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.

FOSAMAX PLUS D (NDA-021762)

(ALENDRONATE SODIUM; CHOLECALCIFEROL)

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

Download Data

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08/16/2019 (SUPPL-22)

Approved Drug Label (PDF)

8 Use in Specific Populations

Lactation

Additions and/or revisions underlined:

Risk Summary

Cholecalciferol and some of its active metabolites pass into breast milk. It is not known whether alendronate is present in human breast milk, affects human milk production, or has effects on the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FOSAMAX PLUS D and any potential adverse effects on the breastfed child from FOSAMAX PLUS D or from the underlying maternal condition.

Pregnancy

Additions and/or revisions underlined:

Risk Summary

Available data on the use of FOSAMAX plus vitamin D use in pregnant women are insufficient to inform a drug-associated risk of adverse maternal or fetal outcomes. Discontinue FOSAMAX PLUS D when pregnancy is recognized.

Alendronate Sodium

In animal reproduction studies, daily oral administration of alendronate to rats from before mating through the end of gestation or lactation showed decreased postimplantation survival and decreased pup body weight gain starting at doses equivalent to less than half of the highest recommended 40 mg clinical daily dose (based on body surface area, mg/m2). Oral administration of alendronate to rats during organogenesis resulted in reduced fetal ossification starting at doses 3 times the 40 mg clinical daily dose. No similar fetal effects were observed in pregnant rabbits dosed orally during organogenesis at doses equivalent to approximately 10 times the 40 mg clinical daily dose.

Delayed or failed delivery of offspring, protracted parturition, and late pregnancy maternal and fetal deaths due to maternal hypocalcemia occurred in rats at oral doses as low as one tenth the 40 mg clinical daily dose.

Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone and available for release into the systemic circulation is directly related to the dose and duration of bisphosphonate use. Consequently, based on the mechanism of action of bisphosphonates, there is a potential risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on the risk has not been studied.

Cholecalciferol

No data are available for cholecalciferol (vitamin D3 ) in animals. However, administration of high doses of vitamin D2 to pregnant rabbits resulted in abortions and an increased incidence of fetal aortic stenosis. Administration of high doses of vitamin D2 to pregnant rats resulted in neonatal death, decreased fetal weight, and impaired osteogenesis of long bones postnatally.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the

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

Data

Animal Data

Alendronate Sodium

Reproduction studies in rats dosed orally from before mating to the end of gestation or lactation showed decreased postimplantation survival starting at 2 mg/kg/day and decreased body weight gain starting at 1 mg/kg/day, doses equivalent to less than half the 40 mg clinical daily dose based on body surface area, mg/m2. Incidence of incomplete fetal ossification in vertebral, skull, and sternebral bones were increased in rats dosed orally during organogenesis starting at 10 mg/kg/day (approximately 3 times the 40 mg clinical daily dose). No similar fetal effects were observed in pregnant rabbits dosed orally during organogenesis at up to 35 mg/kg/day (equivalent to approximately 10 times the 40 mg clinical daily dose).

Both total and ionized calcium decreased in pregnant rats dosed orally with 15 mg/kg/day alendronate (approximately 4 times the 40 mg clinical daily dose) resulting in delays and failures of delivery. Protracted parturition due to maternal hypocalcemia was observed when rats were treated from before mating through gestation starting at 0.5 mg/kg/day (approximately one tenth the 40 mg clinical daily dose). Maternotoxicity (late pregnancy deaths) also occurred in female rats treated orally with 15 mg/kg/day (approximately 4 times the 40 mg clinical daily dose) for varying gestational time periods. These maternal deaths were lessened but not eliminated by cessation of treatment. Calcium supplementation in the drinking water or by subcutaneous minipump to rats dosed orally with 15 mg/kg/day alendronate could not ameliorate the hypocalcemia or prevent the dystocia-related maternal and neonatal deaths. However, intravenous calcium supplementation prevented maternal, but not neonatal deaths.

Cholecalciferol

Administration of high doses (greater than or equal to 10,000 international units/every other day during pregnancy) of ergocalciferol (vitamin D2 ) to pregnant rabbits resulted in abortions and an increased incidence of fetal aortic stenosis. Administration of vitamin D2 (40,000 international units/day) to pregnant rats from gestation day 10 to 21 (organogenesis) resulted in neonatal death, decreased fetal weight, and impaired osteogenesis of long bones postnatally.

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

MEDICATION GUIDE

Newly added section; please refer to label for complete information.

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Medication Guide).