (such

as rash), local reactions at the injection site, and influenza-like symptoms. (6)

To report SUSPECTED ADVERSE REACTIONS contact Novartis Vaccines at 1-

800-244-7668, or VAERS at 1-800-822-7967 and www.vaers.hhs.gov.

DRUG INTERACTIONS

• Do not mix with any other vaccine in the same syringe or vial. (7.1)

• Immunosuppressive therapies may reduce immune response to Influenza A (H1N1)

2009 Monovalent Vaccine. (7.2)

USE IN SPECIFIC POPULATIONS

• Safety and effectiveness of Influenza A (H1N1) 2009 Monovalent Vaccine have not

been established in pregnant women, nursing mothers or children less than 4 years of

age. (8.1, 8.3, 8.4)

• Antibody responses to the trivalent seasonal Influenza Virus Vaccine manufactured

by Novartis (FLUVIRIN) were lower in the geriatric population than in younger

subjects. (8.5)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: September 2009

Vial and Syringe leaflet text Page 2 of 20

———————– Page 3———————–

Novartis Vaccines and Diagnostics Limited BLA 1750

September 2009

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Preparation for Administration

2.2 Recommended Dose and Schedule

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Hypersensitivity

5 WARNINGS AND PRECAUTIONS

5.1 Guillain-Barré Syndrome

5.2 Altered Immunocompetence

5.3 Preventing and Managing Allergic Reactions

5.4 Limitations of Vaccine Effectiveness

6 ADVERSE REACTIONS

6.1 Overall Adverse Reaction Profile

6.2 Clinical Trial Experience

6.3 Postmarketing Experience

6.4 Other Adverse Reactions Associated with Influenza Vaccination

7 DRUG INTERACTIONS

7.1 Concomitant Administration with Other Vaccines

7.2 Concurrent Use with Immunosuppressive Therapies

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Immunogenicity in Adults (18 to 64 years of age)

14.2 Immunogenicity in Geriatric Subjects (65 years of age and over)

14.3 Immunogenicity in Pediatric Subjects

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage and Handling

17 PATIENT COUNSELING INFORMATION

* Sections or subsections omitted from the full prescribing information are not listed.

Vial and Syringe leaflet text Page 3 of 20

———————– Page 4———————–

Novartis Vaccines and Diagnostics Limited BLA 1750

September 2009

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Influenza A (H1N1) 2009 Monovalent Vaccine is an inactivated influenza virus

vaccine indicated for immunization of persons 4 years of age and older against influenza

disease caused by pandemic (H1N1) 2009 virus.

2 DOSAGE AND ADMINISTRATION

2.1 Preparation for Administration

Inspect Influenza A (H1N1) 2009 Monovalent Vaccine syringes and multidose

vials visually for particulate matter and/or discoloration prior to administration. If either

of these conditions exists, the vaccine should not be administered.

Shake the syringe vigorously before administering the vaccine and shake the

multidose vial preparation each time before withdrawing a dose of vaccine.

Between uses, return the multidose vial to the recommended storage conditions

between 2º and 8ºC (36º and 46ºF). Do not freeze. Discard if the vaccine has been

frozen.

A separate syringe and needle or a sterile disposable unit should be used for each

injection to prevent transmission of infectious agents from one person to another.

Needles should be disposed of properly and not recapped.

It is recommended that small syringes (0.5-mL or 1-mL) should be used to

minimize any product loss.

2.2 Recommended Dose and Schedule

Clinical studies are ongoing with Influenza A (H1N1) 2009 Monovalent Vaccine to

determine the optimal dosage, number of doses and schedule.

Available data show that children 9 years of age and younger are largely serologically

naïve to the pandemic (H1N1) 2009 virus (15.1). Based upon these data Influenza A

(H1N1) 2009 Monovalent Vaccine should be administered as follows:

Children (4 to 17 years of age):

Children 4 through 9 years of age should receive two 0.5mL doses by intramuscular

injection approximately 1 month apart.

Children 10 through 17 years of age should receive a single 0.5-mL intramuscular

injection.

The needle size may range from 7/8 to 1¼ inches, depending on the size of the child’s

deltoid muscle, and should be of sufficient length to penetrate the muscle tissue. The

anterolateral thigh can be used, but the needle should be longer, usually 1 inch.

The vaccine should not be injected in the gluteal region or areas where there may be a

major nerve trunk.

Adults (18 years of age and older):

Influenza A (H1N1) 2009 Monovalent Vaccine should be administered as a single 0.5-

mL intramuscular injection preferably in the region of the deltoid muscle of the upper

arm.

Vial and Syringe leaflet text Page 4 of 20

———————– Page 5———————–

Novartis Vaccines and Diagnostics Limited BLA 1750

September 2009

A needle of =1 inch is preferred because needles <1 inch might be of insufficient length

to penetrate muscle tissue in certain adults.

The vaccine should not be injected in the gluteal region or areas where there may be a

major nerve trunk.

3 DOSAGE FORMS AND STRENGTHS

Influenza A (H1N1) 2009 Monovalent Vaccine is a sterile suspension for

intramuscular injection. [see DESCRIPTION (11) for the complete list of ingredients]

Influenza A (H1N1) 2009 Monovalent Vaccine is available in two presentations:

1) Prefilled single dose syringe, 0.5-mL. Thimerosal, a mercury derivative used

during manufacture, is removed by subsequent purification steps to a trace amount (= 1

mcg mercury per 0.5-mL dose).

2) Multidose vial, 5-mL. Contains thimerosal, a mercury derivative, added as a

preservative. Each 0.5-mL dose from the multidose vial contains 25 mcg mercury.

4 CONTRAINDICATIONS

4.1 Hypersensitivity

Influenza A (H1N1) 2009 Monovalent Vaccine should not be administered to

anyone with known systemic hypersensitivity reactions to egg proteins (eggs or egg

products), or to any component of Influenza A (H1N1) 2009 Monovalent Vaccine, or

who has had a life-threatening reaction to previous influenza vaccinations [see

DESCRIPTION (11)].

5 WARNINGS AND PRECAUTIONS

5.1 Guillain-Barré Syndrome

If Guillain-Barré syndrome has occurred within 6 weeks of receipt of prior

influenza vaccine, the decision to give Influenza A (H1N1) 2009 Monovalent Vaccine

should be based on careful consideration of the potential benefits and risks.

5.2 Altered Immunocompetence

If Influenza A (H1N1) 2009 Monovalent Vaccine is administered to

immunocompromised persons, including individuals receiving immunosuppressive

therapy, the expected immune response may not be obtained.

5.3 Preventing and Managing Allergic Reactions

Prior to administration of any dose of Influenza A (H1N1) 2009 Monovalent

Vaccine, the healthcare provider should review the patient’s prior immunization history

for possible adverse events, to determine the existence of any contraindication to

immunization with Influenza A (H1N1) 2009 Monovalent Vaccine and to allow an

assessment of benefits and risks. Appropriate medical treatment and supervision must be

available to manage possible anaphylactic reactions following administration of the

vaccine.

5.4 Limitations of Vaccine Effectiveness

Vaccination with Influenza A (H1N1) 2009 Monovalent Vaccine may not protect

all individuals.

Vial and Syringe leaflet text Page 5 of 20

----------------------- Page 6-----------------------

Novartis Vaccines and Diagnostics Limited BLA 1750

September 2009

6 ADVERSE REACTIONS

Novartis’ Influenza A (H1N1) 2009 Monovalent Vaccine and seasonal trivalent

Influenza Virus Vaccine (FLUVIRIN®) are manufactured by the same process. The data

in this section were obtained from clinical studies and postmarketing experience with

FLUVIRIN.

6.1 Overall Adverse Reaction Profile

Serious allergic reactions, including anaphylactic shock, have been observed in

individuals receiving FLUVIRIN during postmarketing surveillance.

6.2 Clinical Trial Experience

Adverse event information from clinical trials provides a basis for identifying

adverse events that appear to be related to vaccine use and for approximating the rates of

these events. However, because clinical trials are conducted under widely varying

conditions, the adverse reaction rates observed in the clinical trials of a vaccine cannot be

directly compared to rates in the clinical trials of another vaccine, and may not reflect

rates observed in clinical practice.

Adult and Geriatric Subjects

Safety data were collected in a total of 2768 adult and geriatric subjects (18 years

of age and older) who have received FLUVIRIN in 29 clinical studies since 1982.

In 9 clinical studies since 1997, among 1261 recipients of FLUVIRIN, 745 (59%)

were women; 1211 (96%) were White, 23 (2%) Asian, 15 (1%) Black and 12 (1%) other;

370 (29%) of subjects were elderly (=65 years of age). All studies have been conducted

in the UK, apart from a study run in the US in 2005-2006 where FLUVIRIN was used as

a comparator for an unlicensed vaccine.

After vaccination, the subjects were observed for 30 minutes for hypersensitivity

or other immediate reactions. Subjects were instructed to complete a diary card for three

days following immunization (i.e. Day 1 to 4) to collect local and systemic reactions (see

Tables 1 and 2). All local and systemic adverse events were considered to be at least

possibly related to the vaccine. Local and systemic reactions mostly began between day

1 and day 2. The overall adverse events reported in clinical trials since 1998 in at least

5% of the subjects are summarized in Table 3.

Vial and Syringe leaflet text Page 6 of 20

----------------------- Page 7-----------------------

Novartis Vaccines and Diagnostics Limited BLA 1750

September 2009

TABLE 1

Solicited Adverse Events in the First 72-96 Hours after Administration of FLUVIRIN in

Adult (18-64 years of age) and Geriatric (=65 years of age) Subjects.

*§ *§ *§

1998-1999 1999-2000 2000-2001

18-64 yrs = 65 yrs 18-64 yrs = 65 yrs 18-64 yrs = 65 yrs

N = 66 N = 44 N = 76 N = 34 N = 75 N = 35

Local Adverse Events

Pain 16 (24%) 4 (9%) 16 (21%) - 9 (12%) -

Mass 7 (11%) 1 (2%) 4 (5%) - 8 (11%) 1 (3%)

Inflammation 5 (8%) 2 (5%) 6 (8%) - 7 (9%) 1 (3%)

Ecchymosis 4 (6%) 1 (2%) 3 (4%) 1 (3%) 4 (5%) -

Edema 2 (3%) 1 (2%) 1 (1%) 2 (6%) 3 (4%) 1 (3%)

Reaction 2 (3%) - 2 (3%) - 4 (5%) 1 (3%)

Hemorrhage - - 1 (1%) - - -

Systemic Adverse

Events

Headache 7 (11%) 1 (2%) 17 (22%) 3 (9%) 4 (5%) -

Fatigue 3 (5%) 2 (5%) 4 (5%) 1 (3%) 3 (4%) -

Malaise 2 (3%) 1 (2%) 2 (3%) 1 (3%) 1 (1%) -

Myalgia 1 (2%) - 2 (3%) - - -

Fever 1 (2%) - 1 (1%) - - -

Arthralgia - 1 (2%) - 1 (3%) - -

Sweating - - 3 (4%) - 1 (1%) 1 (3%)

*^ *^ ^

2001-2002 2002-2003 2004-2005*

18-64 yrs = 65 yrs 18-64 yrs = 65 yrs 18-64 yrs = 65 yrs

N = 75 N = 35 N = 107 N = 88 N = 74 N = 61

Local Adverse Events

Pain 12 (16%) 1 (3%) 14 (13%) 7 (8%) 15 (20%) 9 (15%)

Mass 4 (5%) 1 (3%) - - - -

Ecchymosis 2 (3%) - 3 (3%) 3 (3%) 2 (3%) 1 (2%)

Edema 2 (3%) 1 (3%) 6 (6%) 2 (2%) - -

Erythema 5 (7%) - 11 (10%) 5 (6%) 16 (22%) 5 (8%)

Swelling - - - - 11 (15%) 4 (7%)

Reaction - - 2 (2%) - - -

Induration - - 14 (13%) 3 (3%) 11 (15%) 1 (2%)

Pruritus - - 1 (1%) - - -

Systemic Adverse

Events

Headache 8 (11%) 1 (3%) 12 (11%) 9 (10%) 14 (19%) 3 (5%)

Fatigue 1 (1%) 1 (3%) - - 5 (7%) 2 (3%)

Malaise 3 (4%) - 3 (3%) 4 (5%) 1 (1%) 1 (2%)

Myalgia 3 (4%) - 5 (5%) 3 (3%) 8 (11%) 1 (2%)

Fever - - - 1 (1%) - -

Arthralgia - - 2 (2%) - 1 (1%) -

Sweating 3 (4%) 1 (3%) - 2 (2%) - -

Shivering - - - 1 (1%) - -

Results reported to the nearest whole percent; Fever defined as >38°C

– not reported

* Solicited adverse events in the first 72 hours after administration of FLUVIRIN

§ Solicited adverse events reported by COSTART preferred term

^ Solicited adverse events reported by MEDDRA preferred term

Vial and Syringe leaflet text Page 7 of 20

———————– Page 8———————–

Novartis Vaccines and Diagnostics Limited BLA 1750

September 2009

TABLE 2

Solicited Adverse Events in the First 72 Hours after Administration of FLUVIRIN in Adult

Subjects (18-49 years of age).

2005-2006 US Trial

FLUVIRIN

N = 304

Local Adverse Events

Pain 168 (55%)

Erythema 48 (16%)

Ecchymosis 22 (7%)

Induration 19 (6%)

Swelling 16 (5%)

Systemic Adverse Events

Headache 91 (30%)

Myalgia 64 (21%)

Malaise 58 (19%)

Fatigue 56 (18%)

Sore throat 23 (8%)

Chills 22 (7%)

Nausea 21 (7%)

Arthralgia 20 (7%)

Sweating 17 (6%)

Cough 18 (6%)

Wheezing 4 (1%)

Chest tightness 4 (1%)

Other difficulties breathing 3 (1%)

Facial edema -

Results reported to the nearest whole percent

– not reported

Vial and Syringe leaflet text Page 8 of 20

———————– Page 9———————–

Novartis Vaccines and Diagnostics Limited BLA 1750

September 2009

TABLE 3

Adverse Events Reported by at least 5% of Subjects in Clinical Trials since 1998

§ § §

1998-1999 1999-2000 2000-2001

18-64 yrs = 65 yrs 18-64 yrs = 65 yrs 18-64 yrs = 65 yrs

N = 66 N = 44 N = 76 N = 34 N = 75 N = 35

Adverse Events

Fatigue 8 (12%) 2 (5%) 8 (11%) 2 (6%) 5 (7%) -

Back pain 4 (6%) 3 (7%) – - – -

Cough increased 2 (3%) 2 (5%) – - – -

Ecchymosis 4 (6%) 1 (2%) 4 (5%) 1 (3%) 5 (7%) -

Fever 3 (5%) – - – - -

Headache 12 (18%) 5 (11%) 22 (29%) 5 (15%) 14 (19%) 2 (6%)

Infection 3 (5%) 2 (5%) – - – -

Malaise 4 (6%) 4 (9%) 4 (5%) 1 (3%) – -

Migraine 4 (6%) 1 (2%) – - – -

Myalgia 4 (6%) 1 (2%) – - – -

Sweating 5 (8%) 1 (2%) – - – -

Rhinitis 3 (5%) 1 (2%) – - 5 (7%) 2 (6%)

Pharingitis 6 (9%) 1 (2%) 10 (13%) – 6 (8%) -

Arthralgia – - – 2 (6%) – -

Injection site pain 16 (24%) 4 (9%) 16 (21%) – 9 (12%) -

Injection site ecchymosis 4 (6%) 1 (2%) – - 4 (5%) -

Injection site mass 7 (11%) 1 (2%) 4 (5%) – 8 (11%) 1 (3%)

Injection site edema – - 1 (1%) 2 (6%) – -

Injection site 5 (8%) 2 (5%) 6 (8%) – 7 (9%) 1 (3%)

inflammation

Injection site reaction – - – - 4 (5%) 1 (3%)

^ ^ ^

2001-2002 2002-2003 2004-2005

18-64 yrs = 65 yrs 18-64 yrs = 65 yrs 18-64 yrs = 65 yrs

N = 75 N = 35 N = 107 N = 88 N = 74 N = 61

Adverse Events

Fatigue 5 (7%) 4 (11%) 11 (10%) 8 (9%) 4 (5%) 2 (3%)

Hypertension – - 1 (1%) 4 (5%) – -

Rinorrhea – - 2 (2%) 5 (6%) – -

Headache 20 (27%) 2 (6%) 35 (33%) 18 (20%) 12 (16%) 1 (2%)

Malaise 6 (8%) 1 (3%) 13 (12%) 8 (9%) – -

Myalgia 4 (5%) 1 (3%) 10 (9%) 4 (5%) – -

Sweating 3 (4%) 3 (9%) 2 (2%) 5 (6%) – -

Rhinitis 4 (5%) – - – - -

Pharingitis – - – - 6 (8%) -

Arthralgia – - 5 (5%) 4 (5%) – -

Sore throat 4 (5%) 1 (3%) 5 (5%) 4 (5%) – -

Injection site pain 13 (17%) 3 (9%) 14 (13%) 7 (8%) 6 (8%) 2 (3%)

Injection site ecchymosis 4 (5%) 1 (3%) 4 (4%) 4 (5%) – -

Injection site erythema 5 (7%) 2 (6%) 11 (10%) 5 (6%) 4 (5%) -

Injection site mass 4 (5%) 1 (3%) – - – -

Injection site edema – - 6 (6%) 2 (2%) 4 (5%) 1 (2%)

Injection site induration – - 14 (13%) 3 (3%) 7 (9%) -

Results reported to the nearest whole percent; Fever defined as >38°C

– not reaching the cut-off of 5%

§ Solicited adverse events reported by COSTART preferred term

^ Solicited adverse events reported by MEDDRA preferred term

Vial and Syringe leaflet text Page 9 of 20

———————– Page 10———————–

Novartis Vaccines and Diagnostics Limited BLA 1750

September 2009

Adults (18 to 64 years of age)

In adult subjects, solicited local adverse events occurred with similar frequency in

all trials. The most common solicited adverse events occurring in the first 96 hours after

administration (Tables 1 and 2) were associated with the injection site (such as pain,

erythema, mass, induration and swelling) but were generally mild/moderate and transient.

The most common solicited systemic adverse events were headache and myalgia.

The most common overall events in adult subjects (18-64 years of age) were

headache, fatigue, injection site reactions (pain, mass, erythema, and induration) and

malaise (Table 3).

Geriatric Subjects (65 years of age and older)

In geriatric subjects, solicited local and systemic adverse events occurred less

frequently than in adult subjects. The most common solicited local and systemic adverse

events were injection site pain, and headache (Tables 1 and 2). All were considered

mild/moderate and were transient.

The most common overall events in elderly subjects (=65 years of age) were

headache and fatigue.

Only 11 serious adverse events in adult and geriatric subjects (18 years and older)

have been reported to date from all the trials performed. These serious adverse events

were a minor stroke experienced by a 67 year old subject 14 days after vaccination

(1990), death of an 82 year old subject 35 days after vaccination (1990) in very early

studies; death of a 72 year old subject 19 days after vaccination (1998-1999), a

hospitalization for hemorrhoidectomy of a 38 year old male subject (1999-2000), a severe

respiratory tract infection experienced by a 74 year old subject 12 days after vaccination

(2002-2003), a planned transurethral resection of the prostate in a subject with prior

history of prostatism (2004-2005), two cases of influenza (2005-2006), a drug overdose

(2005-2006), cholelithiasis (2005-2006) and a nasal septal operation (2005-2006). None

of these events were considered causally related to vaccination.

Clinical Trial Experience in Pediatric Subjects

In 1987 a clinical study was carried out in 38 ‘at risk’ children aged between 4

and 12 years (17 females and 21 males). To record the safety of FLUVIRIN, participants

recorded their symptoms on a diary card during the three days after vaccination and noted

any further symptoms they thought were attributable to the vaccine. The only reactions

recorded were tenderness at the site of vaccination in 21% of the participants on day 1,

which was still present in 16% on day 2 and 5% on day 3. In one child, the tenderness

was also accompanied by redness at the site of injection for two days. The reactions were

not age-dependent and there was no bias towards the younger children.

Three clinical studies were carried out between 1995 and 2004 in a total of 520

pediatric subjects (age range 6 – 47 months). Of these, 285 healthy subjects plus 41 ‘at

risk’ subjects received FLUVIRIN. No serious adverse events were reported.

FLUVIRIN and Influenza A (H1N1) 2009 Monovalent Vaccine should only be

used for the immunization of persons aged 4 years and over.

6.3 Postmarketing Experience

The following additional adverse reactions have been reported during post-

approval use of FLUVIRIN. Because these reactions are reported voluntarily from a

population of uncertain size, it is not always possible to reliably estimate their frequency

Vial and Syringe leaflet text Page 10 of 20

———————– Page 11———————–

Novartis Vaccines and Diagnostics Limited BLA 1750

September 2009

or establish a causal relationship to vaccine exposure. Adverse events described here are

included because: a) they represent reactions which are known to occur following

immunizations generally or influenza immunizations specifically; b) they are potentially

serious; or c) the frequency of reporting.

• Body as a whole: Local injection site reactions (including pain, pain limiting limb

movement, redness, swelling, warmth, ecchymosis, induration), hot flashes/flushes;

chills; fever; malaise; shivering; fatigue; asthenia; facial edema.

• Immune system disorders: Hypersensitivity reactions (including throat and/or mouth

edema). In rare cases, hypersensitivity reactions have lead to anaphylactic shock and

death.

• Cardiovascular disorders: Vasculitis (in rare cases with transient renal involvement),

syncope shortly after vaccination.

• Digestive disorders: Diarrhea; nausea; vomiting; abdominal pain.

• Blood and lymphatic disorders: Local lymphadenopathy; transient thrombocytopenia.

• Metabolic and nutritional disorders: Loss of appetite.

• Musculoskeletal: Arthralgia; myalgia; myasthenia.

• Nervous system disorders: Headache; dizziness; neuralgia; paraesthesia; confusion;

febrile convulsions; Guillain-Barré Syndrome; myelitis (including encephalomyelitis

and transverse myelitis); neuropathy (including neuritis); paralysis (including Bell’s

Palsy).

• Respiratory disorders: Dyspnea; chest pain; cough; pharyngitis; rhinitis.

• Skin and appendages: Stevens-Johnson syndrome; sweating; pruritus; urticaria; rash

(including non-specific, maculopapular, and vesiculobulbous).

6.4 Other Adverse Reactions Associated with Influenza Vaccination

Anaphylaxis has been reported after administration of FLUVIRIN. Although

FLUVIRIN and Influenza A (H1N1) 2009 Monovalent Vaccine contain only a limited

quantity of egg protein, this protein can induce immediate hypersensitivity reactions

among persons who have severe egg allergy. Allergic reactions include hives,

angioedema, allergic asthma, and systemic anaphylaxis [see CONTRAINDICATIONS

(4)].

The 1976 swine influenza vaccine was associated with an increased frequency of

Guillain-Barré syndrome (GBS). Evidence for a causal relation of GBS with subsequent

vaccines prepared from other influenza viruses is unclear. If influenza vaccine does pose

a risk, it is probably slightly more than 1 additional case/1 million persons vaccinated.

Neurological disorders temporally associated with influenza vaccination such as

encephalopathy, optic neuritis/neuropathy, partial facial paralysis, and brachial plexus

neuropathy have been reported.

Microscopic polyangiitis (vasculitis) has been reported temporally associated with

influenza vaccination.

7 DRUG INTERACTIONS

7.1 Concomitant Administration with Other Vaccines

There are no data to assess the concomitant administration of Influenza A (H1N1)

2009 Monovalent Vaccine with other vaccines. If Influenza A (H1N1) 2009 Monovalent

Vaccine is to be given at the same time as another injectable vaccine(s), the vaccines

should always be administered at different injection sites.

Vial and Syringe leaflet text Page 11 of 20

———————– Page 12———————–

Novartis Vaccines and Diagnostics Limited BLA 1750

September 2009

Influenza A (H1N1) 2009 Monovalent Vaccine should not be mixed with any

other vaccine in the same syringe or vial.

7.2 Concurrent Use with Immunosuppressive Therapies

Immunosuppressive therapies, including irradiation, antimetabolites, alkylating

agents, cytotoxic drugs, and corticosteroids (used in greater than physiologic doses), may

reduce the immune response to Influenza A (H1N1) 2009 Monovalent Vaccine.

8 USE IN SPECIFIC POPULATIONS

Novartis’ Influenza A (H1N1) 2009 Monovalent Vaccine and seasonal trivalent

Influenza Virus Vaccine (FLUVIRIN) are manufactured by the same process. Available

information for FLUVIRIN is provided in this section.

8.1 Pregnancy

Pregnancy Category C: Animal reproduction studies have not been conducted

with Influenza A (H1N1) 2009 Monovalent Vaccine or FLUVIRIN. It is also not known

whether Influenza A (H1N1) 2009 Monovalent Vaccine or FLUVIRIN can cause fetal

harm when administered to a pregnant woman or can affect reproduction capacity.

Influenza A (H1N1) 2009 Monovalent Vaccine should be given to a pregnant woman

only if clearly needed.

8.3 Nursing Mothers

It is not known whether FLUVIRIN or Influenza A (H1N1) 2009 Monovalent

Vaccine is excreted in human milk. Because many drugs are excreted in human milk,

caution should be exercised when Influenza A (H1N1) 2009 Monovalent Vaccine is

administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness in pediatric subjects below the age of 4 years have not

been established. [see ADVERSE REACTIONS (6) and CLINICAL STUDIES (14)]

8.5 Geriatric Use

Since 1997, of the total number of geriatric subjects (n = 397) in clinical studies

of FLUVIRIN, 29% of adult subjects were 65 years and over, while 2.1% were 75 years

and over.

Antibody responses were lower in the geriatric population than in younger

subjects. Adverse events occurred less frequently in geriatric subjects (=65 years) than in

younger adults. Other reported clinical experience has not identified differences in

responses between the elderly and younger patients. [See ADVERSE REACTION (6)

and CLINICAL STUDIES (14)].

11 DESCRIPTION

Influenza A (H1N1) 2009 Monovalent Vaccine is a sub-unit (purified surface

antigen) influenza virus vaccine prepared from virus propagated in the allantoic cavity of

embryonated hens’ eggs inoculated with a specific type of influenza virus suspension

containing neomycin and polymyxin. The influenza virus strain is harvested and clarified

by centrifugation and filtration prior to inactivation with betapropiolactone. The

inactivated virus is concentrated and purified by zonal centrifugation. The surface

antigens, hemagglutinin and neuraminidase, are obtained from the influenza virus particle

by further centrifugation in the presence of nonylphenol ethoxylate, a process which

Vial and Syringe leaflet text Page 12 of 20

———————– Page 13———————–

Novartis Vaccines and Diagnostics Limited BLA 1750

September 2009

removes most of the internal proteins. The nonylphenol ethoxylate is removed from the

surface antigen preparation.

Influenza A (H1N1) 2009 Monovalent Vaccine is a homogenized, sterile, slightly

opalescent suspension in a phosphate buffered saline. Influenza A (H1N1) 2009

Monovalent Vaccine is formulated to contain 15 mcg hemagglutinin (HA) per 0.5-mL

dose of the following virus strain: A/California/7/2009 (H1N1)v-like virus.

The 0.5-mL prefilled syringe presentation is formulated without preservative.

Thimerosal, a mercury derivative used during manufacturing, is removed by subsequent

purification steps to a trace amount (= 1 mcg mercury per 0.5-mL dose).

The 5-mL multidose vial formulation contains thimerosal, a mercury derivative,

added as a preservative. Each 0.5-mL dose from the multidose vial contains 25 mcg

mercury.

Each dose from the multidose vial or from the prefilled syringe may also contain

residual amounts of egg proteins (= 1 mcg ovalbumin), polymyxin (= 3.75 mcg),

neomycin (= 2.5 mcg), betapropiolactone (not more than 0.5 mcg) and nonylphenol

ethoxylate (not more than 0.015% w/v).

The multidose vial stopper and the syringe stopper/plunger do not contain latex.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Influenza illness and its complications follow infection with influenza viruses.

Global surveillance of influenza identifies yearly antigenic variants. For example, since

1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B

viruses have been in global circulation. Specific levels of hemagglutination inhibition

(HI) antibody titers post-vaccination with inactivated influenza virus vaccine have not

been correlated with protection from influenza illness. In some human studies, antibody

titer of =1:40 have been associated with protection from influenza illness in up to 50% of

subjects [see REFERENCES (15.2, 15.3)].

Antibody against one influenza virus type or subtype confers limited or no

protection against another. Furthermore, antibody to one antigenic variant of influenza

virus might not protect against a new antigenic variant of the same type or subtype.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Neither FLUVIRIN nor the Influenza A (H1N1) 2009 Monovalent Vaccine have

been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility.

14 CLINICAL STUDIES

Novartis’ Influenza A (H1N1) 2009 Monovalent Vaccine and seasonal trivalent

Influenza Virus Vaccine (FLUVIRIN) are manufactured by the same process. Data in

this section were obtained in clinical studies conducted with FLUVIRIN.

Between 1982 and 1991, twelve clinical studies were conducted in healthy adult

and geriatric subjects and one in children between 4 and 12 years of age who were

considered to be ‘at risk’. Since 1991 an annual clinical study has been conducted in the

UK in healthy adults aged 18 years or older. FLUVIRIN was also used as a control in a

US clinical trial in adults (18-49 years of age). In all the trials, blood samples were taken

prior to vaccination and approximately three weeks after vaccination to assess the

immunogenic response to vaccination by measurement of anti-HA antibodies.

Three clinical studies were carried out between 1995 and 2004 in a total of 520

pediatric subjects (age range 6-48 months). Of these, 285 healthy subjects plus 41 ‘at

Vial and Syringe leaflet text Page 13 of 20

———————– Page 14———————–

Novartis Vaccines and Diagnostics Limited BLA 1750

September 2009

risk’ pediatric subjects, received FLUVIRIN.

Influenza A (H1N1) 2009 Monovalent Vaccine should only be used for the

immunization of persons aged 4 years and over.

14.1 Immunogenicity in Adults (18 to 64 years of age)

Tables 4 and 5 show the immunogenicity data for the adult age group. The seven

clinical studies presented enrolled a total of 774 adult subjects. In the adult group, for all

antigens (A/H1N1, A/H3N2 and B) at least one of the following point estimate criteria

was met: the proportion of subjects with seroconversion (post-vaccination titer =1:40

from a pre-vaccination titer <1:10) or significant increase (at least a four-fold increase

from pre-vaccination titer =1:10) in antibody titer was greater than 40%; the geometric

mean titer (GMT) increase was >2.5; the proportion of subjects with a post-vaccination

hemagglutination inhibition (HI) antibody titer =1:40 was greater than 70%.

Vial and Syringe leaflet text Page 14 of 20

———————– Page 15———————–

Novartis Vaccines and Diagnostics Limited BLA 1750

September 2009

TABLE 4

Summary of the Seroconversion and Proportion of Subjects Achieving an HI titer

=1:40 for Adult Subjects

No. of Seroconversion 8 HI titer =1:40¥

Year/Strain

subjects N % 95% CIf N % 95% CIf

1998-1999

A/H1N1 48 73 (62, 83) 50 76 (65, 86)

A/H3N2 66 43 65 (54, 77) 47 71 (60, 82)

B 42 64 (52, 75) 62 94 (88, 100)

1999-2000

A/H1N1 45 59 (48, 70) 50 66 (55, 76)

A/H3N2 76 51 67 (57, 78) 66 87 (79, 94)

B 53 70 (59, 80) 75 99 (96, 100)

2000-2001

A/H1N1 41 55 (44, 67) 41 55 (44, 67)

A/H3N2 74 45 61 (50, 72) 52 84 (75, 92)

B 50 68 (57, 78) 73 99 (96, 100)

2001-2002

A/H1N1 44 59 (48, 70) 48 64 (53, 75)

A/H3N2 75 46 61 (50, 72) 68 91 (84, 97)

B 42 56 (45, 67) 66 88 (81, 95)

2002-2003

A/H1N1 62 58 (49, 68) 73 69 (60, 78)

A/H3N2 106 72 68 (59, 77) 93 88 (81, 94)

B 78 74 (65, 82) 101 95 (91, 99)

2004-2005

A/H1N1 52 70 (59, 80) 66 89 (80, 95)

A/H3N2 74 60 81 (70, 89) 73 99 (93, 100)

B 57 77 (66, 86) 69 93 (85, 98)

2005-2006

A/H1N1 191 63 (57, 68) 296 98 (95, 99)

A/H3N2 303 273 90 (86, 93) 294 97 (94, 99)

B 213 70 (65, 75) 263 87 (82, 90)

8 Seroconversion: proportion of subjects with either a post-vaccination HI titer =1:40 from a pre-

vaccination titer <1:10 or at least a four-fold increase from pre-vaccination HI titer =1:10 in

antibody titer.

¥ HI titer =1:40: proportion of subjects with a post-vaccination titer = 1:40.

f 95% CI: 95% confidence interval

Vial and Syringe leaflet text Page 15 of 20

----------------------- Page 16-----------------------

Novartis Vaccines and Diagnostics Limited BLA 1750

September 2009

TABLE 5

Summary of the Geometric Mean Hemagglutination Inhibition Antibody Titers,

Pre- and Post-Immunization, for Adult Subjects

Geometric Mean Titer (GMT)

No. of

Year/Strain Pre- Post-

subjects Fold Increase (95% CI)*

vaccination vaccination

1998-1999

A/H1N1 7.26 160.87 22.16 (14.25, 34.46)

A/H3N2 66 8.23 87.02 10.57 (6.91, 16.16)

B 20.97 231.07 110.2 (6.90, 17.59)

1999-2000

A/H1N1 7.43 58.95 7.93 (5.73, 10.97)

A/H3N2 76 15.29 122.83 8.03 (5.80, 11.13)

B 25.70 254.76 9.91 (6.97, 14.10)

2000-2001

A/H1N1 5.42 33.80 6.24 (4.49, 8.69)

A/H3N2 74 15.98 126.01 7.89 (5.61, 11.09)

B 26.24 308.25 11.75 (7.73, 17.85)

2001-2002

A/H1N1 7.76 54.78 7.06 (5.24, 9.52)

A/H3N2 75 23.67 153.81 6.50 (4.78, 8.84)

B 19.91 107.53 5.40 (3.95, 7.38)

2002-2003

A/H1N1 7.78 60.39 7.77 (5.81, 10.39)

A/H3N2 106 23.32 292.03 12.52 (8.77, 17.87)

B 30.20 314.11 10.40 (7.54, 14.34)

2004-2005

A/H1N1 13 159 12 (8.39, 17)

A/H3N2 74 37 658 18 (12, 26)

B 15 156 11 (7.87, 14)

2005-2006

A/H1N1 29 232 8 (6.68, 9.59)

A/H3N2 303 14 221 15 (14, 17)

B 13 83 6.5 (5.73, 7.37)

* 95% CI: 95% confidence interval

14.2 Immunogenicity in Geriatric Subjects (65 years of age and older)

Tables 6 and 7 show the immunogenicity of FLUVIRIN in the geriatric age

group. The six clinical studies presented enrolled a total of 296 geriatric subjects. For

each of the influenza antigens, the percentage of subjects who achieved seroconversion

and the percentage of subjects who achieved HI titers of =1:40 are shown, as well as the

fold increase in GMT.

For all antigens (A/H1N1, A/H3N2 and B) at least one of the following point

estimate criteria was met: the proportion of subjects with seroconversion (post-

vaccination titer =1:40 from a pre-vaccination titer <1:10) or significant increase (at least

a four-fold increase from pre-vaccination titer =1:10) in antibody titer was greater than

30%; the geometric mean titer (GMT) increase was >2.0; the proportion of subjects with

a post-vaccination hemagglutination inhibition (HI) antibody titer =1:40 was greater than

60%. The pre-specified efficacy criteria were met in each study, although a relatively

Vial and Syringe leaflet text Page 16 of 20

———————– Page 17———————–

Novartis Vaccines and Diagnostics Limited BLA 1750

September 2009

lower immunogenicity of A/H1N1 strain was seen in the last four studies (the same strain

was in each of the formulations).

TABLE 6

Summary of the Seroconversion and Proportion of Subjects Achieving an HI titer

=1:40 for Geriatric Subjects

No. of Seroconversion 8 HI titer =1:40¥

Year/Strain

subjects N % 95% CIf N % 95% CIf

1998-1999

A/H1N1 33 79 (66, 91) 38 90 (82, 99)

A/H3N2 42 33 79 (66, 91) 36 86 (75, 96)

B 13 31 (17, 45) 42 100 (100, 100)

1999-2000

A/H1N1 10 29 (14, 45) 23 68 (52, 83)

A/H3N2 34 18 53 (36, 70) 31 91 (82, 100)

B 9 26 (12, 41) 32 94 (86, 100)

2000-2001

A/H1N1 5 14 (3, 26) 10 29 (14, 44)

A/H3N2 35 22 63 (47, 79) 31 89 (78, 99)

B 13 37 (21, 53) 33 94 (87, 100)

2001-2002

A/H1N1 5 14 (3, 26) 14 40 (24, 56)

A/H3N2 35 15 43 (26, 59) 33 94 (87, 100)

B 6 17 (5, 30) 32 91 (82, 100)

2002-2003

A/H1N1 24 27 (18, 36) 52 58 (48, 69)

A/H3N2 89 42 47 (37, 58) 85 96 (91, 100)

B 41 46 (36, 56) 86 97 (93, 100)

2004-2005

A/H1N1 17 28 (17, 41) 46 75 (63, 86)

A/H3N2 61 29 48 (35, 61) 60 98 (91, 100)

B 38 62 (49, 74) 51 84 (72, 92)

8 Seroconversion: proportion of subjects with either a post-vaccination HI titer =1:40 from a pre-

vaccination titer <1:10 or at least a four-fold increase from pre-vaccination HI titer =1:10 in

antibody titer

¥ HI titer =1:40: proportion of subjects with a post-vaccination titer =1:40

f 95% CI: 95% confidence interval

Vial and Syringe leaflet text Page 17 of 20

———————– Page 18———————–

Novartis Vaccines and Diagnostics Limited BLA 1750

September 2009

TABLE 7

Summary of the Geometric Mean Hemagglutination Inhibition Antibody Titers,

Pre- and Post-Immunization, for Geriatric Subjects

Geometric Mean Titer (GMT)

No. of

Year/Strain Pre- Post-

subjects Fold Increase (95% CI)*

vaccination vaccination

1998-1999

A/H1N1 13.92 176.65 12.69 (8.24, 19.56)

A/H3N2 42 10.69 124.92 11.69 (7.02, 19.46)

B 114.1 273.56 2.40 (1.82, 3.17)

1999-2000

A/H1N1 15.82 50.58 3.20 (2.13, 4.80)

A/H3N2 34 28.00 133.19 4.76 (2.92, 7.76)

B 57.16 127.86 2.24 (1.56, 3.20)

2000-2001

A/H1N1 6.66 18.85 2.83 (1.91, 4.18)

A/H3N2 35 25.87 140.68 5.44 (3.72, 7.96)

B 61.24 191.23 3.12 (2.13, 4.59)

2001-2002

A/H1N1 12.69 26.65 2.10 (1.55, 2.84)

A/H3N2 35 47.33 114.26 2.41 (1.73, 3.38)

B 45.49 91.89 2.02 (1.47, 2.78)

2002-2003

A/H1N1 13.29 31.92 2.40 (1.90, 3.03)

A/H3N2 89 65.86 272.79 4.14 (3.09, 5.55)

B 74.87 288.57 3.85 (2.89, 5.13)

2004-2005

A/H1N1 21 64 3.13 (2.33, 4.2)

A/H3N2 61 72 320 4.43 (3.13, 6.27)

B 20 114 5.69 (4.39, 7.38)

* 95% CI: 95% confidence interval

14.3 Immunogenicity in Pediatric Subjects

A small-scale study was conducted in 1987 to evaluate safety and

immunogenicity of FLUVIRIN in 38 ‘at risk’ children, with diabetes and/or asthma, or

lymphoid leukemia. Thirty-eight participants aged between 4 and 12 years of age were

assessed. Ten subjects had diabetes, 21 had asthma, two had both diabetes and asthma,

and one had lymphoid leukemia. There were four healthy control subjects. All

participants received a single 0.5-mL dose of FLUVIRIN.

Immunogenicity results were obtained for 19 of the 38 subjects enrolled in the

study. The point estimate of the percentage of subjects achieving a titer of = 1:40 was

84% for the A/H1N1 strain 79% for the B strain, and 53% for the A/H3N2 strain. The

GMT fold increases were 5.8 for the A/H1N1 strain, 40 for the B strain and 17.7 for the

A/H3N2 strain.

Three clinical studies were carried out between 1995 and 2004 in a total of 520

pediatric subjects (age range 6-47 months). Of these, 285 healthy subjects plus 41 ‘at

risk’ pediatric subjects, received FLUVIRIN.

In a 1995/1996 clinical study, 41 subjects (aged 6-36 months) at increased risk for

influenza-related complications received two 0.25-mL doses of FLUVIRIN. At least

49% of subjects showed a =4-fold increase in HI antibody titer to all three strains. HI

Vial and Syringe leaflet text Page 18 of 20

———————– Page 19———————–

Novartis Vaccines and Diagnostics Limited BLA 1750

September 2009

antibody titers of 1:40 or greater were seen in at least 71% of the subjects for all three

influenza strains, with increases in geometric mean titer of 6.0-fold or greater to all three

strains.

Two clinical studies (1999-2000 and 2004) indicated a lower immunogenicity

profile for FLUVIRIN compared with two commercial split vaccines; in a study in the

age group 6-48 months the comparator was a US licensed vaccine, Fluzone®, and in

another study in the age group 6-36 months the comparator was a non-US licensed

inactivated influenza vaccine. Despite the small sample size (a total of 285 healthy

subjects received FLUVIRIN in these two clinical studies) the lower immunogenicity

profile of FLUVIRIN was greatest versus the comparator vaccines in children <36months

but was also evident in those 36-48 months of age, though the differences were less.

Influenza A (H1N1) 2009 Monovalent Vaccine should only be used for the

immunization of persons aged 4 years and older.

15 REFERENCES

15.1 CDC. Serum cross-reactive antibody response to a novel influenza A (H1N1)

virus after vaccination with seasonal influenza vaccine. MMWR 2009; 58(19):

521-4.

15.2 Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of

influenza vaccination. Virus Res 2004; 103:133-138.

15.3 Hobson D, Curry RL, Beare A, et. al. The role of serum hemagglutinin-inhibiting

antibody in protection against challenge infection with influenza A2 and B

viruses. J Hyg Camb 1972; 767-777.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Influenza A (H1N1) 2009 Monovalent Vaccine is supplied as a 0.5-mL prefilled

single dose syringe, package of 10 syringes per carton. NDC 66521-200-02

Influenza A (H1N1) 2009 Monovalent Vaccine is supplied as a 5-mL multidose

vial, individually packaged in a carton. NDC 66521-200-10

16.2 Storage and Handling

Store Influenza A (H1N1) 2009 Monovalent Vaccine refrigerated between 2º and

8ºC (36º and 46ºF).

Do not freeze. Discard if the vaccine has been frozen.

Store in the original package to protect from light.

Do not use after the expiration date.

Between uses, return the multidose vial to the recommended storage conditions.

17 PATIENT COUNSELING INFORMATION

Vaccine recipients and guardians should be informed by their health care provider

of the potential benefits and risks of immunization with Influenza A (H1N1) 2009

Monovalent Vaccine. When educating vaccine recipients and guardians regarding the

potential side effects, clinicians should emphasize that Influenza A (H1N1) 2009

Monovalent Vaccine contains non-infectious particles and cannot cause influenza.

Vaccine recipients and guardians should be instructed to report any severe or

unusual adverse reactions to their healthcare provider.

Vaccine recipients should be advised that there are two influenza vaccine

formulations for this influenza season, the monovalent pandemic (H1N1) 2009 influenza

vaccine and seasonal trivalent influenza vaccine.

Vial and Syringe leaflet text Page 19 of 20

———————– Page 20———————–

Novartis Vaccines and Diagnostics Limited BLA 1750

September 2009

Manufactured by: Novartis Vaccines and Diagnostics Limited, Speke, Liverpool, UK

An affiliate of: Novartis Vaccines and Diagnostics, Inc., 350 Massachusetts

Avenue, Cambridge, MA 02139 USA

1-800-244-7668

Vial and Syringe leaflet text Page 20 of 20