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.

GLEEVEC (NDA-021588)

(IMATINIB MESYLATE)

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

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01/14/2026 (SUPPL-65)

Approved Drug Label (PDF)

7 Drug Interactions

7.5 Interaction with Methotrexate

Newly added subsection:

Gleevec may delay the clearance of methotrexate and result in sustained methotrexate concentrations when methotrexate is used at high doses (> 500 mg/m2). Refer to the prescribing information for methotrexate injection for recommendations on management of methotrexate concentrations.

08/19/2022 (SUPPL-62)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Skin and Subcutaneous Tissue Disorders:

Additions and/or revisions underlined:

… Estimated 0.1%-1%: exfoliative dermatitis, bullous eruption, psoriasis, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, skin hyperpigmentation, onychoclasis, folliculitis, petechiae, erythema multiforme, panniculitis (including erythema nodosum) …

03/24/2022 (SUPPL-60)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Skin and Subcutaneous Tissue Disorders: lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), pseudoporphyria, pemphigus

08/10/2020 (SUPPL-56)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions underlined)

…

Endocrine Disorders:

Estimated 0.1%–1%: hypothyroidism, hyperthyroidism

….

08/21/2018 (SUPPL-53)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Blood and Lymphatic System Disorders: thrombotic microangiopathy

09/29/2017 (SUPPL-52)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(addition underlined)

…

Skin and Subcutaneous Tissue Disorders: lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), pseudoporphyria.

09/06/2017 (SUPPL-51)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.14 Renal Toxicity

(Newly added subsection)

A decline in renal function may occur in patients receiving Gleevec. Median estimated glomerular filtration rate (eGFR) values in patients on Gleevec 400 mg daily for newly-diagnosed CML (four randomized trials) and malignant GIST (one single-arm trial) declined from a baseline value of 85 ml/min/1.73m2 (N=1190) to 75 ml/min/1.73m2 at 12 months (N=1082) and 69 ml/min/1.73m2 at 60 months (N=549). Evaluate renal function prior to initiating Gleevec and monitor during therapy, with attention to risk factors for renal dysfunction such as pre-existing renal impairment, diabetes mellitus, hypertension, and congestive heart failure.

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following serious adverse reactions are described elsewhere in the labeling:

…

Renal Toxicity

04/24/2017 (SUPPL-49)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Musculoskeletal and Connective Tissue Disorders: avascular necrosis/hip osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children, musculoskeletal pain upon treatment discontinuation (including myalgia, pain in extremity, arthalgia, bone pain).

Other

Minor revisions in order to comply with the Physicians Labeling Rule (PLR)

09/27/2016 (SUPPL-47)

Approved Drug Label (PDF)

6 Adverse Reactions

6.11 Postmarketing Experience (addition underlined)

Infections: hepatitis B virus reactivation

08/25/2016 (SUPPL-45)

Approved Drug Label (PDF)

5 Warnings and Precautions

Embryo-fetal Toxicity

Updated sentences:

Advise sexually active female patients of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) when using Gleevec and for 14 days after stopping Gleevec. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Growth Retardation in Children and Adolescents replaces Children and Adolescents

Impairments Related to Driving and Using Machinery replaces Driving and Using Machinery

Motor vehicle accidents have been reported in patients receiving Gleevec. Advise patients that they may experience side effects such as dizziness, blurred vision or somnolence during treatment with Gleevec. Recommend caution when driving a car or operating machinery.

6 Adverse Reactions

The following serious adverse reactinos are described elsewhere in the labeling:

Fluid Retention and Edema
Hematologic Toxicity
Congestive Heart Failure and Left Ventricular Dysfunction
Hepatotoxicity
Hemorrhage
Gastrointestinal Disorders
Hypereosinophilic Cardiac Toxicity
Dermatologic Toxicities
Hypothyroidism
Growth Retardation in Children and Adolescents
Tumor Lysis Syndrome
Impairments Related to Driving and Using Machinery

Acute Lymphoblastic Leukemia

Revised sentence is bolded:

Superficial edema was a common finding in all studies and were described primarily as periorbital or lower limb edemas. These edemas were reported as Grade 3/4 events in 6.3% of the patients and may be managed with diuretics, other supportive measures, or in some patients by reducing the dose of Gleevec.

7 Drug Interactions

Agents Inducing CYP3A Metabolism (revised)

Concomitant administration of Gleevec and strong CYP3A4 inducers may reduce total exposure of imatinib; consider alternative agents.

Agents Inhibiting CYP3A Metabolism (revised)

Concomitant administration of Gleevec and strong CYP3A4 inhibitors may result in a significant imatinib exposure increase. Grapefruit juice may also increase plasma concentrations of imatinib; avoid grapefruit juice.

Interactions with Drugs Metabolized by CYP2D6 (revised)

Use caution when administering Gleevec with CYP2D6 substrates that have a narrow therapeutic window.

8 Use in Specific Populations

Hepatic Impairment (revised paragraph)

Mild and moderate hepatic impairment do not influence exposure to imatinib and CGP74588. In patients with severehepatic impairment, the imatinib Cmax and AUC increased by 63% and 45% and the CGP74588 Cmax and AUC increased by 56% and 55%, relative to patients with normal hepatic function. Reduce the dose by 25% for patients with severe hepatic impairment.

Renal Impairment

The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 patients with cancer and varying degrees of renal impairment at single and steady state imatinib doses ranging from 100 to 800 mg/day. The mean exposure to imatinib (dose normalized AUC) in patients with mild and moderate renal impairment increased 1.5- to 2-fold compared to patients with normal renal function. There are not sufficient data in patients with severe renal impairment. Dose reductions are necessary for patients with moderate and severe renal impairment.

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

PCI - Fluid Retention and Edema (addition)

Inform patients of the possibility of developing edema and fluid retention. Advise patients to contact their health care provide if unexpected rapid weight gain occurs.

PCI - Hepatotoxicity (addition)

Inform patients of the possibility of developing liver function abnormalities and serious hepatic toxicity. Advise patients to immediately contact their health care provider if signs of liver failure occur, including jaundice, anorexia, bleeding or bruising.

PCI - Pregnancy and Breastfeeding (updated)

Female patients of reproductive potential taking Gleevec should use highly effective contraception during treatment and for fourteen days after stopping treatment with Gleevec. Avoid breastfeeding during treatment and for 1 month after the last dose.

08/25/2016 (SUPPL-46)

Approved Drug Label (PDF)

8 Use in Specific Populations

Females and Males of Reproductive Potential - PLLR Conversion

Pregnancy Testing

Human post-marketing reports and animal studies have shown Gleevec to be harmful to the developing fetus. Test pregnancy status in females with reproductive potential prior to the initiation of treatment with Gleevec.

Contraception

Females

Advise female patients of reproductive potential to use effective contraception (methods that result in less than 1 % pregnancy rates) when using Gleevec during treatment and for fourteen days after stopping treatment with Gleevec

Infertility

The risk of infertility in females or males of reproductive potential has not been studied in humans. In a rat study, the fertility in males and females was not affected.

Lactation - PLLR Conversion

Risk Summary

Imatinib and its active metabolite are excreted into human milk. Because of the potential for serious adverse reactions in breastfed infants from Gleevec, advise a lactating woman not to breastfeed during treatment and for 1 month after the last dose.

Human Data

Based on data from three breastfeeding women taking Gleevec, the milk:plasma ratio is about 0.5 for imatinib and about 0.9 for the active metabolite. Considering the combined concentration of imatinib and active metabolite, a breastfed infant could receive up to 10% of the maternal therapeutic dose based on body weight.

Pregnancy - PLLR Conversion

Risk Summary

Gleevec can cause fetal harm when administered to a pregnant woman based on human and animal data. There are no clinical studies regarding use of Gleevec in pregnant women. There have been post-market reports of spontaneous abortions and congenital anomalies from women who have been exposed to Gleevec during pregnancy . Reproductive studies in rats have demonstrated that imatinib mesylate induced teratogenicity and increased incidence of congenital abnormalities following prenatal exposure to imatinib mesylate at doses equal to the highest recommended human dose of 800 mg/day based on body surface area. Advise women to avoid pregnancy when taking Gleevec. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is not known; however, in the U.S. general population, the estimated background risk of major birth defects of clinically recognized pregnancies is 2-4% and of miscarriage is 15-20%.

Data

Animal Data

In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of imatinib mesylate up to 100 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis.

In rats, imatinib mesylate was teratogenic at 100 mg/kg/day (approximately equal to the maximum human dose of 800 mg/day based on body surface area), the number of fetuses with encephalocoele and exencephaly was higher than historical control values and these findings were associated with missing or underdeveloped cranial bones. Lower mean fetal body weights were associated with retarded skeletal ossifications.

In rabbits, at doses 1.5 times higher than the maximum human dose of 800 mg/day based on body surface area, no effects on the reproductive parameters with respect to implantation sites, number of live fetuses, sex ratio or fetal weight were observed. The examinations of the fetuses did not reveal any drug related morphological changes.

In a pre- and postnatal development study in rats, pregnant rats received oral doses of imatinib mesylate during gestation (organogenesis) and lactation up to 45 mg/kg/day. Five animals developed a red vaginal discharge in the 45 mg/kg/day group on Days 14 or 15 of gestation, the significance of which is unknown since all females produced viable litters and none had increased post-implantation loss. Other maternal effects noted only at the dose of 45 mg/kg/day (approximately one-half the maximum human dose of 800 mg/day based on body surface area) included an increased numbers of stillborn pups and pups dying between postpartum Days 0 and 4. In the F1 offspring at this same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased. There were no other significant effects in developmental parameters or behavioral testing. F1 fertility was not affected but reproductive effects were noted at 45 mg/kg/day including an increased number of resorptions and a decreased number of viable fetuses. The NOEL for both maternal animals and the F1 generation was 15 mg/kg/day.