Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Malignancies
Additions and/or
revisions underlined:
![]()
…
Malignancies in Adults
In the controlled portions of clinical trials of
some TNF-blockers, including adalimumab products, more cases of malignancies
have been observed among TNF-blocker-treated adult patients compared to
control-treated adult patients. During the controlled portions of 39 global
adalimumab clinical trials in adult patients with rheumatoid arthritis (RA),
psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease (CD),
ulcerative colitis (UC), plaque psoriasis (Ps), hidradenitis suppurativa (HS)
and uveitis (UV), malignancies, other than non-melanoma (basal cell and
squamous cell) skin cancer, were observed at a rate (95% confidence interval)
of 0.7 (0.48, 1.03) per 100 patient-years among 7973 adalimumab-treated
patients versus a rate of 0.7 (0.41, 1.17) per 100 patient-years among 4848
control-treated patients (median duration of treatment of 4 months for
adalimumab-treated patients and 4 months for control-treated patients). In 52
global controlled and uncontrolled clinical trials of adalimumab in adult
patients with RA, PsA, AS, CD, UC, Ps, HS and UV, the most frequently
observed malignancies, other than lymphoma and NMSC, were breast, colon,
prostate, lung, and melanoma. The malignancies in adalimumab-treated patients
in the controlled and uncontrolled portions of the studies were similar in type
and number to what would be expected in the general U.S. population according
to the SEER database (adjusted for age, gender, and race).
![]()
…
Non-Melanoma
Skin Cancer
During the controlled portions of 39 global
adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS
and UV, the rate (95% confidence interval) of NMSC was 0.8 (0.52, 1.09)
per 100 patient-years among adalimumab-treated patients and 0.2 (0.10, 0.59)
per 100 patient-years among control-treated patients. Examine all patients, and
in particular patients with a medical history of prior prolonged
immunosuppressant therapy or psoriasis patients with a history of PUVA
treatment for the presence of NMSC prior to and during treatment with CYLTEZO.
![]()
Lymphoma and Leukemia
In the controlled portions of clinical trials of
all the TNF-blockers in adults, more cases of lymphoma have been observed among
TNF-blocker-treated patients compared to control-treated patients. In the
controlled portions of 39 global adalimumab clinical trials in adult patients
with RA, PsA, AS, CD, UC, Ps, HS and UV, 2 lymphomas occurred among 7973
adalimumab-treated patients versus 1 among 4848 control-treated patients. In 52
global controlled and uncontrolled clinical trials of adalimumab in adult
patients with RA, PsA, AS, CD, UC, Ps, HS and UV with a median duration
of approximately 0.7 years, including 24,605 patients and over 40,215
patient-years of adalimumab, the observed rate of lymphomas was approximately 0.11
per 100 patient-years. This is approximately 3-fold higher than expected in the
general U.S. population according to the SEER database (adjusted for age,
gender, and race).1 Rates of lymphoma in clinical trials of adalimumab cannot
be compared to rates of lymphoma in clinical trials of other TNF blockers and
may not predict the rates observed in a broader patient population. Patients
with RA and other chronic inflammatory diseases, particularly those with highly
active disease and/or chronic exposure to immunosuppressant therapies, may be
at a higher risk (up to several fold) than the general population for the
development of lymphoma, even in the absence of TNF
![]()
blockers.
Post-marketing cases of acute and chronic leukemia have been reported in association
with TNF-blocker use in RA and other indications. Even in the absence of
TNF-blocker therapy, patients with RA may be at a higher risk (approximately
2-fold) than the general population for the development of leukemia.
…
5.5 Neurologic Reactions
Additions and/or
revisions underlined:
…
There
is a known association between intermediate uveitis and central demyelinating
disorders.
6
Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or
revisions underlined
…
Tuberculosis
and Opportunistic Infections
In
52 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC,
Ps, HS and UV that included 24,605 adalimumab-treated patients, the rate
of reported active tuberculosis was 0.20 per 100 patient-years and the rate of
positive PPD conversion was 0.09 per 100 patient-years. In a subgroup of 10,113
U.S. and Canadian adalimumab-treated patients, the rate of reported active TB
was 0.05 per 100 patient-years and the rate of positive PPD conversion was 0.07
per 100 patient-years. These trials included reports of miliary, lymphatic,
peritoneal, and pulmonary TB. Most of the TB cases occurred within the first
eight months after initiation of therapy and may reflect recrudescence of
latent disease. In these global clinical trials, cases of serious opportunistic
infections have been reported at an overall rate of 0.05 per 100 patient-years.
Some cases of serious opportunistic infections and TB have been fatal [see Warnings and Precautions (5.1)].
…
Liver Enzyme Elevations
…
In controlled trials of adalimumab (initial doses
of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in
adult patients with uveitis with an exposure of 165.4 PYs and 119.8 PYs in
adalimumab-treated and control-treated patients, respectively, ALT elevations
greater than or equal to 3 x ULN occurred in 2.4% of adalimumab-treated
patients and 2.4% of control-treated patients.
…
Uveitis Clinical Studies
Adalimumab has been studied in 464 adult patients
with uveitis (UV) in placebo-controlled and open-label extension studies [see
Clinical Studies (14.10)]. The safety profile for patients with UV treated
with adalimumab was similar to the safety profile seen in patients with RA.
7
Drug Interactions
7.2 Biological Products
Additions and/or revisions underlined
In clinical studies in patients with RA, an
increased risk of serious infections has been observed with the combination of
TNF blockers with anakinra or abatacept, with no added benefit; therefore, use
of CYLTEZO with abatacept or anakinra is not recommended in patients with RA [see Warnings and Precautions (5.7, 5.11)].
A higher rate of serious infections has also been observed in patients with RA
treated with rituximab who received subsequent treatment with a TNF blocker.
There is insufficient information regarding the concomitant use of CYLTEZO and
other biologic products for the treatment of RA, PsA, AS, CD, UC, Ps, HS and UV.
Concomitant administration of CYLTEZO with other biologic DMARDS (e.g.,
anakinra and abatacept) or other TNF blockers is not recommended based upon the
possible increased risk for infections and other potential pharmacological
interactions.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions and/or revisions underlined:
What
is CYLTEZO?
CYLTEZO is a medicine called a Tumor Necrosis Factor
(TNF) blocker. CYLTEZO is used:
To reduce the signs and symptoms of:
…
…
Approved Drug Label (PDF)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
(Additions
and/or revisions underlined)
For patients who will use the CYLTEZO Pen,
tell them that
they:
1 Will hear a ‘click’ when the injection button is pressed. The
click indicates the start of the injection.
2 Must keep holding
the CYLTEZO Pen against their
squeezed, raised skin until all
of the medicine is injected. This can take
up to 10 seconds.
3 Confirm entire dose was delivered by making sure plunger (seen in window)
reached the bottom of
the pen.
Instruct patients to dispose of their used needles and syringes or used pens in an FDA-cleared sharps disposal container immediately after use. Instruct patients not to dispose of loose needles and syringes or pens in their household trash. Instruct patients that if they do not have an FDA-cleared sharps disposal container, they may use a household container that is made of a heavy-duty plastic,
Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Malignancies
Additions and/or revisions underlined:
Malignancies in Adults
In
the controlled portions of clinical trials of some TNF-blockers, including
adalimumab products, more cases of malignancies have been observed among
TNF-blocker-treated adult patients compared to control-treated adult patients.
During the controlled portions of 39 global adalimumab clinical trials in adult
patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing
spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC), plaque
psoriasis (Ps), hidradenitis suppurativa (HS) and another indication,
malignancies, other than non-melanoma (basal cell and squamous cell) skin
cancer, were observed at a rate (95% confidence interval) of 0.7 (0.48, 1.03)
per 100 patient-years among 7973 adalimumab-treated patients versus a rate of
0.7 (0.41, 1.17) per 100 patient-years among 4848 control-treated patients
(median duration of treatment of 4 months for adalimumab-treated patients and 4
months for control-treated patients). In 52 global controlled and uncontrolled
clinical trials of adalimumab in adult patients with RA, PsA, AS, CD, UC, Ps, HS
and another indication, the most frequently observed malignancies, other than
lymphoma and NMSC, were breast, colon, prostate, lung, and melanoma.
…
Non-Melanoma Skin
Cancer
During
the controlled portions of 39 global adalimumab clinical trials in adult
patients with RA, PsA, AS, CD, UC, Ps, HS and another indication, the
rate (95% confidence interval) of NMSC was 0.8 (0.52, 1.09) per 100
patient-years among adalimumab-treated patients and 0.2 (0.10, 0.59) per 100
patient-years among control-treated patients.
…
Lymphoma and
Leukemia
In
the controlled portions of clinical trials of all the TNF-blockers in adults,
more cases of lymphoma have been observed among TNF-blocker-treated patients
compared to control-treated patients. In the controlled portions of 39 global
adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS
and another indication, 2 lymphomas occurred among 7973 adalimumab-treated
patients versus 1 among 4848 control-treated patients. In 52 global controlled
and uncontrolled clinical trials of adalimumab in adult patients with RA, PsA,
AS, CD, UC, Ps, HS and another indication with a median duration of
approximately 0.7 years, including 24,605 patients and over 40,215
patient-years of adalimumab, the observed rate of lymphomas was approximately
0.11 per 100 patient-years.
…
6
Adverse Reactions
6.1 Clinical
Trials Experience
Additions and/or revisions underlined:
Infections
In the controlled portions of the 39 global
adalimumab clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS
and another indication, the rate of serious infections was 4.3 per 100
patient-years in 7973 adalimumab-treated patients versus a rate of 2.9 per 100
patient-years in 4848 control-treated patients. Serious infections observed
included pneumonia, septic arthritis, prosthetic and post-surgical infections,
erysipelas, cellulitis, diverticulitis, and pyelonephritis [see Warnings and Precautions (5.1)].
Tuberculosis and Opportunistic Infections
In 52 global controlled and uncontrolled clinical
trials in RA, PsA, AS, CD, UC, Ps, HS and another indication that
included 24,605 adalimumab-treated patients, the rate of reported active
tuberculosis was 0.20 per 100 patient-years and the rate of positive PPD
conversion was 0.09 per 100 patient-years.
…
In controlled trials of adalimumab (initial doses of
160 mg at Week 0 and 80 mg at Week 2, followed by 40 mg every week starting at
Week 4), in subjects with HS with a control period duration ranging from 12 to
16 weeks, ALT elevations greater than or equal to 3 x ULN occurred in 0.3% of
adalimumab-treated subjects and 0.6% of control-treated subjects.
…
Hidradenitis Suppurativa Clinical Studies
Adalimumab has been studied in 727 subjects with
hidradenitis suppurativa (HS) in three placebo-controlled studies and one open-
label extension study [see Clinical
Studies (14.9)]. The safety profile for subjects with HS treated with
adalimumab weekly was consistent with the known safety profile of adalimumab.
Flare of HS, defined as greater than or equal to 25%
increase from baseline in abscesses and inflammatory nodule counts and with a
minimum of 2 additional lesions, was documented in 22 (22%) of the 100 subjects
who were withdrawn from adalimumab treatment following the primary efficacy
timepoint in two studies.
6.2 Immunogenicity
Addition
of Hidradenitis Suppurativa to the indications section of Table 2; please refer
to label for complete information
7
Drug Interactions
Additions
and/or revisions underlined:
7.2 Biological Products
In
clinical studies in patients with RA, an increased risk of serious infections
has been observed with the combination of TNF blockers with anakinra or
abatacept, with no added benefit; therefore, use of CYLTEZO with abatacept or
anakinra is not recommended in patients with RA [see Warnings and Precautions (5.7, 5.11)]. A higher rate of
serious infections has also been observed in patients with RA treated with
rituximab who received subsequent treatment with a TNF blocker. There is
insufficient information regarding the concomitant use of CYLTEZO and other
biologic products for the treatment of RA, PsA, AS, CD, UC, Ps, and HS.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
Additions
and/or revisions underlined:
What is CYLTEZO?
CYLTEZO
is a medicine called a Tumor Necrosis Factor (TNF) blocker. CYLTEZO is used:
…
Approved Drug Label (PDF)
6
Adverse Reactions
(Additions and/or revisions
underlined)
The
following clinically significant adverse reactions are described
elsewhere in the labeling:
Serious
Infections [see Warnings and Precautions (5.1)]
Malignancies [see Warnings and Precautions (5.2)]
Hypersensitivity
Reactions [see Warnings and Precautions (5.3)]
Hepatitis B
Virus Reactivation [see Warnings and
Precautions (5.4)]
Neurologic
Reactions [see Warnings and Precautions (5.5)]
Hematological
Reactions [see Warnings and Precautions (5.6)]
Heart Failure [see Warnings and Precautions (5.8)]
Autoimmunity [see Warnings and Precautions (5.9)]
6.1
Clinical Trials Experience
(Extensive
changes; please refer to label)
6.2
Immunogenicity
(Additions
and/or revisions underlined)
As with all therapeutic
proteins, there is potential for immunogenicity. The detection of antibody
formation is highly dependent on the sensitivity and specificity of the assay.
Additionally, the observed incidence of antibody (including neutralizing antibody)
positivity in an assay may be influenced by several factors including assay
methodology, sample handling, timing of sample collection, concomitant
medications, and underlying disease. For these reasons, comparison of the
incidence of antibodies in the studies described below with the incidence of
antibodies in other studies or to other adalimumab products may be misleading.
There are two assays that
have been used to measure anti-adalimumab antibodies. With the ELISA,
antibodies to adalimumab could be detected only when serum adalimumab
concentrations were < 2 mcg/mL. The ECL assay can detect anti-adalimumab
antibody titers independent of adalimumab concentrations in the serum samples.
The incidence of anti-adalimumab antibody (AAA) development in patients treated
with adalimumab are presented in Table 2.
Rheumatoid Arthritis and Psoriatic Arthritis: Patients in
Studies RA-I, RA-II, and RA-III were tested at multiple time points for
antibodies to adalimumab using the ELISA during the 6- to 12-month period.
No apparent correlation of antibody development to adverse reactions was
observed. With monotherapy, patients receiving every other week dosing may
develop antibodies more frequently than those receiving weekly dosing. In
patients receiving the recommended dosage of 40 mg every other week as
monotherapy, the ACR 20 response was lower among antibody-positive patients
than among antibody-negative patients. The long- term immunogenicity
of adalimumab is unknown.
8
Use in Specific Populations
8.4
Pediatric Use
(Additions
and/or revisions underlined)
The safety and effectiveness of CYLTEZO have
been established for:
reducing signs
and symptoms of moderately to severely active polyarticular JIA in pediatric patients 2 years of age and older.
the treatment
of moderately to severely active Crohn’s disease in pediatric patients 6 years
of age and older.
A pediatric assessment for
CYLTEZO demonstrates that CYLTEZO is safe and effective for pediatric patients
in an indication for which Humira (adalimumab) is approved. However, CYLTEZO is
not approved for such indication due to marketing exclusivity for Humira
(adalimumab).
Due to their inhibition
of TNF?, adalimumab products administered during pregnancy could affect immune
response in the in utero- exposed
newborn and infant. Data from eight infants exposed to adalimumab in utero suggest adalimumab crosses the
placenta [see Use in Specific Populations
(8.1)]. The clinical significance of elevated adalimumab concentrations in
infants is unknown. The safety of administering live or live-attenuated
vaccines in exposed infants is unknown. Risks and benefits should be considered
prior to vaccinating (live or live-attenuated) exposed infants.
Post-marketing cases of
lymphoma, including hepatosplenic T-cell lymphoma and other malignancies, some
fatal, have been reported among children, adolescents, and young adults who
received treatment with TNF-blockers including adalimumab products [see Warnings and Precautions (5.2)].
Juvenile Idiopathic Arthritis
In Study JIA-I, adalimumab was shown
to reduce signs and symptoms of active polyarticular JIA in patients 4 to 17
years of age [see Clinical Studies
(14.2)]. In Study JIA-II, the safety profile for patients 2 to <4
years of age was similar to the safety profile for patients 4 to 17 years of
age with polyarticular JIA [see Adverse
Reactions (6.1)]. Adalimumab products have not been studied in patients
with polyarticular JIA less than 2 years of age or in patients with a weight
below 10 kg.
The safety of adalimumab in
patients in the polyarticular JIA trials was generally similar to that observed
in adults with certain exceptions [see
Adverse Reactions (6.1)].
The safety and effectiveness
of adalimumab products have not been established in pediatric patients with JIA
less than 2 years of age. Pediatric Crohn’s Disease
The safety and
effectiveness of adalimumab products for the treatment of moderately to
severely active Crohn’s disease have been established in pediatric patients 6
years of age and older. Use of adalimumab products for this indication is
supported by evidence from adequate and well-controlled studies in adults with
additional data from a randomized, double-blind, 52-week clinical study of two
dose concentrations of adalimumab in 192 pediatric patients (6 years to 17
years of age) [see Adverse Reactions
(6.1), Clinical Pharmacology (12.2, 12.3), Clinical Studies (14.6)]. The
adverse reaction profile in patients 6 years to 17 years of age was similar to
adults.
The safety and
effectiveness of adalimumab products have not been established in pediatric
patients with Crohn’s disease less than 6 years of age.
Approved Drug Label (PDF)
5
Warnings and Precautions
Additions and/or
revisions underlined:
Malignancies
Consider the risks and benefits of TNF-blocker treatment including CYLTEZO prior to initiating therapy
in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC)
or when considering continuing a TNF blocker
in patients who develop a malignancy.
Malignancies in Adults
In the controlled portions of clinical
trials of some TNF-blockers, including adalimumab products, more cases of malignancies have been observed among TNF-blocker-treated adult patients compared
to control-treated adult
patients. During
the controlled portions
of 39 global adalimumab clinical trials in adult patients
with rheumatoid arthritis (RA), psoriatic arthritis (PsA),
ankylosing spondylitis (AS), Crohn’s disease
(CD), ulcerative colitis (UC),
plaque psoriasis (Ps),
and other indications, malignancies, other
than non-melanoma (basal cell and
squamous cell) skin cancer,
were observed at a rate (95% confidence interval) of 0.7 (0.48,
1.03) per 100 patient-years among 7973 adalimumab-treated patients versus a rate of 0.7 (0.41, 1.17) per 100 patient-years among 4848 control-treated patients (median
duration of treatment
of 4 months for adalimumab-treated patients and 4 months for
control-treated patients). In 52 global controlled and uncontrolled clinical trials of adalimumab in adult patients
with RA, PsA, AS, CD, UC, Ps,
and other indications, the most frequently observed malignancies, other than lymphoma and NMSC, were breast,
colon, prostate, lung, and melanoma.
Non-Melanoma Skin Cancer
During the controlled portions of the 39 global adalimumab
clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, and other indications, the rate (95% confidence interval) of NMSC was 0.8 (0.52, 1.09) per 100 patient-years among adalimumab-treated patients
and 0.2 (0.10, 0.59) per 100 patient-years among control-treated patients. Examine
all patients, and in particular patients with a medical history
of prior prolonged immunosuppressant therapy
or psoriasis patients
with a history
of PUVA treatment
for the presence
of NMSC prior to and during treatment with CYLTEZO.
Lymphoma
and Leukemia
In the controlled portions of clinical
trials of all the TNF-blockers in adults, more cases of lymphoma
have been observed among TNF-blocker-treated patients compared to control-treated patients. In the controlled portions of 39 global adalimumab clinical trials
in adult patients with RA, PsA, AS, CD, UC, Ps, and other indications, 2 lymphomas
occurred among 7973 adalimumab-treated patients versus 1 among 4848 control-treated patients. In 52 global controlled and uncontrolled clinical trials of adalimumab in adult patients with RA, PsA, AS, CD, UC, Ps, and other indications with a median duration of approximately 0.7 years, including 24,605 patients and over 40,215 patient-years of adalimumab, the observed rate of lymphomas
was approximately 0.11 per 100 patient-years.
6
Adverse Reactions
Clinical Trials Experience
Additions and/or
revisions underlined:
Infections
In the controlled portions of 39 global
adalimumab clinical trials
in adult patients
with RA, PsA, AS, CD, UC, Ps, and other indications, the rate of serious infections was 4.3 per 100 patient-years in 7973 adalimumab-treated patients versus a rate of 2.9 per 100 patient-years in 4848 control-treated patients.
Tuberculosis and Opportunistic Infections
In 52
global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC, Ps, and other indications that
included 24,605 adalimumab-treated patients, the rate of reported active tuberculosis was 0.20 per 100 patient-years and the rate of positive PPD conversion was 0.09 per 100 patient-years. In a subgroup of 10,113 U.S. and Canadian
adalimumab-treated patients, the rate of reported active
TB was 0.05 per 100 patient-years and the rate of positive PPD conversion was 0.07 per 100 patient-years.
Postmarketing Experience
Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening
psoriasis (all sub-types including pustular and palmoplantar), alopecia, lichenoid
skin reaction
8
Use in Specific Populations
Lactation
Risk Summary
Newly added information:
Published data suggest
that the systemic exposure
to a breastfed
infant is expected
to be low because
adalimumab is a large molecule and is degraded in the gastrointestinal tract. However, the effects
of local exposure
in the gastrointestinal tract are unknown.
Pregnancy
Additions and/or
revisions underlined:
Risk Summary
Available studies
with use of adalimumab during pregnancy do not reliably
establish an association between
adalimumab and major birth defects. Clinical data are available from the Organization of Teratology Information Specialists (OTIS)/MotherToBaby Pregnancy
Registry in pregnant
women with rheumatoid arthritis (RA) or Crohn’s disease
(CD) treated with adalimumab. Registry results
showed a rate of 10%
for major birth defects
with first trimester use of adalimumab in pregnant
women with RA or CD and a rate of 7.5 for major birth defects
in the disease-matched comparison cohort.
The lack of pattern of major birth defects
is reassuring and differences between exposure
groups may have impacted the occurrence of birth defects. . .
The estimated background risk of major birth defects
and miscarriage for the indicated
populations is unknown.
All pregnancies have a background risk of birth defect,
loss, or other adverse
outcomes. In the U.S. general population, the estimated
background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical
Considerations
Disease-associated maternal and embryo/fetal risk
Published data suggest
that the risk of adverse pregnancy outcomes in women with RA or inflammatory bowel disease
(IBD) is associated with increased disease
activity. Adverse pregnancy outcomes include preterm
delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.
. .
Data
Human Data
A prospective cohort
pregnancy exposure
registry conducted by OTIS/MotherToBaby in the U.S. and Canada between
2004 and 2016 compared the risk of major birth defects in live-born
infants of 221 women (69 RA, 152
CD) treated
with adalimumab during
the first trimester
and 106 women (74 RA, 32 CD)
not treated with adalimumab.
The proportion of major birth defects among
live-born infants in the adalimumab-treated and untreated cohorts was 10% (8.7% RA, 10.5% CD) and 7.5% (6.8% RA, 9.4% CD),
respectively. The lack of pattern of major birth defects is reassuring and differences between exposure groups may have impacted the occurrence of birth defects. This study cannot reliably establish whether there is an association between
adalimumab and major birth defects because of methodological limitations of the registry, including small sample size, the voluntary
nature of the study, and the
non-randomized design.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide
Extensive
changes; please refer to label for complete information.
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