Label: METRONIDAZOLE VAGINAL- metronidazole gel

Rx only

FOR INTRAVAGINAL USE ONLY

NOT FOR OPHTHALMIC, DERMAL, OR ORAL USE

Metronidazole vaginal gel is the intravaginal dosage form of the synthetic antibacterial agent, metronidazole, USP at a concentration of 0.75%. Metronidazole is a member of the imidazole class of antibacterial agents and is classified therapeutically as an antiprotozoal and antibacterial agent. Chemically, metronidazole is a 2-methyl-5-nitroimidazole-1-ethanol. It has a molecular formula of C 6H 9N 3O 3, a molecular weight of 171.2 g/mole, and has the following structure:

Metronidazole vaginal gel is a gelled, purified water solution, containing metronidazole, USP at a concentration of 7.5 mg/g (0.75%). The gel is formulated at pH 4.0. The gel also contains carbomer homopolymer, edetate disodium, methylparaben, propylparaben, propylene glycol, and sodium hydroxide.

Each applicator full of 5 grams of vaginal gel contains approximately 37.5 mg of metronidazole.

Normal Subjects

Following a single, intravaginal 5 g dose of metronidazole vaginal gel (equivalent to 37.5 mg of metronidazole) to 12 normal subjects, a mean maximum serum metronidazole concentration of 237 ng/mL was reported (range: 152 ng/mL to 368 ng/mL). This is approximately 2% of the mean maximum serum metronidazole concentration reported in the same subjects administered a single, oral 500 mg dose of metronidazole (mean C max= 12,785 ng/mL, range: 10,013 ng/mL to 17,400 ng/mL). These peak concentrations were obtained in 6 hours to 12 hours after dosing with metronidazole vaginal gel and 1 hour to 3 hours after dosing with oral metronidazole.

The extent of exposure [area under the curve (AUC)] of metronidazole, when administered as a single intravaginal 5 g dose of metronidazole vaginal gel (equivalent to 37.5 mg of metronidazole), was approximately 4% of the AUC of a single oral 500 mg dose of metronidazole (4,977 ng-hr/mL and approximately 125,000 ng-hr/mL, respectively).

Dose-adjusted comparisons of AUCs demonstrated that, on a mg to mg comparison basis, the absorption of metronidazole, when administered vaginally, was approximately half that of an equivalent oral dosage.

Patients with Bacterial Vaginosis

Following single and multiple 5 g doses of metronidazole vaginal gel to 4 patients with bacterial vaginosis, a mean maximum serum metronidazole concentration of 214 ng/mL on day 1 and 294 ng/mL (range: 228 ng/mL to 349 ng/mL) on day five were reported. Steady-state metronidazole serum concentrations following oral dosages of 400 mg to 500 mg BID have been reported to range from 6,000 ng/mL to 20,000 ng/mL.

Microbiology

The intracellular targets of action of metronidazole on anaerobes are largely unknown. The 5-nitro group of metronidazole is reduced by metabolically active anaerobes, and studies have demonstrated that the reduced form of the drug interacts with bacterial DNA. However, it is not clear whether interaction with DNA alone is an important component in the bactericidal action of metronidazole on anaerobic organisms.

Culture and sensitivity testing of bacteria are not routinely performed to establish the diagnosis of bacterial vaginosis. (See INDICATIONS AND USAGE.)

Standard methodology for the susceptibility testing of the potential bacterial vaginosis pathogens, Gardnerella vaginalis, Mobiluncusspp ., and Mycoplasma hominis, has not been defined. Nonetheless, metronidazole is an antimicrobial agent active in vitroagainst most strains of the following organisms that have been reported to be associated with bacterial vaginosis:

Bacteroidesspp .

Gardnerella vaginalis

Mobiluncusspp .

Peptostreptococcusspp .

Metronidazole vaginal gel is indicated in the treatment of bacterial vaginosis (formerly referred to as Haemophilusvaginitis, Gardnerellavaginitis, nonspecific vaginitis, Corynebacteriumvaginitis, or anaerobic vaginosis).

NOTE For purposes of this indication, a clinical diagnosis of bacterial vaginosis is usually defined by the presence of a homogeneous vaginal discharge that (a) has a pH of greater than 4.5, (b) emits a "fishy" amine odor when mixed with a 10% KOH solution, and (c) contains clue cells on microscopic examination. Gram's stain results consistent with a diagnosis of bacterial vaginosis include (a) markedly reduced or absent Lactobacillusmorphology, (b) predominance of Gardnerellamorphotype, and (c) absent or few white blood cells.

Other pathogens commonly associated with vulvovaginitis, e.g., Trichomonas vaginalis, Chlamydia trachomatis, N. gonorrhoeae, Candida albicans, and Herpes simplexvirus should be ruled out.

Metronidazole vaginal gel is contraindicated in patients with a prior history of hypersensitivity to metronidazole, parabens, other ingredients of the formulation, or other nitroimidazole derivatives.

Convulsive Seizures and Peripheral Neuropathy

Convulsive seizures 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. The appearance of abnormal neurologic signs demands the prompt discontinuation of metronidazole vaginal gel therapy. Metronidazole vaginal gel should be administered with caution to patients with central nervous system diseases.

Psychotic Reactions

Psychotic reactions have been reported in alcoholic patients who were using oral metronidazole and disulfiram concurrently. Metronidazole vaginal gel should not be administered to patients who have taken disulfiram within the last 2 weeks.

Metronidazole vaginal gel affords minimal peak serum levels and systemic exposure (AUCs) of metronidazole compared to 500 mg oral metronidazole dosing. Although these lower levels of exposure are less likely to produce the common reactions seen with oral metronidazole, the possibility of these and other reactions cannot be excluded presently. Data from well-controlled trials directly comparing metronidazole administered orally to metronidazole administered vaginally are not available.

Clinical Trials

There were no deaths or serious adverse events related to drug therapy in clinical trials involving 800 non-pregnant women who received metronidazole vaginal gel.

In a randomized, single-blind clinical trial of 505 non-pregnant women who received metronidazole vaginal gel once or twice a day, 2 patients (one from each regimen) discontinued therapy early due to drug-related adverse events. One patient discontinued drug because of moderate abdominal cramping and loose stools, while the other patient discontinued drug because of mild vaginal burning. These symptoms resolved after discontinuation of drug.

Medical events judged to be related, probably related, or possibly related to administration of metronidazole vaginal gel once or twice a day were reported for 195/505 (39%) patients. The incidence of individual adverse reactions were not significantly different between the two regimens. Unless percentages are otherwise stipulated, the incidence of individual adverse reactions listed below was less than 1%:

Reproductive:

Vaginal discharge (12%),

Symptomatic Candidacervicitis/vaginitis (10%),

Vulva/vaginal irritative symptoms (9%),

Pelvic discomfort (3%).

Gastrointestinal:

Gastrointestinal discomfort (7%),

Nausea and/or vomiting (4%),

Unusual taste (2%),

Diarrhea/loose stools (1%),

Decreased appetite (1%),

Abdominal bloating/gas; thirsty, dry mouth.

Neurologic:

Headache (5%),

Dizziness (2%),

Depression.

Dermatologic:

Generalized itching or rash.

Other:

Unspecified cramping (1%),

Fatigue,

Darkened urine.

In previous clinical trials submitted for approved labeling of metronidazole vaginal gel the following was also reported:

Laboratory:

Increased/decreased white blood cell counts (1.7%).

Other Metronidazole Formulations

Other effects that have been reported in association with the use of topical (dermal)formulations of metronidazole include skin irritation, transient skin erythema, and mild skin dryness and burning. None of these adverse events exceeded an incidence of 2% of patients.

Metronidazole vaginal gel affords minimal peak serum levels and systemic exposure (AUC) of metronidazole compared to 500 mg oral metronidazole dosing. Although these lower levels of exposure are less likely to produce the common reactions seen with oral metronidazole, the possibility of these and other reactions cannot be excluded presently.

The following adverse reactions and altered laboratory tests have been reported with the oral or parenteraluse of metronidazole:

Cardiovascular:Flattening of the T-wave may be seen in electrocardiographic tracings.

Central Nervous System:(See WARNINGS.) Headache, dizziness, syncope, ataxia, confusion, convulsive seizures, peripheral neuropathy, vertigo, incoordination, irritability, depression, weakness, insomnia.

Gastrointestinal:Abdominal discomfort, nausea, vomiting, diarrhea, an unpleasant metallic taste, anorexia, epigastric distress, abdominal cramping, constipation, "furry" tongue, glossitis, stomatitis, pancreatitis, and modification of taste of alcoholic beverages.

Genitourinary:Overgrowth of Candidain the vagina, dyspareunia, decreased libido, proctitis.

Hematopoietic:Reversible neutropenia, reversible thrombocytopenia.

Hypersensitivity Reactions:Urticaria; erythematous rash; flushing; nasal congestion; dryness of the mouth, vagina, or vulva; fever; pruritus; fleeting joint pains.

Renal:Dysuria, cystitis, polyuria, incontinence, a sense of pelvic pressure, darkened urine.

To report SUSPECTED ADVERSE REACTIONS, contact Saptalis Pharmaceuticals, LLC. at 1-833-727-8254 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

There is no human experience with overdosage of metronidazole vaginal gel. Vaginally applied metronidazole gel, 0.75% could be absorbed in sufficient amounts to produce systemic effects. (See WARNINGS.)

The recommended dose is one applicator full of metronidazole vaginal gel (approximately 5 grams containing approximately 37.5 mg of metronidazole) intravaginally once or twice a day for 5 days. For once-a-day dosing, metronidazole vaginal gel should be administered at bedtime.

Metronidazole vaginal gel, 0.75% is a clear colorless to yellow gel with no visible grit or particles, supplied in a 70 g aluminum tube with HDPE cap and packaged with 5 vaginal applicators.

The NDC number for the 70 g tube is 71656-067-70.

Store at controlled room temperature 15°C to 30°C (59°F to 86°F). Protect from freezing.

Clinical Studies

In a randomized, single-blind clinical trial of non-pregnant women with bacterial vaginosis who received metronidazole vaginal gel daily for 5 days, the clinical cure rates for evaluable patients determined at 4 weeks after completion of therapy for the QD and BID regimens were 98/185 (53%) and 109/190 (57%), respectively.

Distributed by:
Saptalis Pharmaceuticals, LLC.
Hauppauge, NY 11788
MADE IN USA
Rev.11/2024-R2

1. Filling the applicator

• Remove cap and puncture metal seal on tube with the pointed tip of cap. (See Figure 1)
• Screw end of applicator onto tube. (See Figure 2)
• Slowly squeeze gel out of tube and into applicator. Plunger will stop when the applicator is full. (See Figure 3)
• Unscrew applicator and replace cap on tube.

2. Inserting the applicator

• The applicator may be inserted while lying on your back with your knees bent or in any comfortable position.
• Hold filled applicator by barrel, and gently insert into vagina as far as it will comfortably go. (See Figure 4)
• Slowly press the plunger until it stops to deposit gel into vagina and then withdraw the applicator.

3. Care of the applicator

If physician prescribes twice-a-day dosing:

• After use, pull the plunger out of the barrel. (See Figure 5)
• Wash both plunger and barrel in warm soapy water and rinse thoroughly.
• To reassemble applicator, gently push plunger back into barrel.

IMPORTANT

For once-a-day dosing, apply one applicator full at bedtime. For twice-a-day dosing, apply one applicator full each morning and evening for 5 days, or as directed by physician.

WARNINGS

• If significant irritation develops from the use of this medication, discontinue use and consult your physician.
• Do not use during pregnancy except under the supervision of a physician.
• Keep this and all medications out of reach of children.
• For vaginal use only. Not for use in the eyes, on the skin or in the mouth.

Store at room temperature. Avoid exposure to extreme heat or cold.

See end of carton and bottom of tube for lot number and expiration date.

Distributed by:
Saptalis Pharmaceuticals, LLC.
Hauppauge, NY 11788
MADE IN USA
Rev. 11/2024-R3

Package/Label Display Panel - 70 g Label

NDC 71656-067-70

Metronidazole Vaginal Gel, 0.75%

FOR INTRAVAGINAL USE ONLY

NOT FOR OPHTHALMIC, DERMAL, OR ORAL USE

Rx Only

Net Wt. 70 g

Package/Label Display Panel - 70 g Carton

NDC 71656-067-70

Metronidazole Vaginal Gel, 0.75%

FOR INTRAVAGINAL USE ONLY

NOT FOR OPHTHALMIC, DERMAL, OR ORAL USE

Rx Only

Net Wt. 70 g