Included as part of the PRECAUTIONS section.
Central And Peripheral Nervous System Effects
Convulsive seizures, encephalopathy, aseptic meningitis,
optic and peripheral neuropathy, the latter characterized mainly by numbness or
paresthesia of an extremity, have been reported in patients treated with oral
or intravenous metronidazole. NUVESSA should be administered with caution to
patients with central nervous system diseases. Discontinue promptly if abnormal
neurologic signs develop.
Carcinogenicity In Animals
Metronidazole has been shown to be carcinogenic at high
doses administered orally in mice and rats [see Nonclinical Toxicology].
Unnecessary use of metronidazole should be avoided. Use of NUVESSA should be
reserved for the treatment of bacterial vaginosis [see INDICATIONS AND USAGE].
Drug/Laboratory Test Interactions
Metronidazole may interfere with certain types of
determinations of serum chemistry values, such as aspartate aminotransferase
(AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH),
triglycerides, and glucose hexokinase. Values of zero may be observed. All of
the assays in which interference has been reported involve enzymatic coupling
of the assay to oxidation reduction of nicotinamide-adenine dinucleotides (NAD
+ NADH). Interference is due to the similarity in absorbance peaks of NADH (340
nm) and metronidazole (322 nm) at pH 7.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Patient Information and Instructions for Use).
Interaction With Alcohol
Instruct the patient not to consume alcoholic beverages
and preparations containing ethanol or propylene glycol during and for at least
24 hours after treatment with NUVESSA [see CONTRAINDICATIONS and DRUG
Instruct the patient not to use NUVESSA if disulfiram had
been used within the last two weeks [see CONTRAINDICATIONS], and to
inform their healthcare provider if they are taking oral anticoagulants, or lithium
[see DRUG INTERACTIONS].
Vaginal Intercourse And Use With Vaginal Products
Instruct the patient not to engage in vaginal
intercourse, or use other vaginal products (such as tampons or douches)
following the single administration of NUVESSA.
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 [see Use In Specific
Inform the patient to discontinue use and consult a
healthcare provider if vaginal irritation occurs with use of NUVESSA.
Administration Of Drug
Instruct the patient that NUVESSA is supplied as a single
dose in a pre-filled applicator. See Instructions for Use for complete
instructions on how to use the product and the vaginal applicator.
Carcinogenesis Mutagenesis, Impairment Of Fertility
Metronidazole has shown evidence of carcinogenic activity
in a number of studies involving chronic oral administration in mice and rats.
Pulmonary tumors were reported in several mouse studies in which mice were dosed
orally at 75 mg/kg and above (about 6 or more times the maximum recommended
human dose based on mg/m²). Malignant lymphoma was reported at 66 mg/kg and
above (about 5 or more times the maximum recommended human dose based on mg/m²).
These tumors have been observed in all six reported studies in the mouse,
including one study in which the animals were dosed on an intermittent schedule
(administration during every fourth week only). All these effects were
There were statistically significant increases in the
incidence of mammary tumors, among female rats administered metronidazole at
270 mg/kg and above (about 40 times the maximum human dose based on mg/m²).
Hepatic adenomas and carcinomas were observed in rats administered 300 mg/kg
(about 45 times the maximum human dose based on mg/m²).
Two lifetime oral tumorigenicity studies in hamsters have
been performed and reported to be negative at doses up to 80 mg/kg (about 10
times the maximum human dose based on mg/m²).
Carcinogenesis studies have not been conducted with
Although metronidazole has shown in vitro mutagenic
activity in bacterial reverse mutation tests, it was negative in in vitro mammalian
mutation systems including CHO/HGPRT and CH V79 lung cell assays. Metronidazole
was not clastogenic in vitro chromosome aberration tests in CHO cells up to
5000 μg/mL but was positive in human and monkey peripheral blood
lymphocytes at 0.1 μg/mL.
In general, numerous micronucleus studies in rats and
mice have failed to demonstrate a potential for genetic damage up to single
oral doses 3000 mg/kg in mice (about 225 times the maximum human dose based on mg/m²).
However, a dose dependent increase in the frequency of micronuclei was observed
in CFW mice after intraperitoneal injections of up to 160 mg/kg (about 12 times
the maximum human dose based on mg/m²). Â Fertility studies have been performed
in mice orally dosed up to 500 mg/kg (about 37 times the maximum human dose
based on mg/m²) revealed no evidence of impaired fertility.
While no effects on fertility were observed in female
rats dosed intraperitoneally at doses up to 1000 mg/kg (about 300 times the
maximum human dose based on mg/m²), studies in male rats resulted in effects on
testes and sperm production at oral doses of 100 mg/kg and above (about 30
times the maximum human dose based on mg/m²).
Use In Specific Populations
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, 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(see Data).
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%,
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 [see CLINICAL
PHARMACOLOGY]. 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
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
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
No fetotoxicity or teratogenicity was observed when
metronidazole was administered orally to pregnant rabbits at up to 200 mg/kg
(about 60 times the maximum human dose based on body surface area comparison). Similarly,
no fetotoxic or teratogenic effects were observed in five studies in rats where
dosing was administered orally in the diet or by gastric intubation at doses up
to 200 mg/kg (about 30 times the maximum human dose based on body surface area
As well, no fetotoxicity or teratogenicity was observed
when metronidazole was administered orally to pregnant mice at doses up to 100
mg/kg (about 7 times the maximum human dose based on body surface area comparison).
However, some intrauterine deaths were observed in Swiss Webster mice
administered metronidazole intraperitoneally at doses up to 15 mg/kg (about 1
times the maximum human dose based on body surface area comparison). The
relationship of these intraperitoneal findings in mice to the vaginal use of NUVESSA
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 (see Data). Since some
metronidazole is systemically absorbed following vaginal administration of
NUVESSA, excretion in human milk following topical use is possible.
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 (see 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.
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.
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 [see ADVERSE REACTIONS] 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.
Clinical studies with NUVESSA did not include sufficient
numbers of subjects 65 years of age or older to determine whether they respond
differently than younger subjects.