Metronidazole

Metronidazole vaginal gel is indicated in the treatment of bacterial vaginosis (formerly referred to as

•  
  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
  Lactobacillus
  morphology, (b) predominance of
  Gardnerella
  morphotype, and (c) absent or few white blood cells.

Other pathogens commonly associated with vulvovaginitis, e.g.,

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.

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%:

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  Reproductive:
   
•  Vaginal discharge (12%),
•  Symptomatic
  Candida
  cervicitis/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 effects that have been reported in association with the use of

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

•  
  Cardiovascular:
  Flattening of the T-wave may be seen in electrocardiographic tracings.
•  
  Central Nervous System:
  (See
  WARNINGS

  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.
  ) Headache, dizziness, syncope, ataxia, confusion, convulsive seizures, peripheral neuropathy, vertigo, incoordination, irritability, depression, weakness, insomnia.
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  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
  Candida
  in 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.

Oral metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other coumarin anticoagulants, resulting in a prolongation of prothrombin time. This possible drug interaction should be considered when metronidazole vaginal gel is prescribed for patients on this type of anticoagulant therapy.

In patients stabilized on relatively high doses of lithium, short-term oral metronidazole therapy has been associated with elevation of serum lithium levels and, in a few cases, signs of lithium toxicity.

Use of cimetidine with oral metronidazole may prolong the half-life and decrease plasma clearance of metronidazole.

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 chemical formula of C₆H₉N₃O₃, a molecular weight of 171.15 g/mol, 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 974P, 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, USP.