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.

EVISTA (NDA-020815)

(RALOXIFENE HYDROCHLORIDE)

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

Download Data

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06/27/2018 (SUPPL-34)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Premenopausal Use

(additions underlined)

There is no indication for premenopausal use of EVISTA. Safety of EVISTA in premenopausal women has not been established and its use is not recommended. Additionally, there is concern regarding inadvertent drug exposure in pregnancy in women of reproductive potential who become pregnant, due to risk of fetal harm.

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to EVISTA in 8429 patients who were enrolled in placebo-controlled trials, including 6666 exposed for 1 year and 5685 for at least 3 years.

…

Placebo-Controlled Trial of Postmenopausal Women at Increased Risk for Major Coronary Events (RUTH) — The safety of EVISTA (60 mg once daily) was assessed in a placebo-controlled multinational trial of 10,101 postmenopausal women (age range 55-92) with documented coronary heart disease (CHD) or multiple CHD risk factors. Median study drug exposure was 5.1 years for both treatment groups. Therapy was discontinued due to an adverse reaction in 25% of 5044 EVISTA-treated women and 24% of 5057 placebo-treated women. The incidence per year of all-cause mortality was similar between the raloxifene (2.07%) and placebo (2.25%) groups.

Adverse reactions reported more frequently in EVISTA-treated women than in placebo-treated women included peripheral edema (14.1% raloxifene versus 11.7% placebo), muscle spasms/leg cramps (12.1% raloxifene versus 8.3% placebo), hot flashes (7.8% raloxifene versus 4.7% placebo), venous thromboembolic events (2.0% raloxifene versus 1.4% placebo), and cholelithiasis (3.3% raloxifene versus 2.6% placebo).

Tamoxifen-Controlled Trial of Postmenopausal W omen at Increased Risk for Invasive Breast Cancer (STAR) — The safety of EVISTA 60 mg/day versus tamoxifen 20 mg/day over 5 years was assessed in 19,747 postmenopausal women (age range 35-83 years) in a randomized, double-blind trial. As of 31 December 2005, the median follow-up was 4.3 years. The safety profile of raloxifene was similar to that in the placebo-controlled raloxifene trials.

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

EVISTA is contraindicated for use in pregnant women, and is not indicated for use in females of reproductive potential. Based on mechanism of action, EVISTA may block the important functions that estrogen has during all stages of pregnancy [see Clinical Pharmacology (12.1)]. Limited data with EVISTA use in pregnant women are insufficient to inform any drug associated risks for births defects or miscarriage.

In rabbits and rats dosed during organogenesis or during gestation and lactation, EVISTA produced multiple adverse reproductive and developmental effects, including abortion; fetal anomalies; and delayed or disrupted parturition leading to maternal and neonatal mortality, at doses less than or similar to the maximum recommended human dose (based on human body surface area comparison).

Data

Animal Data

In the developmental and reproductive toxicity studies conducted with EVISTA, numerous adverse effects were observed in multiple animal species. In rabbits dosed during organogenesis, abortion and a low rate of fetal heart anomalies (ventricular septal defects) occurred at doses ?0.1 mg/kg (?0.04 times the human dose based on surface area, mg/m2). In rats dosed during organogenesis, retardation of fetal growth and developmental abnormalities (wavy ribs, kidney cavitation) occurred at doses ?1 mg/kg (?0.2 times the human dose based on surface area, mg/m2). Treatment of rats during gestation and lactation with doses of 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose based on surface area, mg/m2) produced effects that included delayed and disrupted parturition, decreased neonatal survival and altered physical development, sex- and age-specific reductions in growth and changes in pituitary hormone content, and decreased lymphoid compartment size in offspring. At 10 mg/kg, the disruption of parturition resulted in maternal and progeny morbidity and death. Effects in adult offspring (4 months of age) included uterine hypoplasia and reduced fertility; however, no ovarian or vaginal pathology was observed.

8.2Lactation

(PLLR conversion)

Risk Summary

EVISTA is not indicated for use in females of reproductive potential. There is no information on the presence of raloxifene in human milk, the effects on the breastfed child, or the effects on milk production. However, based on mechanism of action, EVISTA may block the important functions that estrogen has in mammary tissue during lactation.

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

PATIENT COUNSELING INFORMATION

17.4 Reduction in Risk of Invasive Breast Cancer in Postmenopausal Women with Osteoporosis or at High Risk of Invasive Breast Cancer

(new subsection added)

Use of EVISTA is associated with the reduction of the risk of invasive breast cancer in postmenopausal women. EVISTA has not been shown to reduce the risk of noninvasive breast cancer. When considering treatment, physicians need to discuss the potential benefits and risks of EVISTA treatment with the patient.

EVISTA is not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence.

Patients should have breast exams and mammograms before starting EVISTA and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with EVISTA.