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.

TARCEVA (NDA-021743)

(ERLOTINIB HYDROCHLORIDE)

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

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10/18/2016 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Embryo-fetal Toxicity (addition underlined)

Based on animal data and its mechanism of action, TARCEVA can cause fetal harm when administered to a pregnant woman. When given during organogenesis, erlotinib administration resulted in embryo-fetal lethality and abortion in rabbits at exposures approximately 3 times the exposure at the recommended human daily dose of 150 mg. Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during therapy and for one month after the last dose of TARCEVA.

5.6 Cerebrovascular Accident (addition underlined)

…The pooled incidence of cerebrovascular accident in the 3 monotherapy lung cancer studies was 0.6% in the TARCEVA arms and not higher than that observed in the control arms.

6 Adverse Reactions

6.1 Clinical Trial Experience (addition underlined)

Non-Small Cell Lung Cancer

Common adverse reactions in Study 1, occurring in at least 10% of patients who received TARCEVA or chemotherapy and an increase in ? 5% in the TARCEVA-treated group, are graded by National Cancer Institute Common Toxicity Criteria for Adverse Events version 3.0 (NCI-CTCAE v3.0) Grade in Table 1. The median duration of TARCEVA treatment was 9.6 months in Study 1.

8 Use in Specific Populations

8.1 Pregnancy (PLLR conversion, addition underlined)

Risk Summary

Based on animal data and its mechanism of action, TARCEVA can cause fetal harm when administered to a pregnant woman. Limited available data on use of TARCEVA in pregnant women are not sufficient to inform a risk of major birth defects or miscarriage. When given during organogenesis, erlotinib administration resulted in embryo-fetal lethality and abortion in rabbits at exposures approximately 3 times the exposure at the recommended human daily dose of 150 mg. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation (PLLR conversion, addition underlined)

Risk Summary

here are no data on the presence of erlotinib in human milk, or the effects of erlotinib on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from TARCEVA, including interstitial lung disease, hepatotoxicity, bullous and exfoliative skin disorders, microangiopathic hemolytic anemia with thrombocytopenia, ocular disorders, and

diarrhea. Advise a lactating woman not to breastfeed during treatment with TARCEVA and for 2 weeks after the final dose.

8.3 Females and Males of Reproductive Potential (PLLR conversion)

Contraception

Females

TARCEVA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with TARCEVA and for one month after the last dose of TARCEVA.

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

17 PATIENT COUNSELING INFORMATION (revised)

Skin rash, bullous and exfoliative skin disorders

Advise patients that skin reactions can occur or worsen on sun-exposed areas while taking TARCEVA, and proactive intervention may include alcohol-free emollient cream and use of sunscreen or avoidance of sun exposure. Advise patients that hyperpigmentation or dry skin, with or without digital skin fissures, have been reported and in the majority of cases were associated with rash

Advise patients that TARCEVA can increase the risk of bullous and exfoliative skin disorders and to seek immediately medical attention for severe skin reactions.

Diarrhea

Advise patients that diarrhea can usually be managed with loperamide and to contact their healthcare provider for severe or persistent diarrhea.

Interstitial lung disease

Advise patients of the risk of severe or fatal ILD, including pneumonitis. Advise patients to contact their healthcare provider immediately to report new of worsening unexplained shortness of breath or coughing

Renal failure

Advise patients of the risk of developing renal failure. Inform patients of the need for the healthcare provider to monitor kidney function and electrolytes.

Hepatotoxicity

Advise patients to immediately report signs or symptoms of hepatotoxicity.

Gastrointestinal perforations

Advise patients that TARCEVA can increase the risk of gastrointestinal perforation or fistula and to seek immediate medical attention for severe abdominal pain.

Cerebrovascular accident

Advise patients of the risk of cerebrovascular accident and see immediate medical attention

Ocular disorders

Advise patients promptly to contact their healthcare provider if they develop eye signs or symptoms, lacrimation, light sensitivity, blurred vision, eye pain, red eye, or changes in vision.

Hemorrhage in patients taking warfarin

Advise patients who are receiving warfarin of the need to monitor INR or other coumarin-derivative anticoagulants.

Hair and nail disorders

Advise patients that hair and nail disorders, including hirsutism and brittle and loose nails, have been reported.

Embryo-fetal toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.

Advise females of reproductive potential to use effective contraception during treatment with TARCEVA, and for 1 month after the last dose

Lactation

Advise women not to breastfeed during treatment with TARCEVA and for 2 weeks after the final dose.

Smoking

Advise patients to contact their health care provider for any changes in smoking status and that the dose of TARCEVA may need to be adjusted if they smoke.

Advise patients to stop smoking

09/28/2016 (SUPPL-26)

Approved Drug Label (PDF)

7 Drug Interactions

(revised- Additions underlined)

CYP3A4 Inhibitors

Co-administration of TARCEVA with a strong CYP3A4 inhibitor or a combined CYP3A4 and CYP1A2 inhibitor increased erlotinib exposure. Erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2. Increased erlotinib exposure may increase the risk of exposure-related toxicity.

Avoid co-administering TARCEVA with strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir,

itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit or grapefruit juice) or a combined CYP3A4 and CYP1A2 inhibitor (e.g., ciprofloxacin). Reduce the TARCEVA dosage when co-administering with a strong CYP3A4 inhibitor or a combined CYP3A4 and CYP1A2 inhibitor if co-administration is unavoidable.

CYP3A4 Inducers

Pre-treatment with a CYP3A4 inducer prior to TARCEVA decreased erlotinib exposure. Increase the TARCEVA dosage if co-administration with CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital and St. John's wort) is unavoidable.

CYP1A2 Inducers and Cigarette Smoking

Cigarette smoking decreased erlotinib exposure. Avoid smoking tobacco (CYP1A2 inducer) and avoid concomitant use of TARCEVA with moderate CYP1A2 inducers (e.g., teriflunomide, rifampin, or phenytoin). Increase the TARCEVA dosage in patients that smoke tobacco or when co-administration with moderate CYP1A2 inducers is unavoidable.

Drugs that Increase Gastric pH

Co-administration of TARCEVA with proton pump inhibitors (e.g., omeprazole) and H-2 receptor antagonists (e.g., ranitidine) decreased erlotinib exposure].For proton pump inhibitors, avoid concomitant use if possible. For H-2 receptor antagonists and antacids, modify the dosing schedule. Increasing the dose of TARCEVA when co-administered with gastric pH elevating agents is not likely to compensate for the loss of exposure.

8 Use in Specific Populations

8.7 Patients with Hepatic Impairment (revised)

Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with TARCEVA treatment in patients with normal hepatic function; the risk of hepatic toxicity is increased in patients with baseline hepatic impairment. Monitor patients with hepatic impairment (total bilirubin greater than upper limit of normal (ULN) or Child-Pugh A, B and C) during therapy with TARCEVA. Treatment with TARCEVA should be used with increased monitoring in patients with total bilirubin greater than 3 x ULN.