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.

NUVESSA (NDA-205223)

(METRONIDAZOLE)

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

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02/25/2022 (SUPPL-6)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined

Risk Summary

There are no data available on the use of NUVESSA in pregnant women. Metronidazole usage in pregnancy has been associated with certain congenital anomalies (see Data). In animal reproduction studies, no fetotoxicity or teratogenicity was observed when metronidazole was administered orally to pregnant rats and rabbits, during organogenesis, at up to 30 times and 60 times the recommended human dose based on body surface area comparison, respectively (see Data).

…

8.2 Lactation

Addition underlined

Risk Summary

There are no data on the presence of metronidazole in human milk following intravaginal administration. Metronidazole is present in human milk following oral metronidazole administration, at concentrations similar to those found in plasma (see Data). The metronidazole vaginal gel achieves 2% of the mean maximum serum concentration of a 500 mg oral metronidazole dose [see Clinical Pharmacology (12.3)]. The published literature reports no adverse effects in infants exposed through breastmilk to maternal orally administered metronidazole. There are no data on the effects on milk 2

production.

…

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

PATIENT COUNSELING INFORMATION

Additions underlined

…

Lactation

A patient may choose to pump and discard breastmilk during treatment with NUVESSA and for 48 hours after last dose, and feed her infant previously stored human milk or formula [see Use in Specific Populations (8.2)].

…

12/06/2021 (SUPPL-5)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.2 Lactation

Risk Summary

Additions and/or revisions underlined:

There are no data on the presence of metronidazole in human milk following intravaginal administration. Metronidazole is present in human milk following oral metronidazole administration, at concentrations similar to those found in plasma (see Data). The metronidazole vaginal gel achieves 2% of the mean maximum serum concentration of a 500 mg oral metronidazole [see Clinical Pharmacology (12.3)]. The published literature reports no adverse effects in infants exposed through breastmilk to maternal orally administered metronidazole. There are no data on the effects on milk production.

Animal studies have shown the potential for tumorigenicity after oral metronidazole was administered chronically to rats and mice [see Nonclinical Toxicology (13.1)]. The clinical relevance of these findings is unclear. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NUVESSA, and any potential adverse effects on the breastfed child from NUVESSA or from the underlying maternal condition. Alternatively, a lactating patient may interrupt breastfeeding and choose to pump and discard breastmilk during treatment with NUVESSA and for 48 hours after the last dose and feed her infant previously stored human milk or formula.

Data

In a study of lactating women receiving oral metronidazole 600 mg (n=11) or 1200 mg (n=4) daily, mean maternal plasma concentrations were 5.0 and 12.5 mcg/mL respectively, within 2 hours following administration; the milk: maternal plasma ratio was approximately 1.

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

PATIENT INFORMATION

Additions and/or revisions underlined:

Do not use NUVESSA if you:

drink alcohol. Do not drink alcohol while you use NUVESSA and for at least 24 hours after you stop using it. It can increase your chances of getting serious side effects.

08/03/2018 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Central and Peripheral Nervous System Effects

Additions and/or revisions underlined:

Convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter …

… patients with central nervous system diseases. Discontinue promptly if abnormal neurologic signs develop.

6 Adverse Reactions

6.1 Clinical Trial Experience

Addition of the following pediatric information:

Clinical Trial Experience in Pediatric Subjects

The safety of NUVESSA was evaluated in a multicenter, open-label study evaluating the safety and tolerability of NUVESSA in 60 pediatric subjects between the ages of 12 and less than 18 years old all of whom were treated with a single dose of NUVESSA administered once at bedtime intravaginally. Most subjects in this study were either Black/African-American, non-Hispanic (47%) or Hispanic (35%)

Safety in pediatric female subjects aged 12 to less than 18 years old was comparable to adult women. No deaths occurred and no subjects discontinued treatment due to adverse reactions. Adverse reactions occurring in ? 1% of pediatric subjects included: vulvovaginal discomfort (2%).

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

There are no data available on the use of NUVESSA in pregnant women. Metronidazole usage in pregnancy has been associated with certain congenital anomalies. In animal reproduction studies, no fetotoxicity or teratogenicity was observed when metronidazole was administered orally, during organogenesis to pregnant rats and rabbits at up to 60 times and 30 times the recommended human dose based on body surface area comparison, respectfully.

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 15 to 20%, respectively.

Data

Human Data

Blood levels following NUVESSA vaginal administration are lower than those achieved with oral metronidazole. Following a single intravaginal 5 g dose of NUVESSA, mean maximum concentration (Cmax) and total exposure (AUC0-?) are approximately 2% and 4%, respectively, of those following a single oral 500 mg dose of metronidazole tablets. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly.

There are published data from case-control studies, cohort studies, and 2 meta-analyses that include more than 5000 pregnant women who used metronidazole during pregnancy. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in utero; however, these findings were not confirmed.

In addition, more than ten randomized placebo-controlled clinical trials enrolled more than 5000 pregnant women to assess the use of antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy.

Three studies conducted to assess the risk of infant cancer following metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited.

Animal Data

No fetotoxicity or teratogenicity was observed … the maximum human dose based on body surface area comparison) … the maximum human dose based on body surface area comparison).

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

There is no information on the presence of metronidazole in human milk, or the effects on the breast-fed child, or the effects on milk production following intravaginal administration of NUVESSA. Metronidazole is present in human milk following oral metronidazole administration, at concentrations similar to plasma concentrations …

Because of the potential risk for tumorigenicity shown in animal studies with metronidazole, breastfeeding is not recommended during treatment with NUVESSA and for 2 days (based on half-life) after NUVESSA therapy ends.

Clinical Considerations

A nursing mother may choose to pump and discard her milk during NUVESSA therapy and for 2 days after NUVESSA therapy ends, and feed her infant stored human milk or formula.

Data

In a study of nursing mothers receiving oral metronidazole 600 (n=11) or 1200 (n=4) mg daily, mean maternal plasma concentrations were 5.0 and 12.5 mcg/mL, respectively, within 2 hours following administration; the milk: maternal plasma ratio was approximately 1.

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of NUVESSA have been established in pediatric subjects between the ages of 12 and less than 18 years old. Use of NUVESSA in this age group is supported by evidence from a multicenter, open-label safety and tolerability study in 60 pediatric subjects with bacterial vaginosis and, evidence from adequate and well-controlled studies in adult women,

The safety and effectiveness of NUVESSA in pediatric subjects below the age of 12 years have not been established.

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

17.4 Lactation

Newly created subsection:

Advise women not to breastfeed during treatment with NUVESSA and to discontinue breastfeeding for 2 days after treatment with NUVESSA. Also advise a nursing mother that she may choose to pump and discard her milk during treatment with NUVESSA and for 2 days after the therapy with NUVESSA and, feed her infant stored human milk or formula.

Other

NUVESSA replaces Metronidazole vaginal gel 1.3% throughout label.