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.

MAGNEVIST (NDA-021037)

(GADOPENTETATE DIMEGLUMINE)

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

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07/25/2018 (SUPPL-37)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

GBCAs cross the placenta and result in fetal exposure and gadolinium retention. The human data on the association between GBCAs and adverse fetal outcomes are limited and inconclusive.

In animal reproduction studies, repeated intravenous dosing of gadopentetate dimeglumine during organogenesis resulted in delayed fetal development in pregnant rats and rabbits at a dose 2 times and 2.4 times, respectively, the recommended human dose (based on body surface area [BSA]). No teratogenic effects were observed in rats or rabbits at doses or 7.3 times (rats) and 9.7 times (rabbits) the recommended human dose, based on BSA. Because of the potential risks of gadolinium to the fetus, use Magnevist only if imaging is essential during pregnancy and cannot be delayed.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and is 15 to 20%, respectively.

Data

Human Data

Contrast enhancement is visualized in the human placenta and fetal tissues after maternal GBCA administration.

Cohort studies and case reports on exposure to GBCAs during pregnancy have not reported a clear association between GBCAs and adverse effects in the exposed neonates. However, a retrospective cohort study, comparing pregnant women who had a GBCA MRI to pregnant women who did not have an MRI, reported a higher occurrence of stillbirths and neonatal deaths in the group receiving GBCA MRI. Limitations of this study include a lack of comparison with non- contrast MRI and lack of information about the maternal indication for MRI. Overall, these data preclude a reliable evaluation of the potential risk of adverse fetal outcomes with the use of GBCAs in pregnancy.

Animal Data Gadolinium Retention

GBCAs administered to pregnant non-human primates (0.1 mmol/kg on gestational days 85 and 135) result in measurable gadolinium concentration in the offspring in bone, brain, skin, liver, kidney, and spleen for at least 7 months. GBCAs administered to pregnant mice (2 mmol/kg daily on gestational days 16 through 19) result in measurable gadolinium concentrations in the pups in bone, brain, kidney, liver, blood, muscle, and spleen at one month postnatal age.

Reproductive Toxicology

Gadopentetate dimeglumine was administered intravenous during organogenesis at doses of at 0.25, 0.75, and 1.25 mmol/kg/day for 10 consecutive days in pregnant rats and for 13 consecutive days in pregnant rabbits. Gadopentetate dimeglumine caused retardation of fetal development at a dose of 1.25 mmol per kg (rats) and 0.75 mmol per kg (rabbits); 2 times and 2.4 times, respectively, the recommended human dose (based on BSA).

Gadopentetate dimeglumine was not teratogenic in pregnant rats and rabbits when given repeatedly during organogenesis at a dose of 3 mmol per kg in rabbits and 4.5 mmol per kg in rats; 9.7 and 7.3 times, respectively, the recommended human dose (based on BSA).

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

Limited literature reports that breastfeeding after gadopentetate dimeglumine administration to the mother would result in the infant receiving an oral dose of 0.001 to 0.04% of the maternal dose. There is no information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. Additionally, there is limited GBCA gastrointestinal absorption. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Magnevist and any potential adverse effects on the breastfed child from Magnevist or from the underlying maternal condition.

8.3 Males and Females of Reproductive Potential

(Newly Added Subsection)

Infertility

Intravenous injections of gadopentetate dimeglumine (16 to 18 doses over 23 to 25 days) caused spermatogenic cell atrophy and degeneration that was irreversible in male rats at a dose of 8 times (based on BSA) the recommended human dose.

04/26/2018 (SUPPL-36)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

Magnevist is contraindicated in patients with:

History of severe hypersensitivity reactions to Gadopentetate dimeglumine.

5 Warnings and Precautions

5.3 Gadolinium Retention

(Newly Added Subsection)

Gadolinium is retained for months or years in several organs. The highest concentrations (nanomoles per gram of tissue) have been identified in the bone, followed by other organs (for example, brain, skin, kidney, liver, and spleen). The duration of retention also varies by tissue and is longest in bone. Linear GBCAs cause more retention than macrocyclic GBCAs. At equivalent doses, gadolinium retention varies among the linear agents with Omniscan (gadodiamide) and Optimark (gadoversetamide) causing greater retention than other linear agents [Eovist (gadoxetate disodium), Magnevist (gadopentetate dimeglumine),MultiHance (gadobenate dimeglumine)]. Retention is lowest and similar among the macrocyclic GBCAs [Dotarem (gadoterate meglumine), Gadavist (gadobutrol), ProHance (gadoteridol)].

Consequences of gadolinium retention in the brain have not been established. Pathologic and clinical consequences of GBCA administration and retention in skin and other organs have been established in patients with impaired renal function. There are rare reports of pathologic skin changes in patients with normal renal function. Adverse events involving multiple organ systems have been reported in patients with normal renal function without an established causal link to gadolinium retention.

While clinical consequences of gadolinium retention have not been established in patients with normal renal function, certain patients might be at higher risk. These include patients requiring multiple lifetime doses, pregnant and pediatric patients, and patients with inflammatory conditions. Consider the retention characteristics of the agent when choosing a GBCA for these patients. Minimize repetitive GBCA imaging studies particularly closely spaced studies, when possible.

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

The following additional adverse reactions have been identified during postmarketing use of Gadopentetate dimeglumine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General Disorders and Administrations Site Conditions: Adverse events with variable onset and duration have been reported after GBCA administration. These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems.
Skin: Gadolinium associated plaques

Hypersensitivity Reactions: …Delayed hypersensitivity reactions have been reported up to several hours after administration of Gadopentetate dimeglumine.

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

GBCAs cross the placenta and result in fetal exposure and gadolinium retention. The human data on the association between GBCAs and adverse fetal outcomes are limited and inconclusive. Because of the potential risks of gadolinium to the fetus, use Magnevist only if imaging is essential during pregnancy and cannot be delayed.

Contrast enhancement is visualized in the human placenta and fetal tissues after maternal GBCA administration. Cohort studies and case reports on exposure to GBCAs during pregnancy have not reported a clear association between GBCAs and adverse effects in the exposed neonates. However, a retrospective cohort study, comparing pregnant women who had a GBCA MRI to pregnant women who did not have an MRI, reported a higher occurrence of stillbirths and neonatal deaths in the group receiving GBCA MRI. Limitations of this study include a lack of comparison with non- contrast MRI and lack of information about the maternal indication for MRI. Overall, these data preclude a reliable evaluation of the potential risk of adverse fetal outcomes with the use of GBCAs in pregnancy.

Magnevist retarded fetal development slightly when given intravenously for 10 consecutive days to pregnant rats …

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

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

Gadolinium Retention

Advise patients that gadolinium is retained for months or years in brain, bone, skin, and other organs in patients with normal renal function. The clinical consequences of retention are unknown. Retention depends on multiple factors and is greater following administration of linear GBCAs than following administration of macrocyclic GBCAs.

Medication Guide

(Newly added Medication Guide; please refer to labeling)