Drug Safety-related Labeling Changes (SrLC)

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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.

HUMIRA (BLA-125057)

(ADALIMUMAB)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/06/2018 (SUPPL-410)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(addition underlined)

…

Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar), alopecia, lichenoid skin reaction

…

09/28/2018 (SUPPL-408)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Uveitis Clinical Studies

Additions and/or revisions underlined:

HUMIRA has been studied in 464 adult patients with uveitis (UV) in placebo-controlled and open-label extension studies and in 90 pediatric patients with uveitis (Study PUV-I). The safety profile for patients with UV treated with HUMIRA was similar to the safety profile seen in patients with RA.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

Safety and efficacy of HUMIRA in pediatric patients for uses other than polyarticular juvenile idiopathic arthritis (JIA), pediatric Crohn’s disease and pediatric uveitis have not been established.

Addition of the following as the last paragraph in the subsection:

Pediatric Uveitis

The safety and effectiveness of HUMIRA for the treatment of non-infectious uveitis have been established in pediatric patients 2 years of age and older. The use of HUMIRA is supported by evidence from adequate and well-controlled studies of HUMIRA in adults and a 2:1 randomized, controlled clinical study in 90 pediatric patients. The safety and effectiveness of HUMIRA has not been established in pediatric patients with uveitis less than 2 years of age.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

WHAT IS HUMIRA?

Additions and/or revisions underlined:

To treat non-infectious intermediate, posterior, and panuveitis (UV) in adults and children 2 years of age and older.

08/02/2018 (SUPPL-406)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Risk Summary

Additions and/or revisions underlined:

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 HUMIRA Pregnancy Registry in pregnant women with rheumatoid arthritis (RA) or Crohn’s disease (CD). 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 …

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

IA 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.

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

Limited data from case reports in the published literature describe the presence of adalimumab in human milk at infant doses of 0.1% to 1% of the maternal serum level. 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. There are no reports of adverse effects …

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

What should I tell my doctor before taking HUMIRA?

Additions and/or revisions underlined:

are pregnant or plan to become pregnant, breastfeeding or plan to breastfeed. You and your doctor should decide if you should take HUMIRA while you are pregnant or breastfeeding.

12/14/2017 (SUPPL-403)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

…

Anti-adalimumab antibodies were measured in clinical trials of subjects with moderate to severe HS with two assays (an original assay capable of detecting antibodies when serum adalimumab concentrations declined to < 2 mcg/mL and a new assay that is capable of detecting anti- adalimumab antibody titers in all subjects, independent of adalimumab concentration). Using the original assay, the rate of anti-adalimumab antibody development in subjects treated with HUMIRA was 6.5%. Among subjects who stopped HUMIRA treatment for up to 24 weeks and in whom adalimumab serum levels subsequently declined to < 2 mcg/mL (approximately 22% of total subjects studied), the immunogenicity rate was 28%. Using the new titer-based assay, anti- adalimumab antibody titers were measurable in 61% of HS subjects treated with HUMIRA. Antibodies to adalimumab were associated with reduced serum adalimumab concentrations. In general, the extent of reduction in serum adalimumab concentrations is greater with increasing titers of antibodies to adalimumab. No apparent association between antibody development and safety was observed.

…

04/21/2017 (SUPPL-401)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions are underlined)

What should I tell my doctor before taking HUMIRA?

HUMIRA may not be right for you. Before starting HUMIRA, tell your doctor about all of your health conditions, including if you:

are allergic to rubber or latex. Tell your doctor if you have any allergies to rubber or latex.
- The black needle cover for the HUMIRA Pen 80 mg/0.8 mL, HUMIRA 80 mg/0.8 mL prefilled syringe, HUMIRA Pen 40 mg/0.4 mL, HUMIRA 40 mg/0.4 mL prefilled syringe and the vial stopper on the HUMIRA institutional use vial are not made with natural rubber or latex.

What are the ingredients in HUMIRA?

…

HUMIRA Pen 80 mg/0.8 mL, HUMIRA 80 mg/0.8 mL prefilled syringe, HUMIRA Pen 40 mg/0.4 mL and HUMIRA 40 mg/0.4 mL prefilled syringe:

Inactive ingredients: mannitol, polysorbate 80, and Water for Injection.

06/30/2016 (SUPPL-397)

Approved Drug Label (PDF)

5 Warnings and Precautions

Malignancies

Malignancies in Adults

39 global HUMIRA clinical trials replaces 37 global HUMIRA clinical trials
Addition of and uveitis (UV), following hidradenitis suppurativa (HS)
(95% confidence interval) of 0.7 (0.48, 1.03)(replaces 0.45m 1.01) per 100 patient-years among 7973 (replaces 7723) HUMIRA-treated patients versus a rate of 0.7 (0.41, 1.17) (replaces 0.48 and 1.31) per 100 patient-years among 4848 (replaces 4598) control-treated patients.
In 52 (replaces 50) global controlled and uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV (addition) the most frequently observed malignancies…

Non-Melanoma Skin Cancer

During the controlled portions of 39 (replaces 37) global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, (addition) the rate (95% confidence interval) of NMSC…

Lymphoma and Leukemia

In the controlled portions of 39 (replaces 37) global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, (addition) 2 lymphomas occurred among 7973 (replaces 7723) HUMIRA-treated patients versus 1 among 4848 (replaces 4598) control-treated patients. In 52 (replaces 50) global controlled and uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV (addition) with a median duration of approximately 0.7 years, including 24,605 (replaces 24,135) patients and over 40,215 (replaces 39,000) patient-years…

Neurologic Reactions

(addition) discontinuation of HUMIRA should be considered if any of these disorders develop. There is a known association between intermediate uveitis and central demyelinating disorders.

Immunizations

(addition) The safety of administering live or live-attenuated vaccines in infants exposed to HUMIRA in utero is unknown. Risks and benefits should be considered prior to vaccinating (live or liveattenuated) exposed infants.

6 Adverse Reactions

Clinical Trials Experience

Infections

In the controlled portions of the 39 (replaces 37) global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV (addition), the rate of serious infections was 4.3 (replaces 4.4) per 100 patient-years in 7973 (replaces 7723) HUMIRA-treated patients versus a rate of 2.9 per 100 patient-years in 4848 (replaces 4598) control-treated patients.

Tuberculosis and Opportunistic Infections

In 52 (replaces 50) global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC, Ps, HS and UV (addition) that included 24,605 (replaces 24,135) HUMIRA-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 (replaces 0.10) per 100 patient-years. In a subgroup of 10,113 (replaces 9959) U.S. and Canadian HUMIRA-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 (replaces 0.8) per 100 patient-years.

Liver Enzyme Elevations

(addition) In controlled trials of HUMIRA (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in patients with uveitis with an exposure of 165.4 PYs and 119.8 PYs in HUMIRA-treated and control-treated patients, respectively, ALT elevations = 3 x ULN occurred in 2.4% of HUMIRA-treated patients and 2.4% of control-treated patients.

Immunogenicity

In patients with non-infectious uveitis, anti-adalimumab antibodies were identified in 4.8% (12/249) of patients treated with adalimumab. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 mcg/mL. Among the patients whose serum adalimumab levels were < 2 mcg/mL (approximately 23% of total patients studied), the immunogenicity rate was 21.1%. Using an assay which could measure an anti-adalimumab antibody titer in all patients, titers were measured in 39.8% (99/249) of non-infectious uveitis patients treated with adalimumab. No correlation of antibody development to safety or efficacy outcomes was observed.
The data reflect the percentage of patients whose test results were considered positive for antibodies to adalimumab or titers (addition), and are highly dependent on the assay.

Other Adverse Reactions

Uveitis Clinical Studies (addition)

HUMIRA has been studied in 464 patients with uveitis (UV) in placebo-controlled and open label extension studies. The safety profile for patients with UV treated with HUMIRA was similar to the safety profile seen in patients with RA.

7 Drug Interactions

Biological Products

There is insufficient information regarding the concomitant use of HUMIRA and other biologic products for the treatment of RA, PsA, AS, CD, UC, Ps, HS and UV. (addition)

8 Use in Specific Populations

PLLR Conversion; please refer to label.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

What is HUMIRA?

HUMIRA is a medicine called a Tumor Necrosis Factor (TNF) blocker. HUMIRA is used:

To treat non-infectious intermediate, posterior and panuveitis (UV) in adults. (addition)

What should I tell my doctor before taking HUMIRA?

HUMIRA may not be right for you. Before starting HUMIRA, tell your doctor about all of your health conditions, including if you:
- have a baby and you were using HUMIRA during your pregnancy. Tell your baby’s doctor before your baby receives any vaccines. (addition)