FLAGYL ER- metronidazole tablet, film coated, extended release 
G.D. Searle LLC Division of Pfizer Inc

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FLAGYL®
(metronidazole) extended release tablets, 750 mg

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

WARNING

Metronidazole has been shown to be carcinogenic in mice and rats (see PRECAUTIONS). Unnecessary use of the drug should be avoided. Its use should be reserved for conditions described in the INDICATIONS AND USAGE section below.

DESCRIPTION

FLAGYL metronidazole extended release tablets is an oral formulation of the synthetic nitroimidazole antimicrobial agent, 2-methyl-5-nitro-1H-imidazole-1-ethanol, which has the following structural formula:

Chemical Structure

FLAGYL (metronidazole) extended release tablets, 750 mg (indicated below as FLAGYL ER) contain 750 mg of metronidazole USP. Inactive ingredients include hypromellose, lactose, magnesium stearate, polyethylene glycol, poly (meth) acrylic acid ester copolymers, polysorbate 80, silicon dioxide, simethicone emulsion, talc, titanium dioxide, FD&C Blue No. 2 Aluminum Lake.

CLINICAL PHARMACOLOGY

Absorption

Disposition of metronidazole in the body is similar for both oral and intravenous dosage forms.

FLAGYL ER 750 mg tablets contain 750 mg of metronidazole in an extended release formulation which allows for once-daily dosing. The steady state pharmacokinetics were determined in 24 healthy adult female subjects with a mean ± SD age of 28.8 ± 8.8 years (range: 19–46).2 The pharmacokinetic parameters of metronidazole after administration of FLAGYL ER 750 mg under fed and fasting conditions are summarized in the following table.

Steady State Pharmacokinetic Parameters of Metronidazole after 750 mg of FLAGYL ER Given Once a Day for 7 Days
FLAGYL ER 750 mg daily Mean±SD (N=24)
Parameterfed    fasted    
AUC(0–24) (µg∙hr/mL)211±60.0198±75.3
Cmax (µg/mL)19.4±4.712.5±4.8
Cmin (µg/mL)3.4±2.04.2±2.2
Tmax (hrs)4.6±2.46.8±2.8
T½ (hrs)7.4±1.68.7±2.2

Relative to the fasting state, the rate of metronidazole absorption from the extended release tablet is increased in the fed state resulting in alteration of the extended release characteristics.

Distribution

Metronidazole is the major component appearing in the plasma, with lesser quantities of metabolites also being present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Metronidazole appears in cerebrospinal fluid, saliva, and breast milk in concentrations similar to those found in plasma. Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses.

Metabolism/Excretion

The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the dose), with fecal excretion accounting for 6% to 15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation [1-(ß-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Both the parent compound and the hydroxyl metabolite possess in vitro antimicrobial activity.

Renal clearance of metronidazole is approximately 10 mL/min/1.73 m2.1 The average elimination half-life of metronidazole in healthy subjects is eight hours.

Renal Impairment

Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole.

Subjects with end-stage renal disease (ESRD; CLCR=8.1±9.1mL/min) and who received a single intravenous infusion of metronidazole 500 mg had no significant change in metronidazole pharmacokinetics but had 2-fold higher Cmax of hydroxy-metronidazole and 5-fold higher Cmax of metronidazole acetate, compared to healthy subjects with normal renal function (CLCR=126±16 mL/min). Thus, on account of the potential accumulation of metronidazole metabolites in ESRD patients, monitoring for metronidazole associated adverse events is recommended (see PRECAUTIONS).

Effect of Dialysis

Following a single intravenous infusion or oral dose of metronidazole 500 mg, the clearance of metronidazole was investigated in ESRD subjects undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). A hemodialysis session lasting for 4 to 8 hours removed 40% to 65% of the administered metronidazole dose, depending on the type of dialyzer membrane used and the duration of the dialysis session. If the administration of metronidazole cannot be separated from the dialysis session, supplementation of metronidazole dose following hemodialysis should be considered (see DOSAGE AND ADMINISTRATION). A peritoneal dialysis session lasting for 7.5 hours removed approximately 10% of the administered metronidazole dose. No adjustment in metronidazole dose is needed in ESRD patients undergoing CAPD.

Hepatic Impairment

Following a single intravenous infusion of 500 mg metronidazole, the mean AUC24 of metronidazole was higher by 114% in patients with severe (Child-Pugh C) hepatic impairment, and by 54% and 53% in patients with mild (Child-Pugh A), and moderate (Child-Pugh B) hepatic impairment, respectively, compared to healthy control subjects. There were no significant changes in the AUC24 of hydroxyl-metronidazole in these hepatically impaired patients. FLAGYL ER tablets should not be administered to patients with severe (Child-Pugh C) hepatic impairment unless it is deemed that the benefits outweigh the risks in these patients. No dosage adjustment is needed for patients with mild to moderate hepatic impairment. Patients with hepatic impairment who receive the usual recommended dose of FLAGYL ER tablet should be monitored for metronidazole associated adverse events (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Geriatric Patients

Following a single 500 mg oral or IV dose of metronidazole, subjects >70 years old with no apparent renal or hepatic dysfunction had a 40% to 80% higher mean AUC of hydroxy-metronidazole (active metabolite), with no apparent increase in the mean AUC of metronidazole (parent compound), compared to young healthy controls <40 years old. In geriatric patients, monitoring for metronidazole associated adverse events is recommended (see PRECAUTIONS).

Pediatric Patients

In one study, newborn infants appeared to demonstrate diminished capacity to eliminate metronidazole. The elimination half-life, measured during the first 3 days of life, was inversely related to gestational age. In infants whose gestational ages were between 28 and 40 weeks, the corresponding elimination half-lives ranged from 109 to 22.5 hours.

Microbiology

Mechanism of Action

Metronidazole exerts antibacterial effects in an anaerobic environment by the following possible mechanism: Once metronidazole enters the organism, the drug is reduced by intracellular electron transport proteins. Because of this alteration to the metronidazole molecule, a concentration gradient is maintained which promotes the drug's intracellular transport. Presumably, free radicals are formed which, in turn, react with cellular components resulting in death of the bacteria.

Metronidazole is active against most obligate anaerobes, but does not possess any clinically relevant activity against facultative anaerobes or obligate aerobes.

Activity In Vitro and In Vivo

Metronidazole has been shown to be active against most isolates of the following bacteria both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Gram-positive anaerobes:
Clostridium species
Eubacterium species
Peptococcus species
Peptostreptococcus species

Gram-negative anaerobes:
Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus)
Fusobacterium
species
Porphyromonas species

The following in vitro data are available, but their clinical significance is unknown:

Metronidazole exhibits in vitro minimal inhibitory concentrations (MIC's) of 8 mcg/mL or less against most (≥90%) isolates of the following bacteria; however, the safety and effectiveness of metronidazole in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Gram-negative anaerobes
Bacteroides fragilis group (B. caccae, B. uniformis)
Prevotella species (P. bivia, P. buccae, P. disiens)

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

Anaerobic techniques

Quantitative methods are used to determine antimicrobial inhibitory concentrations (MICs) provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. For anaerobic bacteria, the susceptibility to metronidazole can be determined by the reference broth and/or agar dilution method3,4. The MIC values obtained should be interpreted according to the following criteria:

Susceptibility Test Interpretive Criteria for Metronidazole
MIC (mcg/mL)Interpretation
≤ 8Susceptible (S)
  16Intermediate (I)
≥ 32Resistant (R)

A report of "Susceptible" indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of the drug product can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1,2 Standard metronidazole powder should provide a value within the MIC ranges noted in the following table:

Acceptable Quality Control Ranges for Metronidazole
QC StrainMinimum Inhibitory Concentration (mcg/mL)
AgarBroth
Bacteroides fragilis ATCC 252850.25–1.00.25–2.0
Bacteroides thetaiotaomicron ATCC 297410.5–2.00.5–4.0

INDICATIONS AND USAGE

Bacterial Vaginosis (BV)

FLAGYL ER 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 FLAGYL ER and other antibacterial drugs, FLAGYL ER 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.

CONTRAINDICATIONS

Hypersensitivity

FLAGYL ER 750 mg tablets are contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives.

Psychotic Reaction with Disulfiram

Use of oral metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently. Do not administer metronidazole to patients who have taken disulfiram within the last two weeks (see PRECAUTIONS, Drug Interactions).

Interaction with Alcohol

Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing. Discontinue consumption of alcohol or products containing propylene glycol during and for at least three days after therapy with metronidazole (see PRECAUTIONS, Drug Interactions).

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).

PRECAUTIONS

General

Hepatic Impairment

Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. FLAGYL ER tablets should not be administered to patients with severe (Child-Pugh C) hepatic impairment unless it is deemed that the benefits outweigh the risks in these patients. For patients with mild to moderate hepatic impairment, no dosage adjustment is needed. Patients with hepatic impairment who receive the usual recommended dose of FLAGYL ER tablets should be monitored for metronidazole associated adverse events (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Renal Impairment

Patients with end-stage renal disease may excrete metronidazole and metabolites slowly in the urine, resulting in significant accumulation of metronidazole metabolites. Monitoring for metronidazole associated adverse events is recommended (see CLINICAL PHARMACOLOGY).

Fungal Superinfections

Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with metronidazole and requires treatment with a candidacidal agent.

Use in Patients with Blood Dyscrasias

Metronidazole is a nitroimidazole and should be used with caution in patients with evidence of or history of blood dyscrasia. A mild leucopenia has been observed during its administration; however, no persistent hematologic abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy.

Drug-Resistant Bacteria and Parasites

Prescribing FLAGYL ER in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria and parasites.

Information for Patients

Interaction with Alcohol

Discontinue consumption of alcoholic beverages or products containing propylene glycol while taking metronidazole and for at least three days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur (see CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions).

Treatment of Bacterial Infections

Patients should be counseled that FLAGYL ER should only be used to treat bacterial infections. FLAGYL ER does not treat viral infections (e.g., the common cold). When FLAGYL ER is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by FLAGYL ER in the future.

Drug Interactions

Disulfiram

Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Metronidazole should not be given to patients who have taken disulfiram within the last 2 weeks (see CONTRAINDICATIONS).

Alcoholic Beverages

Abdominal cramps, nausea, vomiting, headaches, and flushing may occur if alcoholic beverages or products containing propylene glycol are consumed during or following metronidazole therapy (see CONTRAINDICATIONS).

Warfarin and other Oral Anticoagulants

Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. When FLAGYL 375 capsules is prescribed for patients on this type of anticoagulant therapy, prothrombin time and INR should be carefully monitored.

Lithium

In patients stabilized on relatively high doses of lithium, short-term metronidazole therapy has been associated with elevation of serum lithium and, in a few cases, signs of lithium toxicity. Serum lithium and serum creatinine levels should be obtained several days after beginning metronidazole to detect any increase that may precede clinical symptoms of lithium intoxication.

Busulfan

Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Metronidazole should not be administered concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to metronidazole are available, and concomitant administration with busulfan is medically needed, frequent monitoring of busulfan plasma concentration should be performed and the busulfan dose should be adjusted accordingly.

Drugs that Inhibit CYP450 Enzymes

The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole.

Drugs that Induce CYP450 Enzymes

The simultaneous administration of drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma levels; impaired clearance of phenytoin has been reported.

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 dinucleotide (NAD+SymbolNADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Tumors affecting the liver, lung, mammary, and lymphatic tissues have been detected in several studies of metronidazole in rats and mice, but not hamsters.

Pulmonary 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). Malignant liver tumors were increased in male mice treated at approximately 1500 mg/m2 (about 3 times the recommended daily dose, based on body surface area comparisons). Malignant lymphomas and pulmonary neoplasms are also increased with lifetime feeding of the drug to mice. Mammary and hepatic tumors were increased among female rats administered oral metronidazole compared to concurrent controls. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative.

Metronidazole has shown mutagenic activity in in vitro assay systems including the Ames test. Studies in mammals in vivo have failed to demonstrate a potential for genetic damage.

Metronidazole failed to produce any adverse effects on fertility or testicular function in male rats at doses up to 400 mg/kg/day (approximately 5 times the recommended dose based on body surface area comparisons) for 28 days. However, rats treated at the same dose for 6 weeks, or longer were infertile and showed severe degeneration of the seminiferous epithelium in the testes as well as marked decreases in testicular spermatid counts and epididymal sperm counts. Fertility was restored in most rats after an eight week, drug-free recovery period.

Pregnancy

Teratogenic effects

Pregnancy Category B

There are no adequate and well-controlled studies of FLAGYL ER in pregnant women. 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 finding 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.

Metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known. Reproduction studies have been performed in rats, rabbits, and mice at doses about four times the recommended human dose based on body surface area comparisons. There was no evidence of harm to the fetus due to metronidazole.

Nursing mothers

Metronidazole is present in human milk at concentrations similar to maternal serum levels, and infant serum levels can be close to or comparable to infant therapeutic levels. Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Alternatively, a nursing mother may choose to pump and discard human milk for the duration of metronidazole therapy, and for 24 hours after therapy ends and feed her infant stored human milk or formula.

Geriatric use

In geriatric patients, monitoring for metronidazole associated adverse events is recommended (see CLINICAL PHARMACOLOGY, PRECAUTIONS). Decreased liver function in geriatric patients can result in increased concentrations of metronidazole that may necessitate adjustment of metronidazole dosage (see DOSAGE AND ADMINISTRATION).

Pediatric use

The safety and efficacy of FLAGYL ER 750 mg tablets in the treatment of bacterial vaginosis in post-menarchal females has been established on the extrapolation of clinical trial data from adult women. The safety and efficacy of FLAGYL ER 750 mg tablets in pre-menarchal females have not been established.

ADVERSE REACTIONS

In two multicenter clinical trials, a total of 270 patients received 750 mg FLAGYL ER 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).5,6

Most adverse events were described as being of mild or moderate severity. Among patients taking FLAGYL ER 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 FLAGYL ER.

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
FLAGYL ER 7 days
(N=267)
Vaginal Preparation
(N=285)
Headache48 (18%)44 (15%)
Vaginitis39 (15%)32 (12%)
Nausea28 (10%)8 (3%)
Taste Perversion (metallic taste)23 (9%)1 (0%)
Infection Bacterial19 (7%)17 (6%)
Influenza-like Symptoms17 (6%)20 (7%)
Pruritus Genital14 (5%)25 (9%)
Abdominal Pain10 (4%)13 (5%)
Dizziness11 (4%)3 (1%)
Diarrhea11 (4%)3 (1%)
Upper Respiratory Tract Infection11 (4%)10 (4%)
Rhinitis12 (4%)10 (4%)
Sinusitis7 (3%)6 (2%)
Urine Abnormal7 (3%)4 (1%)
Pharyngitis8 (3%)4 (1%)
Dysmenorrhea9 (3%)7 (2%)
Moniliasis9 (3%)8 (3%)
Mouth Dry5 (2%)2 (1%)
Urinary Tract Infection6 (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 FLAGYL ER 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: 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.

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 FLAGYL ER 750 mg tablets.

OVERDOSAGE

Single oral doses of metronidazole, up to 15 g, have been reported in suicide attempts and accidental overdoses. Symptoms reported include nausea, vomiting, and ataxia.

Oral metronidazole has been studied as a radiation sensitizer in the treatment of malignant tumors. Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 to 7 days of doses of 6 g to 10.4 g every other day.

Treatment of Overdosage

There is no specific antidote for metronidazole overdose; therefore, management of the patient should consist of symptomatic and supportive therapy.

DOSAGE AND ADMINISTRATION

Bacterial Vaginosis

750 mg once daily by mouth for seven consecutive days.

FLAGYL ER 750 mg tablets should be taken under fasting conditions, at least one hour before or two hours after meals. The optimum extended-release characteristics of FLAGYL ER 750 mg are obtained when the drug is taken under fasting conditions (See CLINICAL PHARMACOLOGY, Absorption).

FLAGYL ER tablets should not be split, chewed, or crushed.

Dosage Adjustments

Patients Undergoing Hemodialysis

Hemodialysis removes significant amounts of metronidazole and its metabolites from systemic circulation. The clearance of metronidazole will depend on the type of dialysis membrane used, the duration of the dialysis session, and other factors. If the administration of metronidazole cannot be separated from a hemodialysis session, supplementation of metronidazole dosage following the hemodialysis session should be considered, depending on the patient's clinical situation (see CLINICAL PHARMACOLOGY).

HOW SUPPLIED

FLAGYL ER 750 mg tablets are oval, blue, film coated, with SEARLE and 1961 embossed on one side and FLAGYL and ER on the other side, supplied as:

NDC Number Size
0025–1961–30Bottle of 30

Storage and Stability

Store in a dry place at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F). [See USP Controlled Room Temperature.] Dispense in a well-closed container with a child-resistant closure.

CLINICAL STUDIES

Bacterial vaginosis (BV) is a clinical syndrome that results from a replacement of the normal, Lactobacillus-dominant flora with several other organisms including Gardnerella vaginalis, Mobiluncus spp, Mycoplasma hominis and anaerobes (Peptostreptococcus spp and Bacteroides spp).

FLAGYL ER was studied in patients with BV in two randomized, multicenter, well-controlled, investigator blind clinical trials.5,6 A total of 557 otherwise healthy nonpregnant patients with BV were randomized to treatment with FLAGYL ER once a day for 7 days (n=270) or 2% clindamycin vaginal cream one applicator full (5 grams) once a day for 7 days (n=287).

The primary efficacy endpoint for each treatment regimen was defined as clinical cure assessed at 28–32 days post-therapy. Clinical cure was defined as a return to normal of the vaginal pH (≤4.5), absence of a "fishy" amine odor, and absence of clue cells.

The study results are presented in the table below:

Clinical Cure Rates at One Month
FLAGYL ER
% (n/N)
2% clindamycin cream
% (n/N)
*
p<0.05 versus clindamycin cream
Study 161% (77/126)59% (80/135)
Study 262% (74/119)*43% (50/117)

At one month post-therapy the pH of the vagina returned to normal earlier and in a greater percentage of patients in the FLAGYL ER treatment group when compared to the 2% clindamycin vaginal cream group; 72% vs. 65%, respectively. Likewise, FLAGYL ER restored the normal Lactobacillus-predominant vaginal flora in a larger percentage of patients at one month post-therapy when compared to the 2% clindamycin treated group; 74% vs. 63%, respectively.

REFERENCES

  1. Salas-Herrera IG, Pearson RM, Johnston A, and Turner P. Concentration of metronidazole in cervical mucus and serum after single and repeated oral doses. J Antimicrobial Chemotherapy 1991; 28:283–289.
  2. Metronidazole modified-release tablet multiple-dose bioequivalency study (fed/fasting). G.D. Searle & Co., Protocol No. S13-94-02-014; Report No. S13-95-06-014, 11 July 1995.
  3. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Eighth Edition. CLSI document M11-A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2012.
  4. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement, CLSI document M100-S23. CLSI document M100-S23, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2013.
  5. Integrated clinical and statistical report for the treatment of bacterial vaginosis with metronidazole modified release tablet— a dose duration study. G.D. Searle & Co., Protocol No. N13-95-02-015; Report No. N13-96-06-015, 19 Nov 1996.
  6. Integrated clinical and statistical report for the treatment of bacterial vaginosis with metronidazole modified release tablet. G.D. Searle & Co., Protocol No. N13-95-02-017; Report No. N13-96-06-017, 11 Nov 1996.

Rx only

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LAB-0166-9.0
September 2013

PRINCIPAL DISPLAY PANEL - 750 mg Tablet Bottle Label

NDC 0025-1961-30

30 Tablets
Rx only

Flagyl® ER

metronidazole extended
release tablets

750 mg

Pfizer
Distributed by
G.D. Searle LLC
Division of Pfizer Inc, NY, NY 10017

PRINCIPAL DISPLAY PANEL - 750 mg Tablet Bottle Label
FLAGYL ER 
metronidazole tablet, film coated, extended release
Product Information
Product TypeHUMAN PRESCRIPTION DRUG LABELItem Code (Source)NDC:0025-1961
Route of AdministrationORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
METRONIDAZOLE (METRONIDAZOLE) METRONIDAZOLE750 mg
Inactive Ingredients
Ingredient NameStrength
HYPROMELLOSES 
LACTOSE 
MAGNESIUM STEARATE 
POLYETHYLENE GLYCOLS 
POLYSORBATE 80 
SILICON DIOXIDE 
TALC 
TITANIUM DIOXIDE 
FD&C BLUE NO. 2 
ALUMINUM OXIDE 
Product Characteristics
ColorBLUEScoreno score
ShapeOVALSize19mm
FlavorImprint Code SEARLE;1961;FLAGYL;ER
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:0025-1961-3030 in 1 BOTTLE
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA02086811/26/1997
Labeler - G.D. Searle LLC Division of Pfizer Inc (829077085)
Establishment
NameAddressID/FEIBusiness Operations
NEOLPHARMA, INC.078709787LABEL(0025-1961)
Establishment
NameAddressID/FEIBusiness Operations
Farchemia S.R.L.438743601API MANUFACTURE(0025-1961)
Establishment
NameAddressID/FEIBusiness Operations
Patheon Puerto Rico, Inc.174050377LABEL(0025-1961), MANUFACTURE(0025-1961), PACK(0025-1961)

Revised: 9/2013
Document Id: fc9ef6f6-e77c-4383-b7fd-51e2fb85eafa
Set id: 0b0ba593-fe54-456c-a3d7-651c50036e3e
Version: 11
Effective Time: 20130906
 
G.D. Searle LLC Division of Pfizer Inc