Human Papillomavirus Bivalent Vaccine (Cervarix)
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Human Papillomavirus Bivalent Vaccine (Cervarix)

CERVARIX
[Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant] Suspension for Intramuscular Injection

DRUG DESCRIPTION

CERVARIX [Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant] is a non-infectious recombinant, AS04-adjuvanted vaccine that contains recombinant L1 protein, the major antigenic protein of the capsid, of oncogenic HPV types 16 and 18. The L1 proteins are produced in separate bioreactors using the recombinant Baculovirus expression vector system in a serum-free culture media composed of chemically-defined lipids, vitamins, amino acids, and mineral salts. Following replication of the L1 encoding recombinant Baculovirus in Trichoplusia ni insect cells, the L1 protein accumulates in the cytoplasm of the cells. The L1 proteins are released by cell disruption and purified by a series of chromatographic and filtration methods. Assembly of the L1 proteins into virus-like particles (VLPs) occurs at the end of the purification process. The purified, non-infectious VLPs are then adsorbed on to aluminum (as hydroxide salt). The adjuvant system, AS04, is composed of 3-O-desacyl-4'-monophosphoryl lipid A (MPL) adsorbed on to aluminum (as hydroxide salt).

CERVARIX (human papillomavirus bivalent vaccine) is prepared by combining the adsorbed VLPs of each HPV type together with the AS04 adjuvant system in sodium chloride, sodium dihydrogen phosphate dihydrate, and Water for Injection.

CERVARIX (human papillomavirus bivalent vaccine) is a sterile suspension for intramuscular injection. Each 0.5-mL dose is formulated to contain 20 mcg of HPV type 16 L1 protein, 20 mcg of HPV type 18 L1 protein, 50 mcg of the 3-O-desacyl-4'-monophosphoryl lipid A (MPL), and 0.5 mg of aluminum hydroxide. Each dose also contains 4.4 mg of sodium chloride and 0.624 mg of sodium dihydrogen phosphate dihydrate. Each dose may also contain residual amounts of insect cell and viral protein ( < 40 ng) and bacterial cell protein ( < 150 ng) from the manufacturing process. CERVARIX (human papillomavirus bivalent vaccine) does not contain a preservative.

What are the possible side effects of human papillomavirus vaccine (Cervarix)?

You should not receive a booster vaccine if you have had a life-threatening allergic reaction after the first shot.

Developing cancer from HPV is much more dangerous to your health than receiving the vaccine to protect against it. However, like any medicine, this vaccine can cause side effects but the risk of serious side effects is extremely low.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

You may feel faint after receiving this...

Read All Potential Side Effects and See Pictures of Cervarix »

What are the precautions when taking human papillomavirus bivalent vaccine (Cervarix)?

Before receiving this medication, tell your doctor or pharmacist if you are allergic to it; or to latex; or to other vaccines; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before receiving this vaccination, tell your doctor or pharmacist your medical history, especially of: immune system problems (such as HIV infection), bleeding disorders (such as hemophilia, thrombocytopenia), current fever/illness.

This vaccine can cause some patients to faint, which could cause falling and injury. To reduce the risk of this side effect, your doctor may recommend that you stay in a sitting or lying position for 15 minutes after the injection....

Read All Potential Precautions of Cervarix »

Last reviewed on RxList: 10/30/2009
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

Indications

CERVARIX (human papillomavirus bivalent vaccine) ® is indicated for the prevention of the following diseases caused by oncogenic human papillomavirus (HPV) types 16 and 18 [see Clinical Studies]:

CERVARIX (human papillomavirus bivalent vaccine) is approved for use in females 10 through 25 years of age.

Limitations of Use and Effectiveness

CERVARIX (human papillomavirus bivalent vaccine) does not provide protection against disease due to all HPV types [see Clinical Studies].

CERVARIX (human papillomavirus bivalent vaccine) has not been demonstrated to provide protection against disease from vaccine and non-vaccine HPV types to which a woman has previously been exposed through sexual activity [see Clinical Studies].

Females should continue to adhere to recommended cervical cancer screening procedures [see Patient Counseling Information].

Vaccination with CERVARIX (human papillomavirus bivalent vaccine) may not result in protection in all vaccine recipients.

DOSAGE AND ADMINISTRATION

Preparation for Administration

Shake vial or syringe well before withdrawal and use. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. CERVARIX (human papillomavirus bivalent vaccine) also should be inspected visually for cracks in the vial or syringe prior to administration. If any of these conditions exist, the vaccine should not be administered. With thorough agitation, CERVARIX (human papillomavirus bivalent vaccine) is a homogeneous, turbid, white suspension. Discard if it appears otherwise.

Dose and Schedule

Immunization with CERVARIX (human papillomavirus bivalent vaccine) consists of 3 doses of 0.5-mL each, by intramuscular injection according to the following schedule: 0, 1, and 6 months. The preferred site of administration is the deltoid region of the upper arm.

Do not administer this product intravenously, intradermally, or subcutaneously.

HOW SUPPLIED

Dosage Forms And Strengths

CERVARIX (human papillomavirus bivalent vaccine) is a suspension for intramuscular injection available in 0.5-mL single-dose vials and prefilled TIP-LOK® syringes.

CERVARIX (human papillomavirus bivalent vaccine) is available in 0.5-mL single-dose vials and prefilled TIP-LOK syringes.

Single-Dose Vials

NDC 58160-830-11 (package of 10)

Single-Dose Prefilled Disposable TIP-LOK Syringes (packaged without needles)

NDC 58160-830-32 (package of 1)
NDC
58160-830-46 (package of 5)

Store refrigerated between 2? and 8?C (36? and 46?F). Do not freeze. Discard if the vaccine has been frozen. Upon storage, a fine, white deposit with a clear, colorless supernatant may be observed. This does not constitute a sign of deterioration.

Manufactured by GlaxoSmithKline Biologicals. Rixensart, Belgium. Distributed by GlaxoSmithKline Research Triangle Park, NC 27709.

Last reviewed on RxList: 10/30/2009
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

The most common local adverse reactions ( ≥ 20% of subjects) were pain, redness, and swelling at the injection site.

The most common general adverse events ( ≥ 20% of subjects) were fatigue, headache, myalgia, gastrointestinal symptoms, and arthralgia.

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared with rates in the clinical trials of another vaccine, and may not reflect the rates observed in practice. There is the possibility that broad use of CERVARIX (human papillomavirus bivalent vaccine) could reveal adverse reactions not observed in clinical trials.

Studies in Females 10 Through 25 Years of Age: The safety of CERVARIX (human papillomavirus bivalent vaccine) was evaluated by pooling data from controlled and uncontrolled clinical trials involving 23,713 females 10 through 25 years of age in the pre-licensure clinical development program. In these studies, 12,785 females (10 through 25 years of age) received at least one dose of CERVARIX (human papillomavirus bivalent vaccine) and 10,928 females received at least one dose of a control [Hepatitis A Vaccine containing 360 EL.U. (10 through 14 years of age), Hepatitis A Vaccine containing 720 EL.U. (15 through 25 years of age), or Al(OH)3 (500 mcg, 15 through 25 years of age)].

Data on solicited local and general adverse events were collected by subjects or parents using standardized diary cards for 7 consecutive days following each vaccine dose (i.e., day of vaccination and the next 6 days). Unsolicited adverse events were recorded with diary cards for 30 days following each vaccination (day of vaccination and 29 subsequent days). Parents and/or subjects were also asked at each study visit about the occurrence of any adverse events and instructed to immediately report serious adverse events throughout the study period. These studies were conducted in North America, Latin America, Europe, Asia, and Australia. Overall, the majority of subjects were white (59%), followed by Asian (26%), Hispanic (9%), black (3%), and other racial/ethnic groups (3%).

Solicited Adverse Events: The reported frequencies of solicited local injection site reactions (pain, redness, and swelling) and general adverse events (fatigue, fever, gastrointestinal symptoms, headache, arthralgia, myalgia, and urticaria) within 7 days after vaccination in females 10 through 25 years of age are presented in Table 1. An analysis of solicited local injection site reactions by dose is presented in Table 2. Local reactions were reported more frequently with CERVARIX (human papillomavirus bivalent vaccine) when compared with the control groups; in ≥ 84% of recipients of CERVARIX (human papillomavirus bivalent vaccine) , these local reactions were mild to moderate in intensity. Compared with dose 1, pain was reported less frequently after doses 2 and 3 of CERVARIX (human papillomavirus bivalent vaccine) , in contrast to redness and swelling where there was a small increased incidence. There was no increase in the frequency of general adverse events with successive doses.

Table 1. Rates of Solicited Local Adverse Reactions and General Adverse Events in Females 10 Through 25 Years of Age Within 7 Days of Vaccination (Total Vaccinated Cohorta)

Adverse Reaction/Event CERVARIX (human papillomavirus bivalent vaccine)
(10-25 yrs)
%
HAV 720b
(15-25 yrs)
%
HAV 360c
(10-14 yrs)
%
Al(OH)3 Controld
(15-25 yrs)
%
Local Adverse Reaction N = 6,431 N = 3,079 N = 1,027 N = 549
   Pain 91.8 78.0 64.2 87.2
   Redness 48.0 27.6 25.2 24.4
   Swelling 44.1 19.8 17.3 21.3
General Adverse Event N = 6,432 N = 3,079 N = 1,027 N = 549
   Fatigue 55.0 53.7 42.3 53.6
   Headache 53.4 51.3 45.2 61.4
   GIe 27.8 27.3 24.6 32.8
   Fever ( ≥ 99.5°F) 12.8 10.9 16.0 13.5
   Rash 9.6 8.4 6.7 10.0
  N = 5,881 N = 3,079 N = 1,027
   Myalgiaf 49.1 44.9 33.1
   Arthralgiaf 20.8 17.9 19.9
   Urticariaf 7.4 7.9 5.4
a Total vaccinated cohort included subjects with at least one documented dose (N).
b HAV 720 = Hepatitis A Vaccine control group [720 EL.U. of antigen and 500 mcg Al(OH)3].
c HAV 360 = Hepatitis A Vaccine control group [360 EL.U. of antigen and 250 mcg of Al(OH)3].
d Al(OH)3 Control = control containing 500 mcg Al(OH)3.
e GI = Gastrointestinal symptoms, including nausea, vomiting, diarrhea, and/or abdominal pain.
f Adverse events solicited in a subset of subjects.

Table 2. Rates of Solicited Local Adverse Reactions in Females 10 Through 25 Years of Age by Dose Within 7 Days of Vaccination (Total Vaccinated Cohorta)

Adverse Reaction CERVARIX (human papillomavirus bivalent vaccine)
(10-25 yrs)
%
HAV 720b
(15-25 yrs)
%
HAV 360c
(10-14 yrs)
%
Al(OH)3 Controld
(15-25 yrs)
%
Post-Dose Post-Dose Post-Dose Post-Dose
1 2 3 1 2 3 1 2 3 1 2 3
N 6,415 6,197 5,936 3,070 2,919 2,758 1,027 1,021 1,011 546 521 500
Pain 86.9 76.2 78.7 65.6 54.4 56.1 48.5 38.5 36.9 79.1 66.8 72.4
Pain, Grade 3e 7.5 5.7 7.7 2.0 1.4 2.0 0.8 0.2 1.6 9.0 6.0 8.6
Redness 27.8 29.6 35.6 16.6 15.2 16.1 15.6 13.3 12.1 11.5 11.5 15.6
Redness, > 50 mm 0.2 0.5 1.0 0.1 0.1 0.0 0.1 0.2 0.1 0.2 0.0 0.0
Swelling 22.7 25.2 32.7 10.5 9.4 10.5 9.4 8.6 7.6 10.3 10.4 12.0
Swelling, > 50 mm 1.2 1.0 1.3 0.2 0.2 0.2 0.4 0.3 0.0 0.0 0.0 0.0
a Total vaccinated cohort included subjects with at least one documented dose (N).
b HAV 720 = Hepatitis A Vaccine control group [720 EL.U. of antigen and 500 mcg Al(OH)3].
c HAV 360 = Hepatitis A Vaccine control group [360 EL.U. of antigen and 250 mcg of Al(OH)3].
d Al(OH)3 Control = control containing 500 mcg Al(OH)3.
e Defined as spontaneously painful or pain that prevented normal daily activities.

The pattern of solicited local adverse reactions and general adverse events following administration of CERVARIX (human papillomavirus bivalent vaccine) was similar between the age cohorts (10 through 14 years and 15 through 25 years).

Unsolicited Adverse Events: The frequency of unsolicited adverse events that occurred within 30 days of vaccination ( ≥ 1% for CERVARIX (human papillomavirus bivalent vaccine) and greater than any of the control groups) in females 10 through 25 years of age are presented in Table 3.

Table 3. Rates of Unsolicited Adverse Events in Females 10 Through 25 Years of Age Within 30 Days of Vaccination ( ≥ 1% For CERVARIX (human papillomavirus bivalent vaccine) and Greater Than HAV 720, HAV 360, or Al(OH)3 Control) (Total Vaccinated Cohorta)

Adverse Event CERVARIX (human papillomavirus bivalent vaccine)
%
(N = 6,654)
HAV 720b
%
(N = 3,186)
HAV 360c
%
(N = 1,032)
Al(OH)3 Controld
%
(N = 581)
Headache 5.3 7.6 3.3 9.3
Nasopharyngitis 3.6 3.4 5.9 3.3
Influenza 3.2 5.6 1.3 1.9
Pharyngolaryngeal pain 2.9 2.7 2.2 2.2
Dizziness 2.2 2.6 1.5 3.1
Upper respiratory infection 2.0 1.3 6.7 1.5
Chlamydia infection 2.0 4.4 0.0 0.0
Dysmenorrhea 2.0 2.3 1.9 4.0
Pharyngitis 1.5 1.8 2.2 0.5
Injection site bruising 1.4 1.8 0.7 1.5
Vaginal infection 1.4 2.2 0.1 0.9
Injection site pruritus 1.3 0.5 0.6 0.2
Back pain 1.1 1.3 0.7 3.1
Urinary tract infection 1.0 1.4 0.3 1.2
a Total vaccinated cohort included subjects with at least one dose administered (N).
b HAV 720 = Hepatitis A Vaccine control group [720 EL.U. of antigen and 500 mcg Al(OH)3].
c HAV 360 = Hepatitis A Vaccine control group [360 EL.U. of antigen and 250 mcg of Al(OH)3].
d Al(OH)3 Control = control containing 500 mcg Al(OH)3.

New Onset Autoimmune Diseases (NOADs): The pooled safety database, which included controlled and uncontrolled trials which enrolled females 10 through 25 years of age, was searched for new medical conditions indicative of potential new onset autoimmune diseases. Overall, the incidence of potential NOADs, as well as NOADs, in the group receiving CERVARIX (human papillomavirus bivalent vaccine) was 0.8% (95/12,533) and comparable to the pooled control group (0.8%, 87/10,730) during the 4.3 years of follow-up (mean 3.0 years) (Table 4).

In the largest randomized, controlled trial (Study 2) which enrolled females 15 through 25 years of age and which included active surveillance for potential NOADs, the incidence of potential NOADs and NOADs was 0.8% among subjects who received CERVARIX (human papillomavirus bivalent vaccine) (78/9,319) and 0.8% among subjects who received Hepatitis A Vaccine [720 EL.U. of antigen and 500 mcg Al(OH)3] control (77/9,325).

Table 4. Incidence of New Medical Conditions Indicative of Potential New Onset Autoimmune Disease and New Onset Autoimmune Disease Throughout the Follow-up Period Regardless of Causality in Females 10 Through 25 Years of Age (Total Vaccinated Cohorta)

  CERVARIX
(N = 12,533)
Pooled Control Groupb
(N = 10,730)
n (%)c n (%)c
Total Number of Subjects With at Least One Medical Condition 95 (0.8) 87 (0.8)
Arthritisd 9 (0.0) 4 (0.0)
Celiac disease 2 (0.0) 5 (0.0)
Dermatomyositis 0 (0.0) 1 (0.0)
Diabetes mellitus insulin-dependent (Type 1 or unspecified) 5 (0.0) 5 (0.0)
Erythema nodosum 3 (0.0) 0 (0.0)
Hyperthyroidisme 14 (0.1) 15 (0.1)
Hypothyroidismf 30 (0.2) 28 (0.3)
Inflammatory bowel diseaseg 8 (0.1) 4 (0.0)
Multiple sclerosis 4 (0.0) 1 (0.0)
Myelitis transverse 1 (0.0) 0 (0.0)
Optic neuritis/Optic neuritis retrobulbar 3 (0.0) 1 (0.0)
Psoriasish 8 (0.1) 11 (0.1)
Raynaud's phenomenon 0 (0.0) 1 (0.0)
Rheumatoid arthritis 4 (0.0) 3 (0.0)
Systemic lupus erythematosusi 2 (0.0) 3 (0.0)
Thrombocytopeniaj 1 (0.0) 1 (0.0)
Vasculitisk 1 (0.0) 3 (0.0)
Vitiligo 2 (0.0) 2 (0.0)
a Total vaccinated cohort included subjects with at least one documented dose (N).
b Pooled Control Group = Hepatitis A Vaccine control group [720 EL.U. of antigen and 500 mcg Al(OH)3], Hepatitis A Vaccine control group [360 EL.U. of antigen and 250 mcg of Al(OH)3], and a control containing 500 mcg Al(OH)3.
c n (%): number and percentage of subjects with medical condition.
d Term includes reactive arthritis and arthritis.
e Term includes Basedow's disease, goiter, and hyperthyroidism.
f Term includes thyroiditis, autoimmune thyroiditis, and hypothyroidism.
g Term includes colitis ulcerative, Crohn's disease, proctitis ulcerative, and inflammatory bowel disease.
h Term includes psoriatic arthropathy, nail psoriasis, guttate psoriasis, and psoriasis.
i Term includes systemic lupus erythematosus and cutaneous lupus erythematosus.
j Term includes idiopathic thrombocytopenic purpura and thrombocytopenia.
k Term includes leukocytoclastic vasculitis and vasculitis.

Serious Adverse Events: In the pooled safety database, inclusive of controlled and uncontrolled studies, which enrolled females 10 through 72 years of age, 5.3% (862/16,142) of subjects who received CERVARIX (human papillomavirus bivalent vaccine) and 5.9% (814/13,811) of subjects who received control reported at least one serious adverse event, without regard to causality, during the entire follow-up period (up to 7.4 years).

Among females 10 through 25 years of age enrolled in these clinical studies, 6.4% of subjects who received CERVARIX (human papillomavirus bivalent vaccine) and 7.2% of subjects who received the control reported at least one serious adverse event during the entire follow-up period (up to 7.4 years).

Deaths: In completed and ongoing studies which enrolled 57,323 females 9 through 72 years of age, 37 deaths were reported during the 7.4 years of follow-up: 20 in subjects who received CERVARIX (human papillomavirus bivalent vaccine) (0.06%, 20/33,623) and 17 in subjects who received control (0.07%, 17/23,700). Causes of death among subjects were consistent with those reported in adolescent and adult female populations. The most common causes of death were motor vehicle accident (5 subjects who received CERVARIX (human papillomavirus bivalent vaccine) ; 5 subjects who received control) and suicide (2 subjects who received CERVARIX (human papillomavirus bivalent vaccine) ; 5 subjects who received control), followed by neoplasm (3 subjects who received CERVARIX (human papillomavirus bivalent vaccine) ; 2 subjects who received control), autoimmune disease (3 subjects who received CERVARIX (human papillomavirus bivalent vaccine) ; 1 subject who received control), infectious disease (3 subjects who received CERVARIX (human papillomavirus bivalent vaccine) ; 1 subject who received control), homicide (2 subjects who received CERVARIX (human papillomavirus bivalent vaccine) ; 1 subject who received control), cardiovascular disorders (2 subjects who received CERVARIX (human papillomavirus bivalent vaccine) ), and death of unknown cause (2 subjects who received control). Among females 10 through 25 years of age, 31 deaths were reported (0.05%, 16/29,467 of subjects who received CERVARIX (human papillomavirus bivalent vaccine) and 0.07%, 15/20,192 of subjects who received control.

Postmarketing Experience

In addition to reports in clinical trials, worldwide voluntary reports of adverse events received for CERVARIX (human papillomavirus bivalent vaccine) since market introduction (2007) are listed below. This list includes serious events or events which have suspected causal association to CERVARIX (human papillomavirus bivalent vaccine) . Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccination.

Immune System Disorders: Allergic reactions (including anaphylactic and anaphylactoid reactions), angioedema, erythema multiforme.

Nervous System Disorders: Syncope or vasovagal responses to injection (sometimes accompanied by tonic-clonic movements).

Read the Cervarix (human papillomavirus bivalent vaccine) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

Concomitant Vaccine Administration

There are no data to assess the concomitant use of CERVARIX (human papillomavirus bivalent vaccine) with other vaccines. Do not mix CERVARIX (human papillomavirus bivalent vaccine) with any other vaccine in the same syringe or vial.

Hormonal Contraceptives

Among 7,693 subjects 15 through 25 years of age in Study 2 (CERVARIX (human papillomavirus bivalent vaccine) , N = 3,821 or Hepatitis A Vaccine 720 EL.U., N = 3,872) who used hormonal contraceptives for a mean of 2.8 years, the observed efficacy of CERVARIX (human papillomavirus bivalent vaccine) was similar to that observed among subjects who did not report use of hormonal contraceptives.

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 CERVARIX [see Use in Specific Populations].

Last reviewed on RxList: 10/30/2009
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Syncope

Because vaccinees may develop syncope, sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended. Syncope, sometimes associated with tonic-clonic movements and other seizure-like activity, has been reported following vaccination with CERVARIX (human papillomavirus bivalent vaccine) . When syncope is associated with tonic-clonic movements, the activity is usually transient and typically responds to restoring cerebral perfusion by maintaining a supine or Trendelenburg position.

Latex

The tip cap and the rubber plunger of the needleless prefilled syringes contain dry natural latex rubber that may cause allergic reactions in latex sensitive individuals. The vial stopper does not contain latex.

Preventing and Managing Allergic Vaccine Reactions

Prior to administration, the healthcare provider should review the immunization history for possible vaccine hypersensitivity and previous vaccination-related adverse reactions to allow an assessment of benefits and risks. Appropriate medical treatment and supervision should be readily available in case of anaphylactic reactions following administration of CERVARIX (human papillomavirus bivalent vaccine) .

Patient Counseling Information

Provide the Vaccine Information Statements prior to immunization. This is required by the National Childhood Vaccine Injury Act of 1986 and are available free of charge at the Centers for Disease Control and Prevention (CDC) website (www.cdc.gov/vaccines).

Inform the patient, parent, or guardian:

  • Vaccination does not substitute for routine cervical cancer screening. Women who receive CERVARIX (human papillomavirus bivalent vaccine) should continue to undergo cervical cancer screening per standard of care.
  • CERVARIX (human papillomavirus bivalent vaccine) does not protect against disease from HPV types to which a woman has previously been exposed through sexual activity.
  • Since syncope has been reported following vaccination in young females, sometimes resulting in falling with injury, observation for 15 minutes after administration is recommended.
  • Information regarding potential benefits and risks associated with vaccination.
  • Report any adverse events to their healthcare provider.
  • Safety has not been established in pregnant women. CERVARIX (human papillomavirus bivalent vaccine) is not recommended for use in pregnant women or women planning to become pregnant during the vaccination course. Register women who receive CERVARIX (human papillomavirus bivalent vaccine) while pregnant in the pregnancy registry by calling 1-888-452-9622

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

CERVARIX (human papillomavirus bivalent vaccine) has not been evaluated for its carcinogenic or mutagenic potential. Vaccination of female rats with CERVARIX (human papillomavirus bivalent vaccine) , at doses shown to be significantly immunogenic in the rat, had no effect on fertility.

Use In Specific Populations

Pregnancy

Pregnancy Category B

Reproduction studies have been performed in rats at a dose approximately 47 times the human dose (on a mg/kg basis) and revealed no evidence of impaired fertility or harm to the fetus due to CERVARIX (human papillomavirus bivalent vaccine) . There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Non-Clinical Studies: An evaluation of the effect of CERVARIX (human papillomavirus bivalent vaccine) on embryo-fetal, pre-and post-natal development was conducted using rats. One group of rats was administered CERVARIX (human papillomavirus bivalent vaccine) 30 days prior to gestation and during the period of organogenesis (gestation days 6, 8, 11, and 15). A second group of rats was administered saline at 30 days prior to gestation followed by CERVARIX (human papillomavirus bivalent vaccine) on days 6, 8, 11, and 15 of gestation. Two additional groups of rats received either saline or adjuvant following the same dosing regimen. CERVARIX (human papillomavirus bivalent vaccine) was administered at 0.1 mL/rat/occasion (approximately 47-fold excess relative to the projected human dose on a mg/kg basis) by intramuscular injection. No adverse effects on mating, fertility, pregnancy, parturition, lactation, or embryo-fetal, pre- and post-natal development were observed. There were no vaccine-related fetal malformations or other evidence of teratogenesis.

Clinical Studies: Overall Outcomes: In clinical studies, pregnancy testing was performed prior to each vaccine administration and vaccination was discontinued if a subject had a positive pregnancy test. In all clinical trials, subjects were instructed to take precautions to avoid pregnancy until 2 months after the last vaccination. During pre-licensure clinical development, a total of 7,276 pregnancies were reported among 3,696 females receiving CERVARIX (human papillomavirus bivalent vaccine) and 3,580 females receiving a control (Hepatitis A Vaccine 360 EL.U., Hepatitis A Vaccine 720 EL.U., or 500 mcg Al(OH)3). The overall proportions of pregnancy outcomes were similar between treatment groups. The majority of women gave birth to normal infants (62.2% and 62.6% of recipients of CERVARIX (human papillomavirus bivalent vaccine) and control, respectively). Other outcomes included spontaneous abortion (11.0% and 10.8% of recipients of CERVARIX (human papillomavirus bivalent vaccine) and control, respectively), elective termination (5.8% and 6.1% of recipients of CERVARIX (human papillomavirus bivalent vaccine) and control, respectively), abnormal infant other than congenital anomaly (2.8% and 3.2% of recipients of CERVARIX (human papillomavirus bivalent vaccine) and control, respectively), and premature birth (2.0% and 1.7% of recipients of CERVARIX (human papillomavirus bivalent vaccine) and control, respectively). Other outcomes (congenital anomaly, stillbirth, ectopic pregnancy, and therapeutic abortion) were reported less frequently in 0.1% to 0.8% of pregnancies in both groups.

Outcomes Around Time of Vaccination: Sub-analyses were conducted to describe pregnancy outcomes in 761 women [N = 396 for CERVARIX (human papillomavirus bivalent vaccine) and N = 365 pooled control, HAV 360 EL.U., HAV 720 EL.U., and 500 mcg Al(OH)3] who had their last menstrual period within 30 days prior to, or 45 days after a vaccine dose and for whom pregnancy outcome was known. The majority of women gave birth to normal infants (65.2% and 69.3% of recipients of CERVARIX (human papillomavirus bivalent vaccine) and control, respectively). Spontaneous abortion was reported in a total of 11.7% of subjects (13.6% of recipients of CERVARIX (human papillomavirus bivalent vaccine) and 9.6% of control recipients) and elective termination was reported in a total of 9.7% of subjects (9.9% of recipients of CERVARIX (human papillomavirus bivalent vaccine) and 9.6% of control recipients). Abnormal infant other than congenital anomaly was reported in a total of 4.9% of subjects (5.1% of recipients of CERVARIX (human papillomavirus bivalent vaccine) and 4.7% of control recipients) and premature birth was reported in a total of 2.5% of subjects (2.5% of both groups). Other outcomes (congenital anomaly, stillbirth, ectopic pregnancy, and therapeutic abortion) were reported in 0.3% to 1.8% of pregnancies among recipients of CERVARIX (human papillomavirus bivalent vaccine) and in 0.3% to 1.4% of pregnancies among control recipients.

It is not known whether the observed numerical imbalance in spontaneous abortions in pregnancies which occurred around the time of vaccination is due to a vaccine-related effect.

Pregnancy Registry: Healthcare providers are encouraged to register pregnant women who inadvertently receive CERVARIX (human papillomavirus bivalent vaccine) in the GlaxoSmithKline vaccination pregnancy registry by calling 1-888-452-9622.

Nursing Mothers

In non-clinical studies in rats, serological data suggest a transfer of anti-HPV-16 and anti-HPV-18 antibodies via milk during lactation in rats. Excretion of vaccine-induced antibodies in human milk has not been studied for CERVARIX (human papillomavirus bivalent vaccine) . Because many drugs are excreted in human milk, caution should be exercised when CERVARIX (human papillomavirus bivalent vaccine) is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients younger than 10 years of age have not been established. The safety and effectiveness of CERVARIX (human papillomavirus bivalent vaccine) have been evaluated in 1,193 subjects 10 through 14 years of age and 6,316 subjects 15 through 17 years of age. [See ADVERSE REACTIONS and Clinical Studies.]

Geriatric Use

Clinical studies of CERVARIX (human papillomavirus bivalent vaccine) did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger subjects. CERVARIX (human papillomavirus bivalent vaccine) is not approved for use in subjects 65 years of age and older.

Immunocompromised Individuals

The immune response to CERVARIX may be diminished in immunocompromised individuals [see DRUG INTERACTIONS].

Last reviewed on RxList: 10/30/2009
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

No information provided.

CONTRAINDICATIONS

Severe allergic reactions (e.g., anaphylaxis) to any component of CERVARIX [see DESCRIPTION].

Last reviewed on RxList: 10/30/2009
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Mechanism of Action

Animal studies suggest that the efficacy of L1 VLP vaccines may be mediated by the development of IgG neutralizing antibodies directed against HPV-L1 capsid proteins generated as a result of vaccination.

Clinical Studies

Cervical intraepithelial neoplasia (CIN) grade 2 and 3 lesions or cervical adenocarcinoma in situ (AIS) are the immediate and necessary precursors of squamous cell carcinoma and adenocarcinoma of the cervix, respectively. Their detection and removal has been shown to prevent cancer. Therefore, CIN2/3 and AIS (precancerous lesions) serve as surrogate markers for the prevention of cervical cancer. In clinical studies to evaluate the efficacy of CERVARIX (human papillomavirus bivalent vaccine) , the endpoints were cases of CIN2/3 and AIS associated with HPV-16, HPV-18, and other oncogenic HPV types. Persistent infection with HPV-16 and HPV-18 that lasts for 12 months was also an endpoint.

The efficacy of CERVARIX (human papillomavirus bivalent vaccine) to prevent histopathologically-confirmed CIN2/3 or AIS was assessed in 2 double-blind, randomized, controlled clinical studies that enrolled a total of 19,778 females 15 through 25 years of age.

Study 1 (HPV 001) enrolled women who were negative for oncogenic HPV DNA (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) in cervical samples, seronegative for HPV-16 and HPV-18 antibodies and had normal cytology. This represents a population presumed “naïve” without current HPV infection at the time of vaccination and without prior exposure to either HPV-16 or HPV-18. Subjects were enrolled in an extended follow-up study (Study 1 extension [HPV 007]) to evaluate the long-term efficacy, immunogenicity, and safety. These subjects have been followed for up to 6.4 years.

In Study 2 (HPV 008), women were vaccinated regardless of baseline HPV DNA status, serostatus or cytology. This study reflects a population of women naïve (without current infection and without prior exposure) or non-naïve (with current infection and/or with prior exposure) to HPV. Before vaccination, cervical samples were assessed for oncogenic HPV DNA (HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) and serostatus of HPV-16 and HPV-18 antibodies.

In both studies, testing for oncogenic HPV types was conducted using SPF10-LiPA25 PCR to detect HPV DNA in archived biopsy samples.

Prophylactic Efficacy Against HPV Types 16 and 18

Study 2: A randomized, double-blind, controlled clinical trial was conducted in which 18,665 healthy females 15 through 25 years of age received CERVARIX (human papillomavirus bivalent vaccine) or Hepatitis A Vaccine control on a 0-, 1-, and 6-month schedule. Among subjects, 54.8% of subjects were white, 31.5% Asian, 7.1% Hispanic, 3.7% black, and 2.9% were of other racial/ethnic groups.

In this study, women were randomized and vaccinated regardless of baseline HPV DNA status, serostatus or cytology. Women with HPV-16 or HPV-18 DNA present in baseline cervical samples (HPV DNA positive) at study entry were considered currently infected with that specific HPV type. If HPV DNA was not detected by PCR, women were considered HPV DNA negative. Additionally, cervical samples were assessed for cytologic abnormalities and serologic testing was performed for anti-HPV-16 and anti-HPV-18 serum antibodies at baseline. Women with anti-HPV serum antibodies present were considered to have prior exposure to HPV and characterized as seropositive. Women seropositive for HPV-16 or HPV-18 but DNA negative for that specific serotype were considered as having cleared a previous natural infection. Women without antibodies to HPV-16 and HPV-18 were characterized as seronegative. Before vaccination, 73.6% of subjects were naïve (without current infection [DNA negative] and without prior exposure [seronegative]) to HPV-16 and/or HPV-18.

Efficacy endpoints included histological evaluation of precancerous and dysplastic lesions (CIN grade 1, grade 2, or grade 3), and AIS. The mean follow-up after the first dose was approximately 39 months. Virological endpoints (HPV DNA in cervical samples detected by PCR) included 12-month persistent infection (defined as at least 2 positive specimens for the same HPV type over a minimum interval of 10 months).

The according to protocol (ATP) cohort for efficacy analyses for HPV-16 and/or HPV-18 included all subjects who received 3 doses of vaccine, for whom efficacy endpoint measures were available and who were HPV-16 and/or HPV-18 DNA negative and seronegative at baseline and HPV-16 and/or HPV-18 DNA negative at month 6 for the HPV type considered in the analysis. Case counting for the ATP cohort started on day 1 after the third dose of vaccine. This cohort included women who had normal or low-grade cytology (cytological abnormalities including atypical squamous cells of undetermined significance [ASC-US] or low grade squamous intraepithelial lesions [LSIL]) at baseline and excluded women with high-grade cytology.

The total vaccinated cohort (TVC) for each efficacy analysis included all subjects who received at least one dose of the vaccine, for whom efficacy endpoint measures were available, irrespective of their HPV DNA status, cytology, and serostatus at baseline. This cohort included women with or without current HPV infection and/or prior exposure. Case counting for the TVC started on day 1 after the first dose.

The TVC naïve is a subset of the TVC that had normal cytology, and were HPV DNA negative for 14 oncogenic HPV types and seronegative for HPV-16 and HPV-18 at baseline.

CERVARIX (human papillomavirus bivalent vaccine) was efficacious in the prevention of precancerous lesions or AIS associated with HPV-16 or HPV-18 (Table 5).

Table 5. Efficacy of CERVARIX (human papillomavirus bivalent vaccine) Against Histopathological Lesions Associated With HPV-16 or HPV-18 in Females 15 Through 25 Years of Age (According to Protocol Cohorta) (Study 2)

  CERVARIX Controlb % Efficacy (96.1% CI)c
N Number of Cases N Number of Cases
CIN2/3 or AIS 7,344 4 7,312 56 92.9
(79.9, 98.3)
CIN1/2/3 or AIS 7,344 8 7,312 96 91.7
(82.4, 96.7)
CI = Confidence Interval.
a Subjects (including women who had normal cytology, ASC-US, or LSIL at baseline) who received 3 doses of vaccine and were HPV DNA negative and seronegative at baseline and HPV DNA negative at month 6 for the corresponding HPV type (N). The mean follow-up was approximately 35 months.
b Hepatitis A Vaccine control group [720 EL.U. of antigen and 500 mcg Al(OH)3].
c The 96.1% confidence interval reflected in this final analysis results from statistical adjustment for the previously conducted interim analysis.

Since CIN3 or AIS represents a more immediate precursor to cervical cancer, cases of CIN3 or AIS associated with HPV-16 or HPV-18 were evaluated. In the ATP cohort, CERVARIX (human papillomavirus bivalent vaccine) was efficacious in the prevention of CIN3 or AIS associated with HPV-16 or HPV-18 (vaccine efficacy = 80.0% [96.1% CI: 0.3, 98.1]).

Subjects who were already infected with one vaccine HPV type (16 or 18) prior to vaccination were protected from precancerous lesions or AIS and infection caused by the other vaccine HPV type.

Efficacy of CERVARIX (human papillomavirus bivalent vaccine) against 12-month persistent infection with HPV-16 or HPV-18 was also evaluated. In the ATP cohort, CERVARIX (human papillomavirus bivalent vaccine) reduced the incidence of 12-month persistent infection with HPV-16 and/or HPV-18 by 91.2% (96.1% CI: 85.9, 94.8).

Immune response following natural infection does not reliably confer protection against future infections. Among subjects who received 3 doses of CERVARIX (human papillomavirus bivalent vaccine) and who were seropositive at baseline and DNA negative for HPV-16 or HPV-18 at baseline and month 6, CERVARIX (human papillomavirus bivalent vaccine) reduced the incidence of 12-month persistent infection by 91.5% (96.1% CI: 64.0, 99.2%). However, the number of cases of CIN2/3 or AIS was too few to determine efficacy against histopathological endpoints in this population.

Study 1 and Study 1 Extension: In a second double-blind, randomized, controlled study (Study 1), the efficacy of CERVARIX (human papillomavirus bivalent vaccine) in the prevention of HPV-16 or HPV-18 incident and persistent infections was compared with aluminum hydroxide control in 1,113 females 15 through 25 years of age. The population was naïve to current oncogenic HPV infection or prior exposure to HPV-16 and HPV-18 at the time of vaccination (total cohort). A total of 776 subjects were enrolled in the extended follow-up study (Study 1 Extension) to evaluate the long-term efficacy, immunogenicity, and safety of CERVARIX (human papillomavirus bivalent vaccine) . These subjects have been followed for up to 6.4 years.

In Study 1 and Study 1 Extension, with up to 6.4 years of follow-up (mean 5.9 years), in naïve females 15 through 25 years of age, efficacy against CIN2/3 or AIS associated with HPV-16 or HPV-18 was 100% (98.67% CI: 28.4, 100). Efficacy against 12-month persistent infection with HPV-16 or HPV-18 was 100% (98.67% CI: 74.4, 100). The confidence interval reflected in this final analysis results from statistical adjustment for analyses previously conducted.

Efficacy Against HPV Types 16 and 18, Regardless of Current Infection or Prior Exposure to HPV-16 or HPV-18

Study 2: The study included women regardless of HPV DNA status (current infection) and serostatus (prior exposure) to vaccine types, HPV-16 or HPV-18 at baseline. Efficacy analyses included lesions arising among women regardless of baseline DNA status and serostatus, including HPV infections present at first vaccination and those from infections acquired after dose 1. In this population which includes naïve (without current infection and prior exposure) and non-naïve women, CERVARIX (human papillomavirus bivalent vaccine) was efficacious in the prevention of precancerous lesions or AIS associated with HPV-16 or HPV-18 (Table 6).

However, among women HPV DNA positive regardless of serostatus at baseline, there was no clear evidence of efficacy against precancerous lesions or AIS associated with HPV-16 or HPV-18 (Table 6).

Table 6. Efficacy of CERVARIX (human papillomavirus bivalent vaccine) Against Disease Associated With HPV-16 or HPV-18 in Females 15 Through 25 Years of Age, Regardless of Current or Prior Exposure to Vaccine HPV Types (Study 2)

  CERVARIX Control % Efficacy (96.1% CI)b
N Number of Casesa N Number of Casesa
CIN1/2/3 or AIS
  Prophylactic Efficacyc 5,449 3 5,436 85 96.5
(89.0, 99.4)
  HPV-16 or HPV-18 DNA Positiveat Baselined 641 90 592 92 --
  Regardless of Current Infection or Prior Exposure to HPV-16 orHPV-18e 8,667 107 8,682 240 55.5f
(43.2, 65.3)
CIN2/3 or AIS
  Prophylactic Efficacyc 5,449 1 5,436 63 98.4
(90.4, 100)
  HPV-16 or HPV-18 DNA Positiveat Baselined 641 74 592 73 --
  Regardless of Current Infection or Prior Exposure to HPV-16 orHPV-18e 8,667 82 8,682 174 52.8f
(37.5, 64.7)
CIN3 or AIS
  Prophylactic Efficacyc 5,449 0 5,436 13 100
(64.7, 100)
  HPV-16 or HPV-18 DNA Positiveat Baselined 641 41 592 38 --
  Regardless of Current Infection or Prior Exposure to HPV-16 orHPV-18e 8,667 43 8,682 65 33.6f
(-1.1, 56.9)
CI = Confidence Interval.
Table does not include disease due to non-vaccine HPV types.
a Cases = Histopathological cases associated with HPV-16 and/or HPV-18.
b The 96.1% confidence interval reflected in this final analysis results from statistical adjustment for the previously conducted interim analysis.
c TVC naïve: includes all vaccinated subjects (who received at least one dose of vaccine) who had normal cytology, were HPV DNA negative for 14 oncogenic HPV types, and seronegative for HPV-16 and HPV-18 at baseline (N). Case counting started on day 1 after the first dose.
d TVC subset: includes all vaccinated subjects (who received at least one dose of vaccine) who were HPV DNA positive for HPV-16 or HPV-18 irrespective of serostatus at baseline (N). Case counting started on day 1 after the first dose.
e TVC: includes all vaccinated subjects (who received at least one dose of vaccine) irrespective of HPV DNA status and serostatus at baseline (N). Case counting started on day 1 after the first dose.
f Observed vaccine efficacy includes the prophylactic efficacy of CERVARIX (human papillomavirus bivalent vaccine) and the impact of CERVARIX (human papillomavirus bivalent vaccine) on the course of infections present at first vaccination.

Efficacy Against Cervical Disease Irrespective of HPV Type, Regardless of Current or Prior Infection with Vaccine or Non-Vaccine HPV Types

Study 2: The impact of CERVARIX (human papillomavirus bivalent vaccine) against the overall burden of HPV-related cervical disease results from a combination of prophylactic efficacy against, and disease contribution of, HPV-16, HPV-18, and non-vaccine HPV types.

In the population naïve to oncogenic HPV (TVC naïve), CERVARIX (human papillomavirus bivalent vaccine) reduced the overall incidence of CIN1/2/3 or AIS, CIN2/3 or AIS, and CIN3 or AIS regardless of the HPV DNA type in the lesion (Table 7). In the population of women naïve and non-naïve (TVC), vaccine efficacy against CIN1/2/3 or AIS, CIN2/3 or AIS, and CIN3 or AIS was demonstrated in all women regardless of HPV DNA type in the lesion (Table 7).

Table 7. Efficacy of CERVARIX (human papillomavirus bivalent vaccine) in Prevention of CIN or AIS Irrespective of Any HPV Type in Females 15 Through 25 Years of Age, Regardless of Current or Prior Infection with Vaccine or Non-Vaccine Types (Study 2)

  CERVARIX Control % Efficacy (96.1% CI)a
N Number of Cases N Number of Cases
CIN1/2/3 or AIS
  Prophylactic Efficacyb 5,449 106 5,436 211 50.1
(35.9, 61.4)
  Irrespective of HPV DNA atBaselinec 8,667 451 8,682 577 21.7
(10.7, 31.4)
CIN2/3 or AIS
  Prophylactic Efficacyb 5,449 33 5,436 110 70.2
(54.7, 80.9)
  Irrespective of HPV DNA atBaselinec 8,667 224 8,682 322 30.4
(16.4, 42.1)
CIN3 or AIS
  Prophylactic Efficacyb 5,449 3 5,436 23 87.0
(54.9, 97.7)
  Irrespective of HPV DNA atBaselinec 8,667 77 8,682 116 33.4
(9.1, 51.5)
CI = Confidence Interval.
a The 96.1% confidence interval reflected in this final analysis results from statistical adjustment for the previously conducted interim analysis.
b TVC naïve: includes all vaccinated subjects (who received at least one dose of vaccine) who had normal cytology, were HPV DNA negative for 14 oncogenic HPV types (including HPV-16 and HPV-18), and seronegative for HPV-16 and HPV-18 at baseline (N). Case counting started on day 1 after the first dose.
c TVC: includes all vaccinated subjects (who received at least one dose of vaccine) irrespective of HPV DNA status and serostatus at baseline (N). Case counting started on day 1 after the first dose.

In exploratory analyses, CERVARIX (human papillomavirus bivalent vaccine) reduced definitive cervical therapy procedures (includes loop electrosurgical excision procedure [LEEP], cold-knife Cone, and laser procedures) by 24.7% (96.1% CI: 7.4, 38.9) in the TVC and by 68.8% (96.1% CI: 50.0, 81.2) in the TVC naïve.

To assess reductions in disease caused by non-vaccine HPV types, two analyses were conducted combining 12 non-vaccine oncogenic HPV types, including and excluding lesions in which HPV-16 or HPV-18 were also detected. In these analyses, among females who received 3 doses of CERVARIX (human papillomavirus bivalent vaccine) and were DNA negative for the specific HPV type at baseline and month 6, CERVARIX (human papillomavirus bivalent vaccine) reduced the incidence of CIN2/3 or AIS by 54.0% (96.1% CI: 34.0, 68.4) and 37.4% (96.1% CI: 7.4, 58.2), respectively.

Post-hoc analyses, adjusted for multiplicity, were conducted to assess the impact of CERVARIX (human papillomavirus bivalent vaccine) on CIN2/3 or AIS due to specific non-vaccine HPV types. The ATP cohort for these analyses included all subjects irrespective of serostatus who received 3 doses of CERVARIX (human papillomavirus bivalent vaccine) and were DNA negative for the specific HPV type at baseline and month 6. These post-hoc analyses were also conducted in the TVC naïve population. In analyses including lesions in which HPV-16 or HPV-18 were also detected, vaccine efficacy in prevention of CIN2/3 or AIS associated with HPV-31 was 92.0% (99.7% CI: 49.0, 99.8) and 100% (99.7% CI: 62.3, 100), respectively. In analyses excluding lesions in which HPV-16 or HPV-18 were detected, vaccine efficacy in prevention of CIN2/3 or AIS associated with HPV-31 was 89.4% (99.7% CI: 29.0, 99.7) and 100% (99.7% CI: 36.3, 100), respectively.

Immunogenicity

The minimum anti-HPV titer that confers protective efficacy has not been determined.

The antibody response to HPV-16 and HPV-18 was measured using a type-specific binding ELISA (developed by GlaxoSmithKline) and a pseudovirion-based neutralization assay (PBNA). In a subset of subjects tested for HPV-16 and HPV-18, the ELISA has been shown to correlate with the PBNA. The scales for these assays are unique to each HPV type and each assay, thus, comparison between HPV types or assays is not appropriate.

Duration of Immune Response: The duration of immunity following a complete schedule of immunization with CERVARIX (human papillomavirus bivalent vaccine) has not been established. In Study 1 and Study 1 Extension, the immune response against HPV-16 and HPV-18 was evaluated for up to 76 months post-dose 1, in females 15 through 25 years of age. Vaccine-induced geometric mean titers (GMTs) for both HPV-16 and HPV-18 peaked at month 7 and thereafter reached a plateau that was sustained from month 18 up to month 76. At all timepoints, > 98% of subjects were seropositive for both HPV-16 ( ≥ 8 EL.U./mL, the limit of detection) and HPV-18 ( ≥ 7 EL.U./mL, the limit of detection) by ELISA.

In Study 2, GMTs for ELISA and PBNA one month post-dose 3 were measured (Table 8). The ATP cohort for immunogenicity included all evaluable subjects for whom data concerning immunogenicity endpoint measures were available. These included subjects for whom assay results were available for antibodies against at least one vaccine type. Subjects who acquired either HPV-16 or HPV-18 infection during the trial were excluded. Of subjects seronegative at baseline, 99.5% were seropositive for anti-HPV-16 and anti-HPV-18 antibodies at month 7 post-vaccination.

Table 8. Summary of Anti-HPV Geometric Mean Titers (GMTs) for HPV-16 and HPV-18 at Month 7 for Initially Seronegative Females 15 Through 25 Years of Age (According to Protocol Cohort for Immunogenicitya) (Study 2)

Antibody Assay N CERVARIX GMT (95% CI) N Control GMT (95% CI)
ELISAb (EL.U./mL)
  Anti-HPV-16 861 9,206.4 (8,607.2, 9,847.2) 738 4.4 (4.2, 4.6)
  Anti-HPV-18 924 4,744.6 (4,454.1, 5,053.9) 769 3.8 (3.6, 3.9)
PBNAc (ED50)
  Anti-HPV-16 46 27,364.8 (19,780.1, 37,857.9) 44 20.0 (20.0, 20.0)
  Anti-HPV-18 46 9,052 (6,851.8, 11,960.5) 44 20.0 (20.0, 20.0)
a Subjects who received 3 doses of vaccine for whom assay results were available for at least one post-vaccination antibody measurement (N). Subjects who acquired either HPV-16 or HPV-18 infection during the study were excluded.
b Enzyme linked immunosorbent assay (assay cut-off 8 EL.U./mL for anti-HPV-16 antibody and 7 EL.U./mL for anti-HPV-18 antibody).
c Pseudovirion-based neutralization assay (assay cut-off 40 ED50 for both anti-HPV-16 antibody and anti-HPV-18 antibody).

Bridging of Efficacy from Women to Adolescent Girls

The immunogenicity of CERVARIX (human papillomavirus bivalent vaccine) was evaluated in 2 clinical studies involving 1,193 girls 10 through 14 years of age who received CERVARIX (human papillomavirus bivalent vaccine) .

Study 3 (HPV 013) was a double-blind, randomized, controlled study in which 1,035 subjects received CERVARIX (human papillomavirus bivalent vaccine) and 1,032 subjects received a Hepatitis A Vaccine 360 EL.U. as the control vaccine with a subset of subjects evaluated for immunogenicity. All initially seronegative subjects in the group who received CERVARIX (human papillomavirus bivalent vaccine) were seropositive after vaccination, i.e., had levels of antibody greater than the limit of detection of the assay to both HPV-16 ( ≥ 8 EL.U./mL) and HPV-18 ( ≥ 7 EL.U./mL) antigens. The GMTs for anti-HPV-16 and anti-HPV-18 antibodies in initially seronegative subjects are presented in Table 9.

Table 9. Geometric Mean Titers (GMTs) at Months 7 and 18 for Initially Seronegative Females 10 Through 14 Years of Age (According To Protocol Cohort for Immunogenicitya) (Study 3)

Age Group Anti-HPV-16 Antibodies GMT EL.U./mL
(95% CI)
Anti-HPV-18 Antibodies GMT EL.U./mL
(95% CI)
N Month 7 Month 18 N Month 7 Month 18
10-14 years of age 556-619 19,882.0 (18,626.7, 21,221.9) 3,888.8 (3,605.0, 4,195.0) 562-628 8,262.0 (7,725.0, 8,836.2) 1,539.4 (1,418.8, 1,670.3)
a Subjects who received 3 doses of vaccine for whom assay results were available for at least one post-vaccination antibody measurement (N).

In Study 4 (HPV 012), the immunogenicity of CERVARIX (human papillomavirus bivalent vaccine) administered to girls 10 through 14 years of age was compared to that in females 15 through 25 years of age. The immune response in girls 10 through 14 years of age measured one month post-dose 3 was non-inferior to that seen in females 15 through 25 years of age for both HPV-16 and HPV-18 antigens (Table 10).

Table 10. Geometric Mean Titers (GMTs) and Seropositivity Rates at Month 7 for Initially Seronegative Females 10 Through 14 Years of Age Compared to 15 Through 25 Years of Age (According To Protocol Cohort for Immunogenicitya) (Study 4)

  10-14 Years of Age 15-25 Years of Age
Antibody Assay N GMTb EL.U./mL
(95% CI)
Seropositivity Ratec % N GMTb EL.U./mL (95% CI) Seropositivity Ratec %
Anti-HPV-16 143 17,272.5 (15,117.9, 19,734.1) 100 118 7,438.9 (6,324.6, 8,749.6) 100
Anti-HPV-18 141 6,863.8 (5,976.3, 7,883.0) 100 116 3,070.1 (2,600.0, 3,625.4) 100
a Subjects who received 3 doses of vaccine for whom assay results were available for at least one post-vaccination antibody measurement (N).
b Non-inferiority based on the upper limit of the 2-sided 95% CI for the GMT ratio (15-25 year olds/10-14 year olds) was < 2.
c Non-inferiority based on the upper limit of the 2-sided 95% CI for the difference between the seropositivity rates for 10-14 year olds and 15-25 year olds was < 10%. Based on these immunogenicity data, the efficacy of CERVARIX (human papillomavirus bivalent vaccine) is inferred in girls 10 through 14 years of age.

Last reviewed on RxList: 10/30/2009
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

Cervarix (human papillomavirus bivalent vaccine) suspension for injection in pre-filled syringe

Human Papillomavirus vaccine [Types 16, 18] (Recombinant, adjuvanted, adsorbed)

Read all of this leaflet carefully before you start receiving this vaccine.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you. Do not pass it on to others.
  • If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

  1. What Cervarix (human papillomavirus bivalent vaccine) is and what it is used for
  2. Before you receive Cervarix (human papillomavirus bivalent vaccine)
  3. How Cervarix (human papillomavirus bivalent vaccine) is given
  4. Possible side effects
  5. How to store Cervarix (human papillomavirus bivalent vaccine)
  6. Further information

1. WHAT CERVARIX (human papillomavirus bivalent vaccine) IS AND WHAT IT IS USED FOR

Cervarix (human papillomavirus bivalent vaccine) is a vaccine intended to protect females against the diseases caused by infection with Human Papillomavirus (HPV) types 16 and 18.

These diseases include:

  • cervical cancer (cancer of the cervix i.e. lower part of the uterus or womb),
  • precancerous cervical lesions (changes in cells of the cervix that have a risk of turning into cancer).

Cervarix will not protect against all types of Human Papillomavirus. HPV types 16 and 18 are responsible for approximately 70% of cervical cancer cases.

When a female is vaccinated with Cervarix (human papillomavirus bivalent vaccine) , the immune system (the body's natural defence system) will make antibodies against HPV types 16 and 18. In clinical trials Cervarix has been shown to prevent HPV types 16 and 18 related diseases in women 15-25 years of age. Cervarix (human papillomavirus bivalent vaccine) also stimulates production of antibodies in females 10-14 years of age.

Cervarix (human papillomavirus bivalent vaccine) is not infectious and so, it cannot cause HPV related diseases.

Cervarix (human papillomavirus bivalent vaccine) is not used to treat HPV related diseases already present at the time of vaccination.

Cervarix (human papillomavirus bivalent vaccine) should be used in accordance with official guidelines.

2. BEFORE YOU RECEIVE CERVARIX (human papillomavirus bivalent vaccine)

Cervarix (human papillomavirus bivalent vaccine) should not be given if

the person to be vaccinated:

  • is allergic (hypersensitive) to any of the active substances or any of the other ingredients of Cervarix (human papillomavirus bivalent vaccine) . The active substances and other ingredients of Cervarix (human papillomavirus bivalent vaccine) are listed at the end of the leaflet (see section 6). Signs of an allergic reaction may include itchy skin rash, shortness of breath and swelling of the face or tongue.
  • has a severe infection with a high temperature. It might be necessary to postpone the vaccination until recovery. A minor infection such as a cold should not be a problem, but talk to the doctor first.

Take special care with Cervarix (human papillomavirus bivalent vaccine)

You should tell the doctor if the person to be vaccinated:

  • has a bleeding problem or bruises easily.
  • has any disease which reduces her resistance to infection such as HIV infection

As with all vaccines, Cervarix (human papillomavirus bivalent vaccine) may not fully protect all people who are vaccinated.

Cervarix (human papillomavirus bivalent vaccine) does not protect people from diseases caused by infection with HPV types 16 or 18 if they are already infected with Human Papillomavirus type 16 or 18 at the time of vaccination.

Although vaccination may protect you against cervical cancer, it is not a substitute for regular cervical screening. You should continue to follow your doctor's advice on cervical smear/Pap test (test to screen for changes in cells of the cervix caused by an HPV infection) and preventative and protective measures.

As Cervarix (human papillomavirus bivalent vaccine) will not protect against all types of Human Papillomavirus, appropriate precautions against exposure to HPV and sexually transmitted diseases should continue to be used.

Cervarix (human papillomavirus bivalent vaccine) will not protect against other diseases that are not caused by Human Papillomavirus.

The duration of protection after vaccination is currently unknown. In clinical trials, sustained protection has been observed in females aged 15 to 25 years for up to 6.4 years after the first dose. The need for booster dose(s) has not been investigated.

Using other medicines

Cervarix (human papillomavirus bivalent vaccine) can be given with a combined booster vaccine containing diphtheria (d), tetanus (T) and pertussis [acellular] (pa) with or without inactivated poliomyelitis (IPV), (dTpa, dTpa -IPV vaccines), at a separate injection site (another part of your body, e.g. the other arm) during the same visit.

Cervarix (human papillomavirus bivalent vaccine) may not have an optimal effect if used with medicines that suppress the immune system.

In clinical trials, oral contraceptives (e.g. the pill) did not reduce the protection obtained by Cervarix (human papillomavirus bivalent vaccine) .

Please tell the doctor if the person to be vaccinated is taking or has recently taken any other medicines, including medicines obtained without a prescription or has recently received any other vaccine.

Pregnancy and breast-feeding

There are insufficient data concerning the use of Cervarix (human papillomavirus bivalent vaccine) during pregnancy. If pregnancy occurs during the course of vaccination your doctor should be consulted. It is recommended to postpone vaccination until after completion of the pregnancy.

Ask your doctor for advice about breast-feeding before receiving Cervarix (human papillomavirus bivalent vaccine) .

Driving and using machines

There is no information on the effect of Cervarix (human papillomavirus bivalent vaccine) on your ability to drive or use machinery.

3. HOW CERVARIX (human papillomavirus bivalent vaccine) IS GIVEN

The doctor or nurse will give Cervarix (human papillomavirus bivalent vaccine) as an injection into the muscle of the upper arm.

Cervarix (human papillomavirus bivalent vaccine) is intended for females from 10 years of age onwards. A total of three injections will be administered by your doctor or nurse according to the following schedule:

First injection: at chosen date

Second injection: 1 month after first injection

Third injection: 6 months after first injection

If necessary, the vaccination schedule can be more flexible. Please speak to your doctor for more information.

When Cervarix (human papillomavirus bivalent vaccine) is given for the first dose, it is recommended that Cervarix (human papillomavirus bivalent vaccine) (and not another vaccine against HPV) be given for the complete 3-dose vaccination course.

The vaccine should never be given into a vein.

If you forget a return visit for Cervarix (human papillomavirus bivalent vaccine) :

It is important that you follow the instructions of your doctor or nurse regarding return visits. If you forget to go back to your doctor at the scheduled time, ask your doctor for advice.

If you do not finish the complete vaccination course of three injections, you may not get the best response and protection from the vaccination.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Cervarix (human papillomavirus bivalent vaccine) can cause side effects, although not everybody gets them. Side effects that occurred during clinical trials with Cervarix (human papillomavirus bivalent vaccine) were as follows:

  • Very common (side effects which may occur in more than 1 per 10 doses of vaccine):
    • pain or discomfort at the injection site
    • redness or swelling at the injection site
    • headache
    • aching muscles, muscle tenderness or weakness (not caused by exercise)
    • tiredness
  • Common (side effects which may occur in less than 1 per 10 but more than 1 per 100 doses of vaccine):
  • Uncommon (side effects which may occur in less than 1 per 100 but more than 1 per 1,000 doses of vaccine):
    • upper respiratory tract infection (infection of the nose, throat or trachea)
    • dizziness
    • other injection site reactions such as hard lump, tingling or numbness.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

5. HOW TO STORE CERVARIX (human papillomavirus bivalent vaccine)

Keep out of the reach and sight of children.

Do not use Cervarix (human papillomavirus bivalent vaccine) after the expiry date which is stated on the carton. The expiry date refers to the last day of that month.

Store in a refrigerator (2°C - 8°C). Do not freeze.

Store in the original package in order to protect from light.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. FURTHER INFORMATION

What Cervarix (human papillomavirus bivalent vaccine) contains

- The active substances are:

Human Papillomavirus1 type 16 L1 protein2,3,4 20 micrograms
Human Papillomavirus1 type 18 L1 protein2,3,4 20 micrograms

1Human Papillomavirus = HPV
2adjuvanted by AS04 containing: 3-O-desacyl-4'- monophosphoryl lipid A (MPL)3........................50 micrograms
3adsorbed on aluminium hydroxide, hydrated (Al(OH)3)...................0.5 milligrams Al3+ in total
4L1 protein in the form of non-infectious virus-like particles (VLPs) produced by recombinant DNA technology using a Baculovirus expression system which uses Hi-5 Rix4446 cells derived from the insect Trichoplusia ni.

  • The other ingredients are sodium chloride (NaCl), sodium dihydrogen phosphate dihydrate (NaH2PO4.2 H2O) and water for injections.

What Cervarix (human papillomavirus bivalent vaccine) looks like and contents of the pack

Suspension for injection in pre-filled syringe.

Cervarix (human papillomavirus bivalent vaccine) is a turbid white suspension.

Cervarix (human papillomavirus bivalent vaccine) is available in pre-filled syringes with or without needles in packs of 1 and 10.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

GlaxoSmithKline Biologicals s.a., Rue de l'Institut 89, B-1330 Rixensart, Belgium

For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien
GlaxoSmithKline s.a./n.v.
Tél/Tel: + 32 2 656 21 11
Luxembourg/Luxemburg
GlaxoSmithKline s.a./n.v.
Tél/Tel: + 32 2 656 21 11
EfcjirapHH
TjiaKcoCMHTRjiaHH EOOfl yji. flHMHTbp MaHOB 6ji.10 Co(J)hh 1408 Ten. + 359 2 953 10 34
Magyarorsz?g
GlaxoSmithKline Kft.
Tel.: + 36-1-2255300
Cesk? republika
GlaxoSmithKline s.r.o.
Tel: + 420 2 22 00 11 11 gsk.czmail@gsk.com
Malta
GlaxoSmithKline Malta
Tel: + 356 21 238131
Danmark
GlaxoSmithKline Pharma A/S
Tlf: + 45 36 35 91 00 info@glaxosmithkline.dk
Nederland
GlaxoSmithKline BV
Tel: + 31 (0)30 69 38 100 nlinfo@gsk.com
Deutschland
GlaxoSmithKline GmbH & Co. KG
Tel: + 49 (0)89 360448701 produkt.info@gsk.com
Norge
GlaxoSmithKline AS
Tlf: + 47 22 70 20 00 firmapost@gsk.no
Eesti
GlaxoSmithKline Eesti O?
Tel: +372 667 6900 estonia@gsk.com
österreich
GlaxoSmithKline Pharma GmbH.
Tel: + 43 1 970 75-0 at.info@gsk.com
Eλλ&alpha;&gamma;&alpha;
GlaxoSmithKline A.E.B.E
Trλ: + 30 210 68 82 100
Polska
GSK Commercial Sp. z o.o. Tel.: + 48 (22) 576 9000
España
GlaxoSmithKline, S.A.
Tel: + 34 902 202 700 es-ci@gsk.com
Portugal
GlaxoSmithKline, Produtos Farmacêuticos, Lda.
Tel: + 351 21 412 95 00FI.PT@gsk.com
France
Laboratoire GlaxoSmithKline
Tél: + 33 (0) 1 39 17 84 44 diam@gsk.com
România
GlaxoSmithKline (GSK) SRL
Tel: +40 (0)21 3028 208
Ireland
GlaxoSmithKline (Ireland) Ltd
Tel: + 353 (0)1 4955000
Slovenija
GlaxoSmithKline d.o.o.
Tel: + 386 (0) 1 280 25 00 medical.x.si@gsk.com
?sland
GlaxoSmithKline ehf.
S?mi: +354-530 3700
Slovensk? republika
GlaxoSmithKline Slovakia s.r.o.
Tel: + 421 (0)2 48 26 11 11 recepcia.sk@gsk.com
Italia
GlaxoSmithKline S.p.A.
Tel:+ 39 04 59 21 81 11
Suomi/Finland
GlaxoSmithKline Oy
Puh/Tel: + 358 10 30 30 30 Finland.tuoteinfo@gsk.com
Kvnpoq
GlaxoSmithKline (Cyprus) Ltd Tr(k: + 357 22 39 70 00
Sverige
GlaxoSmithKline AB Tel: + 46 (0)8 638 93 00 info.produkt@gsk.com
Latvija
GlaxoSmithKline Latvia SIA
Tel: + 371 67312687 lv-epasts@gsk.com
United Kingdom
GlaxoSmithKline UK
Tel: + 44 (0)808 100 9997 customercontactuk@gsk.com
LietuvaGlaxoSmithKline Lietuva UAB Tel: +370 5 264 90 00 info.lt@gsk.com

This leaflet was last approved in July 2009

Detailed information on this medicine is available on the European Medicines Agency (EMEA) web site: http://www.emea.europa.eu/.

The following information is intended for medical or healthcare professionals only:

Cervarix (human papillomavirus bivalent vaccine) should be administered as soon as possible after being removed from the refrigerator. However, stability data generated indicate that Cervarix (human papillomavirus bivalent vaccine) presented in monodose containers remains stable and can be administered in case it has been stored outside the refrigerator up to three days at temperatures between 8°C and 25°C or up to one day at temperatures between 25°C and 37°C.

A fine white deposit with a clear colourless supernatant may be observed upon storage of the syringe. This does not constitute a sign of deterioration.

The content of the syringe should be inspected visually both before and after shaking for any foreign particulate matter and/or abnormal physical appearance prior to administration. In the event of either being observed, discard the vaccine.

The vaccine should be well shaken before use.

Any unused product or waste material should be disposed of in accordance with local requirements.

Last reviewed on RxList: 10/30/2009
This monograph has been modified to include the generic and brand name in many instances.

>

PATIENT INFORMATION

Cervarix (human papillomavirus bivalent vaccine) suspension for injection in pre-filled syringe

Human Papillomavirus vaccine [Types 16, 18] (Recombinant, adjuvanted, adsorbed)

Read all of this leaflet carefully before you start receiving this vaccine.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you. Do not pass it on to others.
  • If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

  1. What Cervarix (human papillomavirus bivalent vaccine) is and what it is used for
  2. Before you receive Cervarix (human papillomavirus bivalent vaccine)
  3. How Cervarix (human papillomavirus bivalent vaccine) is given
  4. Possible side effects
  5. How to store Cervarix (human papillomavirus bivalent vaccine)
  6. Further information

1. WHAT CERVARIX (human papillomavirus bivalent vaccine) IS AND WHAT IT IS USED FOR

Cervarix (human papillomavirus bivalent vaccine) is a vaccine intended to protect females against the diseases caused by infection with Human Papillomavirus (HPV) types 16 and 18.

These diseases include:

  • cervical cancer (cancer of the cervix i.e. lower part of the uterus or womb),
  • precancerous cervical lesions (changes in cells of the cervix that have a risk of turning into cancer).

Cervarix will not protect against all types of Human Papillomavirus. HPV types 16 and 18 are responsible for approximately 70% of cervical cancer cases.

When a female is vaccinated with Cervarix (human papillomavirus bivalent vaccine) , the immune system (the body's natural defence system) will make antibodies against HPV types 16 and 18. In clinical trials Cervarix has been shown to prevent HPV types 16 and 18 related diseases in women 15-25 years of age. Cervarix (human papillomavirus bivalent vaccine) also stimulates production of antibodies in females 10-14 years of age.

Cervarix (human papillomavirus bivalent vaccine) is not infectious and so, it cannot cause HPV related diseases.

Cervarix (human papillomavirus bivalent vaccine) is not used to treat HPV related diseases already present at the time of vaccination.

Cervarix (human papillomavirus bivalent vaccine) should be used in accordance with official guidelines.

2. BEFORE YOU RECEIVE CERVARIX (human papillomavirus bivalent vaccine)

Cervarix (human papillomavirus bivalent vaccine) should not be given if

the person to be vaccinated:

  • is allergic (hypersensitive) to any of the active substances or any of the other ingredients of Cervarix (human papillomavirus bivalent vaccine) . The active substances and other ingredients of Cervarix (human papillomavirus bivalent vaccine) are listed at the end of the leaflet (see section 6). Signs of an allergic reaction may include itchy skin rash, shortness of breath and swelling of the face or tongue.
  • has a severe infection with a high temperature. It might be necessary to postpone the vaccination until recovery. A minor infection such as a cold should not be a problem, but talk to the doctor first.

Take special care with Cervarix (human papillomavirus bivalent vaccine)

You should tell the doctor if the person to be vaccinated:

  • has a bleeding problem or bruises easily.
  • has any disease which reduces her resistance to infection such as HIV infection

As with all vaccines, Cervarix (human papillomavirus bivalent vaccine) may not fully protect all people who are vaccinated.

Cervarix (human papillomavirus bivalent vaccine) does not protect people from diseases caused by infection with HPV types 16 or 18 if they are already infected with Human Papillomavirus type 16 or 18 at the time of vaccination.

Although vaccination may protect you against cervical cancer, it is not a substitute for regular cervical screening. You should continue to follow your doctor's advice on cervical smear/Pap test (test to screen for changes in cells of the cervix caused by an HPV infection) and preventative and protective measures.

As Cervarix (human papillomavirus bivalent vaccine) will not protect against all types of Human Papillomavirus, appropriate precautions against exposure to HPV and sexually transmitted diseases should continue to be used.

Cervarix (human papillomavirus bivalent vaccine) will not protect against other diseases that are not caused by Human Papillomavirus.

The duration of protection after vaccination is currently unknown. In clinical trials, sustained protection has been observed in females aged 15 to 25 years for up to 6.4 years after the first dose. The need for booster dose(s) has not been investigated.

Using other medicines

Cervarix (human papillomavirus bivalent vaccine) can be given with a combined booster vaccine containing diphtheria (d), tetanus (T) and pertussis [acellular] (pa) with or without inactivated poliomyelitis (IPV), (dTpa, dTpa -IPV vaccines), at a separate injection site (another part of your body, e.g. the other arm) during the same visit.

Cervarix (human papillomavirus bivalent vaccine) may not have an optimal effect if used with medicines that suppress the immune system.

In clinical trials, oral contraceptives (e.g. the pill) did not reduce the protection obtained by Cervarix (human papillomavirus bivalent vaccine) .

Please tell the doctor if the person to be vaccinated is taking or has recently taken any other medicines, including medicines obtained without a prescription or has recently received any other vaccine.

Pregnancy and breast-feeding

There are insufficient data concerning the use of Cervarix (human papillomavirus bivalent vaccine) during pregnancy. If pregnancy occurs during the course of vaccination your doctor should be consulted. It is recommended to postpone vaccination until after completion of the pregnancy.

Ask your doctor for advice about breast-feeding before receiving Cervarix (human papillomavirus bivalent vaccine) .

Driving and using machines

There is no information on the effect of Cervarix (human papillomavirus bivalent vaccine) on your ability to drive or use machinery.

3. HOW CERVARIX (human papillomavirus bivalent vaccine) IS GIVEN

The doctor or nurse will give Cervarix (human papillomavirus bivalent vaccine) as an injection into the muscle of the upper arm.

Cervarix (human papillomavirus bivalent vaccine) is intended for females from 10 years of age onwards. A total of three injections will be administered by your doctor or nurse according to the following schedule:

First injection: at chosen date

Second injection: 1 month after first injection

Third injection: 6 months after first injection

If necessary, the vaccination schedule can be more flexible. Please speak to your doctor for more information.

When Cervarix (human papillomavirus bivalent vaccine) is given for the first dose, it is recommended that Cervarix (human papillomavirus bivalent vaccine) (and not another vaccine against HPV) be given for the complete 3-dose vaccination course.

The vaccine should never be given into a vein.

If you forget a return visit for Cervarix (human papillomavirus bivalent vaccine) :

It is important that you follow the instructions of your doctor or nurse regarding return visits. If you forget to go back to your doctor at the scheduled time, ask your doctor for advice.

If you do not finish the complete vaccination course of three injections, you may not get the best response and protection from the vaccination.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Cervarix (human papillomavirus bivalent vaccine) can cause side effects, although not everybody gets them. Side effects that occurred during clinical trials with Cervarix (human papillomavirus bivalent vaccine) were as follows:

  • Very common (side effects which may occur in more than 1 per 10 doses of vaccine):
    • pain or discomfort at the injection site
    • redness or swelling at the injection site
    • headache
    • aching muscles, muscle tenderness or weakness (not caused by exercise)
    • tiredness
  • Common (side effects which may occur in less than 1 per 10 but more than 1 per 100 doses of vaccine):
  • Uncommon (side effects which may occur in less than 1 per 100 but more than 1 per 1,000 doses of vaccine):
    • upper respiratory tract infection (infection of the nose, throat or trachea)
    • dizziness
    • other injection site reactions such as hard lump, tingling or numbness.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

5. HOW TO STORE CERVARIX (human papillomavirus bivalent vaccine)

Keep out of the reach and sight of children.

Do not use Cervarix (human papillomavirus bivalent vaccine) after the expiry date which is stated on the carton. The expiry date refers to the last day of that month.

Store in a refrigerator (2°C - 8°C). Do not freeze.

Store in the original package in order to protect from light.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

6. FURTHER INFORMATION

What Cervarix (human papillomavirus bivalent vaccine) contains

- The active substances are:

Human Papillomavirus1 type 16 L1 protein2,3,4 20 micrograms
Human Papillomavirus1 type 18 L1 protein2,3,4 20 micrograms

1Human Papillomavirus = HPV
2adjuvanted by AS04 containing: 3-O-desacyl-4'- monophosphoryl lipid A (MPL)3........................50 micrograms
3adsorbed on aluminium hydroxide, hydrated (Al(OH)3)...................0.5 milligrams Al3+ in total
4L1 protein in the form of non-infectious virus-like particles (VLPs) produced by recombinant DNA technology using a Baculovirus expression system which uses Hi-5 Rix4446 cells derived from the insect Trichoplusia ni.

  • The other ingredients are sodium chloride (NaCl), sodium dihydrogen phosphate dihydrate (NaH2PO4.2 H2O) and water for injections.

What Cervarix (human papillomavirus bivalent vaccine) looks like and contents of the pack

Suspension for injection in pre-filled syringe.

Cervarix (human papillomavirus bivalent vaccine) is a turbid white suspension.

Cervarix (human papillomavirus bivalent vaccine) is available in pre-filled syringes with or without needles in packs of 1 and 10.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

GlaxoSmithKline Biologicals s.a., Rue de l'Institut 89, B-1330 Rixensart, Belgium

For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien
GlaxoSmithKline s.a./n.v.
Tél/Tel: + 32 2 656 21 11
Luxembourg/Luxemburg
GlaxoSmithKline s.a./n.v.
Tél/Tel: + 32 2 656 21 11
EfcjirapHH
TjiaKcoCMHTRjiaHH EOOfl yji. flHMHTbp MaHOB 6ji.10 Co(J)hh 1408 Ten. + 359 2 953 10 34
Magyarorsz?g
GlaxoSmithKline Kft.
Tel.: + 36-1-2255300
Cesk? republika
GlaxoSmithKline s.r.o.
Tel: + 420 2 22 00 11 11 gsk.czmail@gsk.com
Malta
GlaxoSmithKline Malta
Tel: + 356 21 238131
Danmark
GlaxoSmithKline Pharma A/S
Tlf: + 45 36 35 91 00 info@glaxosmithkline.dk
Nederland
GlaxoSmithKline BV
Tel: + 31 (0)30 69 38 100 nlinfo@gsk.com
Deutschland
GlaxoSmithKline GmbH & Co. KG
Tel: + 49 (0)89 360448701 produkt.info@gsk.com
Norge
GlaxoSmithKline AS
Tlf: + 47 22 70 20 00 firmapost@gsk.no
Eesti
GlaxoSmithKline Eesti O?
Tel: +372 667 6900 estonia@gsk.com
österreich
GlaxoSmithKline Pharma GmbH.
Tel: + 43 1 970 75-0 at.info@gsk.com
Eλλ&alpha;&gamma;&alpha;
GlaxoSmithKline A.E.B.E
Trλ: + 30 210 68 82 100
Polska
GSK Commercial Sp. z o.o. Tel.: + 48 (22) 576 9000
España
GlaxoSmithKline, S.A.
Tel: + 34 902 202 700 es-ci@gsk.com
Portugal
GlaxoSmithKline, Produtos Farmacêuticos, Lda.
Tel: + 351 21 412 95 00FI.PT@gsk.com
France
Laboratoire GlaxoSmithKline
Tél: + 33 (0) 1 39 17 84 44 diam@gsk.com
România
GlaxoSmithKline (GSK) SRL
Tel: +40 (0)21 3028 208
Ireland
GlaxoSmithKline (Ireland) Ltd
Tel: + 353 (0)1 4955000
Slovenija
GlaxoSmithKline d.o.o.
Tel: + 386 (0) 1 280 25 00 medical.x.si@gsk.com
?sland
GlaxoSmithKline ehf.
S?mi: +354-530 3700
Slovensk? republika
GlaxoSmithKline Slovakia s.r.o.
Tel: + 421 (0)2 48 26 11 11 recepcia.sk@gsk.com
Italia
GlaxoSmithKline S.p.A.
Tel:+ 39 04 59 21 81 11
Suomi/Finland
GlaxoSmithKline Oy
Puh/Tel: + 358 10 30 30 30 Finland.tuoteinfo@gsk.com
Kvnpoq
GlaxoSmithKline (Cyprus) Ltd Tr(k: + 357 22 39 70 00
Sverige
GlaxoSmithKline AB Tel: + 46 (0)8 638 93 00 info.produkt@gsk.com
Latvija
GlaxoSmithKline Latvia SIA
Tel: + 371 67312687 lv-epasts@gsk.com
United Kingdom
GlaxoSmithKline UK
Tel: + 44 (0)808 100 9997 customercontactuk@gsk.com
LietuvaGlaxoSmithKline Lietuva UAB Tel: +370 5 264 90 00 info.lt@gsk.com

This leaflet was last approved in July 2009

Detailed information on this medicine is available on the European Medicines Agency (EMEA) web site: http://www.emea.europa.eu/.

The following information is intended for medical or healthcare professionals only:

Cervarix (human papillomavirus bivalent vaccine) should be administered as soon as possible after being removed from the refrigerator. However, stability data generated indicate that Cervarix (human papillomavirus bivalent vaccine) presented in monodose containers remains stable and can be administered in case it has been stored outside the refrigerator up to three days at temperatures between 8°C and 25°C or up to one day at temperatures between 25°C and 37°C.

A fine white deposit with a clear colourless supernatant may be observed upon storage of the syringe. This does not constitute a sign of deterioration.

The content of the syringe should be inspected visually both before and after shaking for any foreign particulate matter and/or abnormal physical appearance prior to administration. In the event of either being observed, discard the vaccine.

The vaccine should be well shaken before use.

Any unused product or waste material should be disposed of in accordance with local requirements.

Last reviewed on RxList: 10/30/2009
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Cervarix Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

HUMAN PAPILLOMAVIRUS VACCINE (TYPES 16,18) - INJECTION

COMMON BRAND NAME(S): Cervarix

USES: This medication is a vaccine used to prevent cancer of the cervix. It is also used to prevent abnormal tissue growth in the cervix that can lead to cancer. These conditions are commonly caused by certain types of human papillomavirus (HPV). Vaccines work by increasing the body's natural defense (immunity) against the virus.

This medication does not protect against all types of HPV, only the types in the vaccine. It is used to prevent the diseases and will not treat active cervical cancer or other diseases caused by the types of HPV in the vaccine.

HOW TO USE: Read the Vaccine Information Statement available from your health care provider before receiving the vaccine. If you have any questions, consult your health care provider.

This vaccine is given by injection into the muscle of the upper arm by a health care professional.

This vaccine is given as 3 separate doses. The second dose should be given 1 month after the first dose, and the third dose should be given 6 months after the first dose. Follow the vaccination schedule closely for the vaccine to be most effective. To help you remember, mark your calendar to keep track of when to receive your next dose.

Disclaimer

Cervarix Consumer (continued)

SIDE EFFECTS: Redness, swelling, and pain at the injection site may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Some patients have fainted after receiving this vaccine. See also Precautions section.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US, you may report side effects to the Vaccine Adverse Event Reporting System (VAERS) at 1-800-822-7967. In Canada, you may report side effects to Health Canada at 1-866-234-2345.

Read the Cervarix (human papillomavirus bivalent vaccine) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before receiving this medication, tell your doctor or pharmacist if you are allergic to it; or to latex; or to other vaccines; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before receiving this vaccination, tell your doctor or pharmacist your medical history, especially of: immune system problems (such as HIV infection), bleeding disorders (such as hemophilia, thrombocytopenia), current fever/illness.

This vaccine can cause some patients to faint, which could cause falling and injury. To reduce the risk of this side effect, your doctor may recommend that you stay in a sitting or lying position for 15 minutes after the injection. Infrequently, fainting along with seizure-like movements have occurred, and have usually been stopped by placing the patient in a lying position with the face up.

This vaccine is not recommended for use during pregnancy. Consult your doctor for more details.

It is unknown if this medication passes into breast milk. Consult your doctor before breast-feeding.

Disclaimer

Cervarix Consumer (continued)

DRUG INTERACTIONS: The effects of some drugs can change if you take other drugs or herbal products at the same time. This can increase your risk for serious side effects or may cause your medications not to work correctly. These drug interactions are possible, but do not always occur. Your doctor or pharmacist can often prevent or manage interactions by changing how you use your medications or by close monitoring.

To help your doctor and pharmacist give you the best care, be sure to tell your doctor and pharmacist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products) before starting treatment with this product. While using this product, do not start, stop, or change the dosage of any other medicines you are using without your doctor's approval.

Some products that may interact with this drug include: "blood thinners" (such as warfarin), cancer chemotherapy, corticosteroids (such as prednisone, dexamethasone), drugs that weaken the immune system (such as cyclosporine, tacrolimus).

This document does not contain all possible interactions. Keep a list of all the products you use. Share this list with your doctor and pharmacist to lessen your risk for serious medication problems.

OVERDOSE: Overdose with this vaccine is highly unlikely. If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: As with any vaccine, this vaccine may not fully protect everyone who receives it.

Getting this vaccine does not replace cervical cancer screening. Continue to have regular obstetrician/gynecologist checkups.

Keep vaccine records for yourself and all of your children, and after your children are grown provide their records to them and their doctors. This will prevent unnecessary re-vaccinations.

MISSED DOSE: If you miss a dose in the vaccination schedule, contact your doctor immediately.

STORAGE: Not applicable. This vaccine is given in a doctor's office and will not be stored at home.

Information last revised June 2010. Copyright(c) 2010 First Databank, Inc.

Cervarix Patient Information Including Side Effects

Brand Names: Cervarix

Generic Name: human papillomavirus (HPV) vaccine, bivalent (Pronunciation: HYOO man pap il OH ma VI rus vax EEN, bye VAY lent)

What is human papillomavirus vaccine (Cervarix)?

Human papillomavirus (HPV) can cause genital warts, cancer of the cervix, and various cancers of the vulva or vagina.

The bivalent (bye-VAY-lent) form of HPV vaccine ( Cervarix) is used only in females. Another form of HPV vaccine (Gardasil) is used in both females and males. This medication guide provides information only for Cervarix.

HPV bivalent (Cervarix) vaccine is used to prevent cervical cancer caused by certain types of HPV (types 16 and 18) in girls and young women ages 10 through 25.

HPV vaccine may also be used for purposes not listed in this medication guide.

What are the possible side effects of human papillomavirus vaccine (Cervarix)?

You should not receive a booster vaccine if you have had a life-threatening allergic reaction after the first shot.

Developing cancer from HPV is much more dangerous to your health than receiving the vaccine to protect against it. However, like any medicine, this vaccine can cause side effects but the risk of serious side effects is extremely low.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

You may feel faint after receiving this vaccine. Some people have had seizure-like reactions after receiving this vaccine. Your doctor may want you to remain under observation during the first 15 minutes after the injection.

Other side effects may include:

  • pain, swelling, or redness where the shot was given;
  • headache, tired feeling;
  • joint or muscle pain.
  • nausea, vomiting, diarrhea, stomach pain;
  • menstrual pain;
  • runny or stuffy nose, sore throat, cough; or

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report vaccine side effects to the US Department of Health and Human Services at 1-800-822-7967.

Read the Cervarix (human papillomavirus bivalent vaccine) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about human papillomavirus vaccine (Cervarix)?

The bivalent (bye-VAY-lent) form of HPV vaccine ( Cervarix) is used only in females. Another form of HPV vaccine (Gardasil) is used in both females and males. This medication guide provides information only for Cervarix.

You should not receive a booster vaccine if you have had a life-threatening allergic reaction after the first shot.

Before receiving HPV bivalent vaccine, tell your doctor if you have a weak immune system, or if you are allergic to latex rubber.

HPV vaccine should not be used in place of having a routine pelvic exam and Pap smear to screen for cervical cancer.

You may feel faint after receiving this vaccine. Some people have had seizure-like reactions after receiving this vaccine. Your doctor may want you to remain under observation during the first 15 minutes after the injection.

Developing cancer from HPV is much more dangerous to your health than receiving the vaccine to protect against it. However, like any medicine, this vaccine can cause side effects but the risk of serious side effects is extremely low.

HPV vaccine will not protect against sexually transmitted diseases such as chlamydia, gonorrhea, herpes, HIV, syphilis, and trichomoniasis.

Side Effects Centers

Cervarix Patient Information including How Should I Take

What should I discuss with my health care provider before receiving human papillomavirus vaccine (Cervarix)?

To make sure you can safely receive this vaccine, tell your doctor if you have any of these other conditions:

  • a weak immune system; or
  • if you are allergic to latex rubber.

FDA pregnancy category B. This medication is not expected to be harmful to an unborn baby. However, you should not receive HPV vaccine without telling your doctor if you are pregnant or plan to become pregnant before you have received all doses of this vaccine.

It is not known whether HPV vaccine passes into breast milk or if it could harm a nursing baby. Do not receive this vaccine without telling your doctor if you are breast-feeding a baby.

HPV vaccine will not protect against sexually transmitted diseases such as chlamydia, gonorrhea, herpes, HIV, syphilis, and trichomoniasis.

HPV bivalent vaccine will not prevent diseases caused by HPV types other than types 16 and 18. There are over 100 different types of HPV.

How is human papillomavirus vaccine given (Cervarix)?

HPV vaccine is given as an injection (shot) into a muscle in your upper arm. You will receive this injection in a doctor's office or other clinic setting.

HPV bivalent vaccine is given in a series of 3 shots. You may have the first shot at any time as long as you are between the ages of 10 and 25 years old. Then you will need to receive a second dose 1 month after your first shot, and a third dose 6 months after your first shot.

Be sure to receive all doses of this vaccine recommended by your healthcare provider or your state's health department. You may not be fully protected if you do not receive the full series.

HPV vaccine should not be used in place of having a routine pelvic exam and Pap smear to screen for cervical cancer.

Side Effects Centers

Cervarix Patient Information including If I Miss a Dose

What happens if I miss a dose (Cervarix)?

Contact your doctor if you will miss an HPV vaccine booster 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 you 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.

What happens if I overdose (Cervarix)?

An overdose of this vaccine is unlikely to occur.

What should I avoid while receiving human papillomavirus vaccine (Cervarix)?

There may be certain other vaccines that should not be given at the same time as the HPV vaccine. Until you have completed the series of 3 HPV vaccines, do not receive any other vaccine (including a flu shot) without first asking your doctor.

What other drugs will affect human papillomavirus vaccine (Cervarix)?

Before receiving the HPV vaccine, tell the doctor about all other vaccines you have recently received.

Also tell the doctor if you have recently received drugs or treatments that can weaken the immune system, including:

  • an oral, nasal, inhaled, or injectable steroid medicine;
  • chemotherapy or radiation;
  • medications to treat psoriasis, rheumatoid arthritis, or other autoimmune disorders, such as azathioprine (Imuran), efalizumab (Raptiva), etanercept (Enbrel), leflunomide (Arava), and others; or
  • medicines to treat or prevent organ transplant rejection, such as basiliximab (Simulect), cyclosporine (Sandimmune, Neoral, Gengraf), muromonab-CD3 (Orthoclone), mycophenolate mofetil (CellCept), sirolimus (Rapamune), or tacrolimus (Prograf).

This list is not complete and other drugs may interact with this vaccine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your doctor or pharmacist can provide more information about this vaccine. Additional information is available 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.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

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