INDICATIONS AND USAGE Bacterial Vaginosis (BV).

Metronidazole extended-release 750 mg tablets are indicated in the treatment of BV in non-pregnant women.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of metronidazole extended-release tablets and other antibacterial drugs, metronidazole extended-release tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy.

In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

WARNINGS Central and Peripheral Nervous System Effects Encephalopathy and peripheral neuropathy: Cases of encephalopathy and peripheral neuropathy (including optic neuropathy) have been reported with metronidazole.

Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria.

CNS lesions seen on MRI have been described in reports of encephalopathy.

CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole.

CNS lesions seen on MRI have also been described as reversible.

Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity.

Convulsive seizures have been reported in patients treated with metronidazole.

Aseptic meningitis: Cases of aseptic meningitis have been reported with metronidazole.

Symptoms can occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued.

The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy (see ADVERSE REACTIONS ).

ADVERSE REACTIONS In two multicenter clinical trials, a total of 270 patients received 750 mg metronidazole extended-release tablets orally once daily for 7 days, and 287 were treated with a comparator agent administered intravaginally once daily for 7 days (See CLINICAL STUDIES).

3,4 Most adverse events were described as being of mild or moderate severity.

Among patients taking metronidazole extended-release tablets who reported headaches, 10% considered them severe, and less than 2% of reported episodes of nausea were considered severe.

Metallic taste was reported by 9% of patients taking metronidazole extended-release tablets.

Adverse events reported at ≥2% incidence for either treatment group, irrespective of treatment causality, are summarized in the table below.

Adverse Events (≥2% Incidence Rate)—Irrespective of Treatment Causality Metronidazole Extended-Release Tablets 7 days (N=267) Vaginal Preparation (N=285) Headache 48 (18%) 44 (15%) Vaginitis 39 (15%) 32 (12%) Nausea 28 (10%) 8 (3%) Taste Perversion (metallic taste) 23 (9%) 1 (0%) Infection Bacterial 19 (7%) 17 (6%) Influenza-like Symptoms 17 (6%) 20 (7%) Pruritus Genital 14 (5%) 25 (9%) Abdominal Pain 10 (4%) 13 (5%) Dizziness 11 (4%) 3 (1%) Diarrhea 11 (4%) 3 (1%) Upper Respiratory Tract Infection 11 (4%) 10 (4%) Rhinitis 12 (4%) 10 (4%) Sinusitis 7 (3%) 6 (2%) Urine Abnormal 7 (3%) 4 (1%) Pharyngitis 8 (3%) 4 (1%) Dysmenorrhea 9 (3%) 7 (2%) Moniliasis 9 (3%) 8 (3%) Mouth Dry 5 (2%) 2 (1%) Urinary Tract Infection 6 (2%) 16 (6%) Vulvovaginal candidiasis is a recognized consequence of treatment with many anti-infective agents.

In these multicenter clinical trials, there were no statistically significant differences in the incidence rates of yeast vaginitis for groups of patients treated with metronidazole extended-release tablets or the vaginal comparator.

The following reactions have been reported during treatment with metronidazole: Central Nervous System: The most serious adverse reactions reported in patients treated with metronidazole have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity.

Since persistent peripheral neuropathy has been reported in some patients receiving prolonged administration of metronidazole, patients should be specifically warned about these reactions and should be told to stop the drug and report immediately to their physicians if any neurologic symptoms occur.

In addition, patients have reported headache, syncope, dizziness, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia (See WARNINGS ).

Gastrointestinal: The most common adverse reactions reported have been referable to the gastrointestinal tract, particularly nausea, sometimes accompanied by headache, anorexia, and occasionally vomiting, diarrhea, epigastric distress; abdominal cramping; and constipation.

Mouth: A sharp, unpleasant metallic taste is not unusual.

Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of Candida which may occur during therapy.

Dermatologic: Erythematous rash and pruritus.

Hematopoietic: Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia.

Cardiovascular: QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval.

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

Hypersensitivity: Urticaria, erythematous rash, Stevens-Johnson Syndrome, toxic epidermal necrolysis, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever.

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

Instances of darkened urine have been reported by approximately one patient in 100,000.

Although the pigment which is probably responsible for this phenomenon has not been positively identified, it is almost certainly a metabolite of metronidazole and seems to have no clinical significance.

Hepatic: Cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole, have been reported in patients with Cockayne Syndrome (latency from drug start to signs of liver failure as short as 2 days) ( see CONTRAINDICATIONS ).

Other: Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling “serum sickness.” Rare cases of pancreatitis, which generally abated on withdrawal of the drug, have been reported.

Patients with Crohn’s disease are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers.

There have been some reports in the medical literature of breast and colon cancer in Crohn’s disease patients who have been treated with metronidazole at high doses for extended periods of time.

A cause and effect relationship has not been established.

Crohn’s disease is not an approved indication for metronidazole extended-release 750 mg tablets.