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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
HADLIMA (BLA-761059)
(ADALIMUMAB-BWWD)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
10/17/2025 (SUPPL-32)
5 Warnings and Precautions
5.9 Autoimmunity
Additions and/or revisions underlined:
Treatment with adalimumab products may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome or autoimmune hepatitis [see Adverse Reactions (6.1, 6.3)]. If a patient develops symptoms and findings suggestive of a lupus-like syndrome or autoimmune hepatitis following treatment with HADLIMA, discontinue treatment and evaluate the patient.
6 Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
. . .
Less Common Adverse Reactions in Rheumatoid Arthritis Clinical Studies
Other infrequent serious adverse reactions that do not appear in the Warnings and Precautions or Adverse Reaction sections that occurred at an incidence of less than 5% in adalimumab-treated subjects in RA studies (RA-I, RA-II, RA-III, and RA-IV) were:
Body As A Whole: Pain in extremity, pelvic pain, surgery, thorax pain
Cardiovascular System: Arrhythmia, atrial fibrillation, chest pain, coronary artery disorder, heart arrest, hypertensive encephalopathy, myocardial infarct, palpitation, pericardial effusion, pericarditis, syncope, tachycardia
. . .
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.
. . .
6.3 Postmarketing Experience
Additions and/or revisions underlined:
. . .
Hepato-biliary disorders: Liver failure, hepatitis, autoimmune hepatitis
. . .
8 Use in Specific Populations
8.4 Pediatric Use
Additions and/or revisions underlined:
The safety and effectiveness of HADLIMA have not been established in pediatric patients with psoriatic arthritis, ankylosing spondylitis, or plaque psoriasis.
. . .
Juvenile Idiopathic Arthritis
The safety and effectiveness of HADLIMA for the treatment of moderately to severely active polyarticular JIA have been established in pediatric patients 2 years of age and older. Use for this indication is supported by evidence from an adequate and well-controlled study (Study JIA) in patients 4 to 17 years of age [see Clinical Studies (14.2)] and a safety study (Study JIA-II) in patients 2 to <4 years of age where the safety profile was similar to patients 4 to 17 years of age [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 pediatric 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 HADLIMA have not been established in pediatric patients with JIA less than 2 years of age.
. . .
8.5 Geriatric Use
Additions and/or revisions underlined:
In clinical studies of RA (Studies RA-I, RA-II, RA-III, and RA-IV), a total of 519 RA subjects 65 years of age and older, including 107 subjects 75 years of age and older, received adalimumab in clinical studies RA-I through IV. No overall difference in effectiveness was observed between these subjects and younger adult subjects.
The frequency of serious infection and malignancy among adalimumab treated subjects 65 years of age and older was higher than for those less than 65 years of age. Consider the benefits and risks of HADLIMA in patients 65 years of age and older. In patients treated with HADLIMA closely monitor for the development of infection or malignancy [see Warnings and Precautions (5.1, 5.2)].
06/28/2024 (SUPPL-18)
6 Adverse Reactions
6.2 ImmunogenicityAdditions and revisions underlined:
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidences of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of adalimumab or of other adalimumab products.
07/11/2023 (SUPPL-8)
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).1
In controlled trials of other TNF blockers
in adult patients
at higher risk for malignancies (i.e., patients with COPD with a significant smoking
history and cyclophosphamide-treated patients
with Wegener’s
granulomatosis), a greater
portion of malignancies occurred in the TNF blocker
group compared to the
control group.
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 HADLIMA.
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:
Use of TNF blocking
agents, including adalimumab products, has been associated with rare cases of new onset or exacerbation of clinical
symptoms and/or radiographic evidence of central nervous system demyelinating disease,
including multiple sclerosis
(MS) and optic neuritis, and peripheral demyelinating disease, including
Guillain-Barré syndrome. Exercise caution in considering the use of HADLIMA in
patients with preexisting or recent-onset central or peripheral nervous system
demyelinating disorders; discontinuation of HADLIMA should be considered if any
of these disorders develop. There is a known association between
intermediate uveitis and central demyelinating disorders.
6 Adverse Reactions
6.1 Clinical Trials ExperienceChanges to Table 2; please refer to label
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 HADLIMA 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 HADLIMA
and other biologic
products for the treatment of RA, PsA, AS, CD, UC, Ps, HS and UV.
Concomitant administration of HADLIMA 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.
7.4 Cytochrome P450 Substrates
Additions and/or revisions underlined:The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines (e.g., TNF?, IL-6) during chronic inflammation. It is possible for products that antagonize cytokine activity, such as adalimumab products, to influence the formation of CYP450 enzymes. Upon initiation or discontinuation of HADLIMA in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.
8 Use in Specific Populations
8.4 Pediatric UseAdditions and/or revisions underlined:
…
Due to their inhibition of TNF alpha, 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.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEAdditions and/or revisions underlined:
…
What is HADLIMA?
HADLIMA is a medicine called a Tumor Necrosis Factor (TNF) blocker. HADLIMA is used:
…
to treat non-infectious intermediate, posterior, and panuveitis in adults
06/26/2023 (SUPPL-6)
5 Warnings and Precautions
5.2 MalignanciesAdditions 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. 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).1
…
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. 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 HADLIMA.
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 ExperienceAdditions and/or revisions underlined:
…
Liver Enzyme Elevations
…
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.
…
Other Adverse Reactions
…
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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEAdditions and/or revisions underlined:
What is HADLIMA?
HADLIMA is a medicine called a Tumor Necrosis Factor (TNF) blocker. HADLIMA is used:
…
moderate to severe hidradenitis suppurativa (HS) in adults.
…
08/15/2022 (SUPPL-5)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDENewly added information:
What are the ingredients in HADLIMA? Active ingredient: adalimumab-bwwd
HADLIMA PushTouch 40 mg/0.4 mL and HADLIMA 40 mg/0.4 mL prefilled syringe:
Inactive ingredients: L-histidine, L-histidine hydrochloride monohydrate, mannitol, polysorbate 20, sodium phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate, sodium succinate dibasic, succinic acid, and Water for Injection, USP
06/17/2022 (SUPPL-4)
5 Warnings and Precautions
5.11 Increased Risk of Infection When Used with AbataceptSubsection title revised
Additions and 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), 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. 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).1
In controlled trials of other TNF blockers in adult patients at higher risk for malignancies (i.e., patients with COPD with a significant smoking history and cyclophosphamide-treated patients with Wegener’s granulomatosis), a greater portion of malignancies occurred in the TNF blocker group compared to the control group.
Non-Melanoma Skin Cancer
During the controlled portions of 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 HADLIMA.
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. 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
Subsection title revised
6 Adverse Reactions
Extensive changes; please refer to label
Newly added section; please refer to label
8 Use in Specific Populations
8.4 Pediatric UseAdditions and revisions underlined:
The safety and effectiveness of HADLIMA 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 HADLIMA demonstrates that HADLIMA is safe and effective for pediatric patients in an indication for which Humira (adalimumab) is approved. However, HADLIMA 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.
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.
Additions and revisions underlined:
A total of 519 RA patients 65 years of age and older, including 107 patients 75 years of age and older, received adalimumab in clinical studies RA-I through IV. No overall difference in effectiveness was observed between these patients and younger patients. The frequency of serious infection and malignancy among adalimumab treated patients 65 years of age and older was higher than for those less than 65 years of age. Consider the benefits and risks of HADLIMA in patients 65 years of age and older. In patients treated with HADLIMA. closely monitor for the development of infection or malignancy [see Warnings and Precautions (5.1, 5.2)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONExtensive changes; please refer to label