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.

INFUGEM (NDA-208313)

(GEMCITABINE HYDROCHLORIDE)

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

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09/24/2024 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Severe Cutaneous Adverse Reactions (SCARs)

Newly added subsection:

SCARs, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported in association with gemcitabine treatment [see Adverse Reactions (6.2)]. Monitor patients for signs and symptoms of severe cutaneous adverse reactions. Permanently discontinue gemcitabine in patients who develop SCARs.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.3)]

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Skin: Cellulitis, pseudocellulitis, severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP); desquamation and bullous skin eruptions

…

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Severe Cutaneous Adverse Reactions (SCARs)

Advise patients of the risks of SCARs, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP). Instruct patients to immediately contact their healthcare provider should any signs or symptoms of severe skin rash or skin peeling, blistering and/or mouth sores occur [see Warnings and Precautions (5.3)].

…

01/08/2020 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Myelosuppression

Additions and/or revisions underlined:

… In clinical trials, Grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 25%, 8%, and 5%, respectively of the 979 patients who received single agent gemcitabine …

5.3 Pulmonary Toxicity and Respiratory Failure

Additions and/or revisions underlined:

… Permanently discontinue INFUGEM in patients who develop unexplained dyspnea, with or without bronchospasm, or evidence of severe pulmonary toxicity.

5.4 Hemolytic Uremic Syndrome

Additions and/or revisions underlined:

Hemolytic uremic syndrome (HUS), including fatalities from renal failure or the requirement for dialysis, can occur with INFUGEM. In clinical trials, HUS occurred in 0.25% of 2429 patients. Most fatal cases of renal failure were due to HUS [see Adverse Reactions (6.1)]. Serious cases of thrombotic microangiopathy other than HUS have been reported with gemcitabine [see Adverse Reactions (6.2)].

Assess renal function prior to initiation of INFUGEM and periodically during treatment. Consider the diagnosis of HUS in patients who develop anemia with evidence of microangiopathic hemolysis; increased bilirubin or LDH; reticulocytosis; severe thrombocytopenia; or renal failure (increased serum creatinine or BUN …

5.5 Hepatic Toxicity

Additions and/or revisions underlined:

Assess hepatic function prior to initiation of INFUGEM and periodically during treatment. Permanently discontinue INFUGEM in patients who develop severe hepatic toxicity.

5.6 Embryo-Fetal Toxicity

Additions and/or revisions underlined:

Based on animal data and its mechanism of action, INFUGEM can cause fetal harm when administered to a pregnant woman.

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with INFUGEM and for 3 months following the final dose [see Use in Specific Populations (8.1, 8.3)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

… Tables 7 and 8 present the incidence of selected adverse reactions and laboratory abnormalities reported in patients with various malignancies receiving single agent gemcitabine across 5 clinical trials. Additional clinically significant adverse reactions are provided following Table 8.

Ovarian Cancer

… for the second-line treatment of ovarian cancer in women with disease that had relapsed more than 6 months following first-line platinum-based chemotherapy [see Clinical Studies (14.1)]. Additional clinically significant adverse reactions, occurring in <10% of patients, are provided following Table 10.

The proportion of patients with dose adjustments for carboplatin (1.8% versus 3.8%), doses of carboplatin omitted (0.2% versus 0) and discontinuing treatment for adverse reactions (11% versus 10%), were similar between arms. Dose adjustment for gemcitabine occurred in 10% of patients and gemcitabine dose was omitted in 14% of patients in the gemcitabine/carboplatin arm. Table 9: Adverse Reactions Occurring in >10% of Patients Receiving Gemcitabine with Carboplatin and at Higher Incidence than in Patients Receiving Single Agent Carboplatin [Between Arm Difference of greater than or equal to 5% (All Grades) or greater than or equal to 2% (Grades 3-4)] in Study 1a

Table 10: Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Carboplatin and at Higher Incidence than in Patients Receiving Single Agent Carboplatin [Between Arm Difference of greater than or equal to 5% (All Grades) or greater than or equal to 2% (Grades 3-4)] in Study 1a

Hematopoietic growth factors were administered more frequently in the gemcitabine-containing arm: leukocyte growth factor (24% and 10%) and erythropoiesis-stimulating agent (7% and 3.9%).

The following clinically relevant Grade 3 and 4 adverse reactions occurred more frequently in the gemcitabine with carboplatin arm: dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1 %), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0).

Breast Cancer

Tables 11 and 12 present the incidence of selected adverse reactions and laboratory abnormalities, occurring in greater than or equal to 10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with paclitaxel arm, reported in a randomized trial (Study 2) of gemcitabine with paclitaxel (n=262) compared to paclitaxel alone (n=259) for the first-line treatment of metastatic breast cancer (MBC) in women who received anthracycline-containing chemotherapy in the adjuvant/neo-adjuvant setting or for whom anthracyclines were contraindicated [see Clinical Studies (14.2)]. Additional clinically significant adverse reactions, occurring in <10% of patients, are provided following Table 12.

The requirement for dose reduction of paclitaxel was higher for patients in the gemcitabine/paclitaxel arm (5% versus 2%). The number of paclitaxel doses omitted (<1%), the proportion of patients discontinuing treatment for adverse reactions (7% versus 5%) and the number of treatment-related deaths (1 patient in each arm) were similar between the two arms.

Table 11: Selected Adverse Reactions Occurring in Patients Receiving Gemcitabine with Paclitaxel and at Higher Incidence than in Patients Receiving Single Agent Paclitaxel [Between Arm Difference of greater than or equal to 5% (All Grades) or greater than or equal to 2% (Grades 3-4)] in Study 2a

Table 12: Selected Laboratory Abnormalities Occurring in >10% of Patients Receiving Gemcitabine with Paclitaxel and at a Higher Incidence than Patients Receiving Single Agent Paclitaxel [Between Arm Difference of greater than or equal to 5% (All Grades) or greater than or equal to 2% (Grades 3-4)] in Study 2a

Non-Small Cell Lung Cancer

Tables 13 and 14 present the incidence of selected adverse reactions and laboratory abnormalities occurring in greater than or equal to 10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with cisplatin arm, reported in a randomized trial (Study 3) of gemcitabine with cisplatin (n=260) administered in 28-day cycles as compared to cisplatin alone (n=262) in patients receiving first-line treatment for locally advanced or metastatic NSCLC.

Tables 15 and 16 present the incidence of selected adverse reactions and laboratory abnormalities occurring in greater than or equal to 10% of gemcitabine-treated patients and at a higher incidence in the gemcitabine with cisplatin arm, reported in a randomized trial (Study 4) of gemcitabine with cisplatin (n=69) administered in 21-day cycles as compared to etoposide with cisplatin (n=66) in patients receiving first-line treatment for locally advanced or metastatic NSCLC [see Clinical Studies (14.3)]. Additional clinically significant adverse reactions are provided following Table 16.

Table 15: Selected Adverse Reactions in Patients Receiving Gemcitabine with Cisplatin in Study 4a

Table 16: Selected Laboratory Abnormalities Occurring in Patients Receiving Gemcitabine with Cisplatin in Study 4a

6.2 Postmarketing Experience

Newly added information:

Blood and Lymphatic System: Thrombotic microangiopathy (TMA)

Pulmonary: Addition of ‘pulmonary eosinophilia’

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:
… Contraception

Females

Because of the potential for genotoxicity, advise females of reproductive potential to use effective contraception during treatment with INFUGEM and for 6 months after the final dose [see Use in Specific Populations (8.1)].

Males

Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use effective contraception during treatment with INFUGEM and for 3 months after the final dose [see Nonclinical Toxicology (13.1)].

Infertility

Males

Based on animal studies, INFUGEM may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)]. It is not known whether these effects on fertility are reversible.

8.5 Geriatric Use

Additions and/or revisions underlined:

… In a randomized trial in women with ovarian cancer (Study 1), 175 women received gemcitabine with carboplatin, of which 29% were age 65 years or older.

Gemcitabine clearance is affected by age; however, there are no recommended dose adjustments based on patients’ age [see Clinical Pharmacology (12.3)].