Cervarix

Cervarix is a brand name medication included in a group of medications called Papillomavirus vaccines.

• If you have an allergy to Cervarix (papillomavirus (types 16, 18) vaccine (human, recombinant)) or any part of this medicine.
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This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Cervarix with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

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• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Cervarix, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Cervarix. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Cervarix.

Review Date: October 4, 2017

Indications

Cervarix® is indicated for the prevention of the following diseases caused by oncogenic human papillomavirus (HPV) types 16 and 18 [see Clinical Studies (14)]:

• cervical cancer,
• cervical intraepithelial neoplasia (CIN) grade 2 or worse and adenocarcinoma in situ, and
• cervical intraepithelial neoplasia (CIN) grade 1.

Cervarix is approved for use in females 10 through 25 years of age.

Limitations of Use and Effectiveness

Cervarix does not provide protection against disease due to all HPV types [see Clinical Studies (14.3)].

Cervarix 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 (14.2)].

Females should continue to adhere to recommended cervical cancer screening procedures [see Patient Counseling Information (17)].

Vaccination with Cervarix may not result in protection in all vaccine recipients.

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.

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, 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 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 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 was efficacious in the prevention of precancerous lesions or AIS associated with HPV-16 or HPV-18 (Table 5).

Table 5. Efficacy of Cervarix 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.

aSubjects (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.

bHepatitis A Vaccine control group [720 EL.U. of antigen and 500 mcg Al(OH)3].

cThe 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 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 against 12-month persistent infection with HPV-16 or HPV-18 was also evaluated. In the ATP cohort, Cervarix reduced the incidence of 12-month persistent infection with HPV-16 and/or HPV-18 by 91.4% (96.1% CI: 86.1, 95.0).

Immune response following natural infection does not reliably confer protection against future infections. Among subjects who received 3 doses of Cervarix and who were seropositive at baseline and DNA negative for HPV-16 or HPV-18 at baseline and month 6, Cervarix reduced the incidence of 12-month persistent infection by 95.8% (96.1% CI: 72.4, 99.9). 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 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. 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 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 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 Positive at Baselined	641	90	592	92	--
Regardless of Current Infection or Prior Exposure to HPV-16 or HPV-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 Positive at Baselined	641	74	592	73	--
Regardless of Current Infection or Prior Exposure to HPV-16 or HPV-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 Positive at Baselined	641	41	592	38	--
Regardless of Current Infection or Prior Exposure to HPV-16 or HPV-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.

aCases = Histopathological cases associated with HPV-16 and/or HPV-18.

bThe 96.1% confidence interval reflected in this final analysis results from statistical adjustment for the previously conducted interim analysis.

cTVC 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.

dTVC 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.

eTVC: 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.

fObserved vaccine efficacy includes the prophylactic efficacy of Cervarix and the impact of Cervarix 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 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 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 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 at Baselinec	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 at Baselinec	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 at Baselinec	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.

bTVC 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 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 and were DNA negative for the specific HPV type at baseline and month 6, Cervarix 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 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 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 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	865	9,206.5 (8,609.4, 9,845.1)	740	4.4 (4.2, 4.6)
Anti-HPV-18	930	4,741.3 (4,452.2, 5,049.1)	772	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)

aSubjects 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.

bEnzyme 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).

cPseudovirion-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 was evaluated in 2 clinical studies involving 1,193 girls 10 through 14 years of age who received Cervarix.

Study 3 (HPV 013) was a double-blind, randomized, controlled study in which 1,035 subjects received Cervarix 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 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)

aSubjects 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 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)

Antibody Assay	10-14 Years of Age			15-25 Years of Age
	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

aSubjects who received 3 doses of vaccine for whom assay results were available for at least one post-vaccination antibody measurement (N).

bNon-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.

cNon-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 is inferred in girls 10 through 14 years of age.

Cervarix 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 2º and 8ºC (36º and 46ºF). 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.