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.

KEVZARA (BLA-761037)

(SARILUMAB)

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

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06/10/2024 (SUPPL-15)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Live Vaccines

Newly added information:

Prior to initiating treatment, it is recommended that all patients be brought up to date with all immunizations in agreement with current immunization guidelines.

6 Adverse Reactions

6.1 Clinical Trials Experience

Newly added information:

Polyarticular Juvenile Idiopathic Arthritis (pJIA)

The safety of KEVZARA was studied in patients 2 to 17 years of age with pJIA who have had an inadequate response to current therapy (Study 4) [see Clinical Studies (14.3)]. A total of 93 patients received at least one administration of the recommended dose: 79 (84.9%) patients received the recommended dose for 52 weeks, 53 (57%) patients received it for 96 weeks and 30 (32.2%) patients received it for 156 weeks.

The overall median duration of study treatment for the recommended dose was 672 days. The cumulative exposure to treatment for patients who received the recommended dose at any time during the study was 184.1 patient-years.

The most common adverse drug reactions were nasopharyngitis, neutropenia, upper respiratory tract infection, and injection site erythema.

The most common adverse drug reaction that resulted in permanent discontinuation of therapy with KEVZARA was neutropenia (5.4%).

No new adverse reactions and safety concerns were identified in the pJIA population compared to the RA population.

Infections

In Study 4, the rate of infections was 146.6 events per 100 patient-years. The most common infections observed were nasopharyngitis (36.6%) and upper respiratory tract infections (URTI) (14.0%).

Injection Site Reactions

In Study 4, injection site reactions (ISRs) occurred in 13 (14.0%) patients and the most commonly reported ISR was injection site erythema (9.7%). The majority of these events were mild and none of the ISRs required patient withdrawal from treatment or dose interruption.

Laboratory Abnormalities

Decrease neutrophil count

In Study 4, decreases in neutrophil counts less than 1000 per mm3 occurred in 10/52 (19.2%) patients weighing in ?30 kg and 20/41 (48.8%) patients weighing 10 to <30 kg. The frequency of decreased neutrophil count was higher until Week 12. Decrease in ANC was not associated with an occurrence of infections, including serious infections.

Decrease monocyte count

In Study 4, decrease in monocyte counts occurred in 4 (4.3%) patients and were mild in severity and non-serious.

Elevated liver enzymes

In Study 4, nine (9.7%) patients had ALT increases, including one (1.1%) patient who had ALT

>3 times upper limit of normal (ULN) and up to ?5 times ULN, and two (2.2%) patients who had ALT increases >5 times ULN and up to ?10 times ULN that resulted in permanent discontinuation. All patients recovered.

Lipid Abnormalities

In Study 4, triglyceride levels of ?150 mg/dL (1 x ULN) were observed in one (1.1%) patient. Three (3.2%) patients overall had elevation in triglycerides, and all were mild in severity and non-serious. No significant changes in mean LDL, HDL or total cholesterol were observed during the entire 156-week treatment period.

8 Use in Specific Populations

8.4 Pediatric Use

Newly added information:

KEVZARA is approved for active polyarticular juvenile idiopathic arthritis (pJIA) in pediatric patients who weigh 63 kg or greater. Use of KEVZARA in this patient population is supported by evidence from adequate and well-controlled studies of KEVZARA in adults with RA, pharmacokinetic data from adult patients with RA, and a pharmacokinetic, pharmacodynamic, dose-finding, and safety study in pediatric patients with pJIA 2 years of age and older.

KEVZARA is not approved in pediatric patients weighing less than 63 kg because of the lack of an appropriate dosage form [see Adverse Reactions (6.1), Pharmacokinetics (12.3), and Clinical Studies (14.1, 14.3)].

The safety and effectiveness of KEVZARA have not been established in pediatric patients with pJIA below the age of 2 years.

02/28/2023 (SUPPL-13)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Newly added information:

Polymyalgia Rheumatica

Safety has been studied in one Phase 3 study (Study 3) in 117 PMR patients of whom 59 received subcutaneous KEVZARA 200 mg [see Clinical Studies (14.2)]. Of these, 45 patients received KEVZARA for at least 24 weeks, 44 patients for at least 40 weeks, and 10 patients for at least 52 weeks. The total patient years duration in the KEVZARA PMR population was 47.37 patient years during the 12-month double blind, placebo-controlled study.

The common adverse reactions occurring in ?5% of patients treated with KEVZARA were neutropenia (15.3%), leukopenia (6.8%), constipation (6.8%), rash pruritic (5.1%), myalgia (6.8%), fatigue (5.1%), and injection site pruritus (5.1%).

Serious adverse reactions of neutropenia occurred in 2 patients (3.4%) in the KEVZARA group compared to none in the placebo group. In both cases of neutropenia, the participants had a neutrophil count less than 500 per mm3 without any infections and resolved following permanent discontinuation of study drug.

The most common adverse reactions that resulted in permanent discontinuation of therapy with KEVZARA were neutropenia in 3 patients (5.1%) and infection in 3 separate patients (5.1%), including COVID-19 (n=1), intervertebral discitis (n=1), and pneumonia (n=1).

Overall Infections

In Study 3, the proportion of patients with infections was lower in the KEVZARA group (37.3%) compared to the placebo group (50.0%). Two patients (3.2%) in the KEVZARA group and 1 patient (1.7%) in the placebo group had an event of herpes zoster.

Serious infections

In Study 3, the proportion of patients with serious infections was similar in the KEVZARA group (5.1%) compared to the placebo group (5.2%).

Injection Site Reactions

In Study 3, three patients (5.1%) in the KEVZARA group experienced injection site reactions of pruritus which were mild in severity. No patient in the placebo group experienced injection site reactions.

Laboratory Abnormalities

Decreased neutrophil count

In Study 3, decreases in neutrophil counts less than 1000 per mm3 occurred in 12% of the KEVZARA treated group and no patient in the placebo treated group. Decreases in neutrophil counts less than 500 per mm3 occurred in 3.4% of patients in KEVZARA treated group compared to no patient in the placebo treated group.

Decreased platelet count

In Study 3, decreases in platelet counts between 75,000 to 100,000 per mm3 occurred in two patients (3.4%) in the KEVZARA group, compared to no patient in the placebo treated group. These platelet count decreases were transient and not associated with bleeding events.

Elevated liver enzymes

In Study 3, no KEVZARA treated patients had an ALT or AST greater than 3 times the upper limit of normal (ULN). In the placebo treated group, 2 patients had ALT elevations greater than 3 times the ULN.

Lipid Abnormalities

In Study 3, cholesterol levels ?299.27 mg/dL were observed in 8/58 (13.8%) patients in the KEVZARA group compared to 4/58 (6.9%) patients in the placebo group. Triglycerides ?407.4 mg/dL were observed in 3/58 (5.2%) patients in the KEVZARA group compared to 1/58 (1.7%) in the placebo group.

No significant differences in mean HDL between KEVZARA group and placebo group were observed. At Week 52, mean increase from baseline for LDL and triglycerides levels were observed in the KEVZARA group though both remained within the normal range.

8 Use in Specific Populations

8.5 Geriatric Use

Additions and revisions underlined:

Of the total number of patients with RA exposed to KEVZARA in clinical studies [see Clinical Studies (14.1)], 450 patients (15%) were 65 years of age and over, while 48 patients (1.6%) were 75 years and over. In clinical studies, no overall differences in safety and efficacy were observed between older and younger patients. The frequency of serious infections among KEVZARA and placebo-treated patients 65 years of age and older was higher than those under the age of 65.

Of the total number of patients with PMR exposed to KEVZARA in the clinical study (Study 3) [see Clinical Studies (14.2)], 16 patients (27.1%) were under 65 years of age, 33 patients (55.9%) were 65 to 75 years of age, and 10 patients (17.0%) were 75 years and over. The median age in the PMR study was 69.0 years and all patients were on baseline corticosteroid. There were no differences in the incidence of serious infections between the KEVZARA group and placebo group. In Study 3, no overall differences in safety were observed between older and younger patients.

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

Medication Guide

Additions and revisions underlined:

. . .

What is KEVZARA?

KEVZARA is an injectable prescription medicine called an interleukin-6 (IL-6) receptor blocker. KEVZARA is used:

To treat adults with moderately to severely active rheumatoid arthritis (RA) after at least one other medicine called a disease modifying antirheumatic drug (DMARD) has been used and did not work well or could not be tolerated.
To treat adults with polymyalgia rheumatica (PMR) after corticosteroids have been used and did not work well or

when a slow decrease in the dose of corticosteroids (taper) cannot be tolerated.

. . .

Common side effects of KEVZARA include:

injection site redness
injection site itching

. . .

04/13/2018 (SUPPL-1)

Approved Drug Label (PDF)

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

PATIENT COUNSELING INFORMATION

Additions and/or subtractions underlined:

Instruction on Injection Technique

Provide guidance to patients and caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the pre-filled syringe or pre-filled pen correctly.

The pre-filled syringe or pre-filled pen should be left at room temperature for 30 minutes or 60 minutes respectively (see the Instructions for Use) prior to use. The syringe or pen should be used within 14 days after being taken out of the refrigerator. A puncture-resistant container should be used to dispose the used pre-filled syringes or pre-filled pens and should be kept out of the reach for children. Instruct patients or caregivers in the technique as well as proper pre-filled syringe or pre-filled pen disposal, and caution against reuse of these items.