Metronidazole

NCS HealthCare of KY, Inc dba Vangard Labs

Metronidazole Tablets

FULL PRESCRIBING INFORMATION: CONTENTS*

• BOXED WARNING
• METRONIDAZOLE DESCRIPTION
• CLINICAL PHARMACOLOGY
• METRONIDAZOLE INDICATIONS AND USAGE
• METRONIDAZOLE CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
  • General
  • Drug Interactions
  • Carcinogenesis, Mutagenesis, Impairment of Fertility
  • Pregnancy
  • Nursing Mothers
  • Pediatric Use
  • GERIATRIC USE
• METRONIDAZOLE ADVERSE REACTIONS
• OVERDOSAGE
• METRONIDAZOLE DOSAGE AND ADMINISTRATION
• HOW SUPPLIED
• REFERENCES
• PRINCIPAL DISPLAY PANEL
• PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

METRONIDAZOLE DESCRIPTION

Metronidazole is an oral synthetic antiprotozoal and antibacterial agent,

1-(_-hydroxyethyl)-2-methyl-5-nitroimidazole, which has the following

structural formula:

Metronidazole 250 mg and 500 mg tablets, for oral administration, contain the

inactive ingredients: colloidal silicon dioxide, hydroxypropyl cellulose, lactose

(anhydrous), microcrystalline cellulose, sodium starch glycolate, and stearic acid.

CLINICAL PHARMACOLOGY

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

dosage forms, with an average elimination half-life in healthy humans of eight hours.

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-(_-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. Renal clearance of

metronidazole is approximately 10 mL/min/1.73 m2.

Metronidazole is the major component appearing in the plasma, with lesser quantities

of the 2-hydroxymethyl metabolite also being present. Less than 20% of the

circulating metronidazole is bound to plasma proteins. Both the parent compound

and the metabolite possess in vitro bactericidal activity against most strains of

anaerobic bacteria and in vitro trichomonacidal activity.

Metronidazole appears in cerebrospinal fluid, saliva, and human milk in concentrations

similar to those found in plasma. Bactericidal concentrations of metronidazole have

also been detected in pus from hepatic abscesses.

Following oral administration, metronidazole is well absorbed, with peak plasma

concentrations occurring between one and two hours after administration. Plasma

concentrations of metronidazole are proportional to the administered dose.

Oral administration of 250 mg, 500 mg, or 2,000 mg produced peak plasma

concentrations of 6 mcg/mL, 12 mcg/mL, and 40 mcg/mL, respectively. Studies

reveal no significant bioavailability differences between males and females;

however, because of weight differences, the resulting plasma levels in males are

generally lower.

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

metronidazole. However, plasma clearance of metronidazole is decreased in

patients with decreased liver function.

Microbiology

Trichomonas vaginalis, Entamoeba histolytica. Metronidazole possesses direct

trichomonacidal and amebacidal activity against T. vaginalis and E. histolytica. The

in vitro minimal inhibitory concentration (MIC) for most strains of these organisms

is 1 mcg/mL or less.

Anaerobic Bacteria. Metronidazole is active in vitro against most obligate anaerobes

but does not appear to possess any clinically relevant activity against facultative

anaerobes or obligate aerobes. Against susceptible organisms, metronidazole is

generally bactericidal at concentrations equal to or slightly higher than the minimal

inhibitory concentrations. Metronidazole has been shown to have in vitro and

clinical activity against the following organisms:

Anaerobic gram-negative bacilli, including:

Bacteroides species, including the Bacteroides fragilis group (B. fragilis, B. distasonis,

B. ovatus, B. thetaiotaomicron, B. vulgatus)

Fusobacterium species

Anaerobic gram-positive bacilli, including:

Clostridium species and susceptible strains of Eubacterium

Anaerobic gram positive cocci, including:

Peptococcus niger

Peptostreptococcus species

Susceptibility Tests

Bacteriologic studies should be performed to determine the causative organisms

and their susceptibility to metronidazole; however, the rapid, routine susceptibility

testing of individual isolates of anaerobic bacteria is not always practical, and

therapy may be started while awaiting these results.

Quantitative methods give the most precise estimates of susceptibility to

antibacterial drugs. A standardized agar dilution method and a broth microdilution

method are recommended.1

Control strains are recommended for standardized susceptibility testing. Each time

the test is performed, one or more of the following strains should be included:

Clostridium perfringens ATCC 13124, Bacteroides fragilis ATCC 25285, and

Bacteroides thetaiotaomicron ATCC 29741. The mode metronidazole MICs for

those three strains are reported to be 0.25, 0.25, and 0.5 mcg/mL, respectively.

A clinical laboratory is considered under acceptable control if the results of the

control strains are within one doubling dilution of the mode MICs reported for

metronidazole.

A bacterial isolate may be considered susceptible if the MIC value for metronidazole

is not more than 16 mcg/mL. An organism is considered resistant if the MIC is

greater than 16 mcg/mL. A report of “resistant” from the laboratory indicates that

the infecting organism is not likely to respond to therapy.

METRONIDAZOLE INDICATIONS AND USAGE

Symptomatic Trichomoniasis

Metronidazole tablets are indicated for the treatment of symptomatic trichomoniasis

in females and males when the presence of the trichomonad has been confirmed

by appropriate laboratory procedures (wet smears and/or cultures).

Asymptomatic Trichomoniasis

Metronidazole tablets are indicated in the treatment of asymptomatic females when

the organism is associated with endocervicitis, cervicitis, or cervical erosion.

Since there is evidence that presence of the trichomonad can interfere with

accurate assessment of abnormal cytological smears, additional smears should be

performed after eradication of the parasite.

Treatment of Asymptomatic Consorts

T. vaginalis infection is a venereal disease. Therefore, asymptomatic sexual

partners of treated patients should be treated simultaneously if the organism has

been found to be present, in order to prevent reinfection of the partner. The decision

as to whether to treat an asymptomatic male partner who has a negative culture

or one for whom no culture has been attempted is an individual one. In making

this decision, it should be noted that there is evidence that a woman may become

reinfected if her consort is not treated. Also, since there can be considerable

difficulty in isolating the organism from the asymptomatic male carrier, negative

smears and cultures cannot be relied upon in this regard. In any event, the consort

should be treated with metronidazole tablets in cases of reinfection.

Amebiasis

Metronidazole tablets are indicated in the treatment of acute intestinal amebiasis

(amebic dysentery) and amebic liver abscess.

In amebic liver abscess, metronidazole tablet therapy does not obviate the

need for aspiration or drainage of pus.

Anaerobic Bacterial Infections

Metronidazole tablets are indicated in the treatment of serious infections caused by

susceptible anaerobic bacteria. Indicated surgical procedures should be performed

in conjunction with metronidazole tablet therapy. In a mixed aerobic and anaerobic

infection, antimicrobials appropriate for the treatment of the aerobic infection

should be used in addition to metronidazole tablets.

In the treatment of most serious anaerobic infections, the intravenous form of

metronidazole is usually administered initially. This may be followed by oral

therapy with metronidazole tablets at the discretion of the physician.

INTRA-ABDOMINAL INFECTIONS, including peritonitis, intra-abdominal abscess, and

liver abscess, caused by Bacteroides species including the B. fragilis group (B. fragilis,

B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus), Clostridium species,

Eubacterium species, Peptococcus niger, and Peptostreptococcus species.

SKIN AND SKIN STRUCTURE INFECTIONS caused by Bacteroides species

including the B. fragilis group, Clostridium species, Peptococcus niger,

Peptostreptococcus species, and Fusobacterium species.

GYNECOLOGIC INFECTIONS, including endometritis, endomyometritis, tubo-ovarian

abscess, and postsurgical vaginal cuff infection, caused by Bacteroides species

including the B. fragilis group, Clostridium species, Peptococcus niger, and

Peptostreptococcus species.

BACTERIAL SEPTICEMIA caused by Bacteroides species including the B. fragilis group,

and Clostridium species.

BONE AND JOINT INFECTIONS, as adjunctive therapy, caused by Bacteroides species

including the B. fragilis group.

CENTRAL NERVOUS SYSTEM (CNS) INFECTIONS, including meningitis and brain

abscess, caused by Bacteroides species including the B. fragilis group.

LOWER RESPIRATORY TRACT INFECTIONS, including pneumonia, empyema, and

lung abscess, caused by Bacteroides species including the B. fragilis group.

ENDOCARDITIS caused by Bacteroides species including the B. fragilis group.

To reduce the development of drug-resistant bacteria and maintain the effectiveness

of metronidazole tablets and other antibacterial drugs, metronidazole 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.

METRONIDAZOLE CONTRAINDICATIONS

Metronidazole tablets are contraindicated in patients with a prior history of

hypersensitivity to metronidazole or other nitroimidazole derivatives.

In patients with trichomoniasis, metronidazole tablets are contraindicated during

the first trimester of pregnancy. (See WARNINGS.)

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 metronidazole. The appearance of abnormal neurologic signs demands

the prompt discontinuation of metronidazole therapy. Metronidazole should be

administered with caution to patients with central nervous system diseases.

PRECAUTIONS

General

Patients with severe hepatic disease metabolize metronidazole slowly, with

resultant accumulation of metronidazole and its metabolites in the plasma.

Accordingly, for such patients, doses below those usually recommended should be

administered cautiously.

Known or previously unrecognized candidiasis may present more prominent

symptoms during therapy with metronidazole and requires treatment with a

candicidal agent.

Prescribing metronidazole tablets 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 development of drug-resistant bacteria.

Information for Patients

Alcoholic beverages should be avoided while taking metronidazole tablets and

for at least one day afterward. See Drug Interactions.

Patients should be counseled that antibacterial drugs including metronidazole tablets

should only be used to treat bacterial infections. They do not treat viral infections

(e.g., the common cold). When metronidazole tablets are 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 metronidazole tablets or other

antibacterial drugs in the future.

Laboratory Tests

Metronidazole is a nitroimidazole and should be used with caution in patients with

evidence of or history of blood dyscrasia. A mild leukopenia 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 for

trichomoniasis and amebiasis, especially if a second course of therapy is

necessary, and before and after therapy for anaerobic infections.

Drug Interactions

Metronidazole has been reported to potentiate the anticoagulant effect of warfarin

and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin

time. This possible drug interaction should be considered when metronidazole is

prescribed for patients on this type of anticoagulant therapy.

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 also been reported.

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. 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.

Alcoholic beverages should not be consumed during metronidazole therapy and

for at least one day afterward because abdominal cramps, nausea, vomiting,

headaches, and flushing may occur.

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 two weeks.

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 hexokinase glucose. 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+ _ NADH).

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

Metronidazole has shown evidence of carcinogenic activity in a number of studies

involving chronic, oral administration in mice and rats.

Prominent among the effects in the mouse was the promotion of pulmonary

tumorigenesis. This has been observed in all six reported studies in that species,

including one study in which the animals were dosed on an intermittent schedule

(administration during every fourth week only). At very high dose levels

(approx. 500 mg/kg/day which is approximately 33 times the most frequently

recommended human dose for a 50 kg adult based on mg/kg body weight)

there was a statistically significant increase in the incidence of malignant liver

tumors in males. Also, the published results of one of the mouse studies indicate

an increase in the incidence of malignant lymphomas as well as pulmonary

neoplasms associated with lifetime feeding of the drug. All these effects are

statistically significant.

Several long-term, oral-dosing studies in the rat have been completed. There

were statistically significant increases in the incidence of various neoplasms,

particularly in mammary and hepatic tumors, among female rats administered

metronidazole over those noted in the concurrent female control groups.

Two lifetime tumorigenicity studies in hamsters have been performed and

reported to be negative.

Although metronidazole has shown mutagenic activity in a number of in vitro assay

systems, studies in mammals (in vivo) have failed to demonstrate a potential for

genetic damage.

Fertility studies have been performed in mice at doses up to six times the

maximum recommended human dose based on mg per sq. m. and have

revealed no evidence of impaired fertility.

Pregnancy

Teratogenic Effects

Pregnancy category B

Metronidazole crosses the placental barrier and enters the fetal circulation rapidly.

Reproduction studies have been performed in rats at doses up to five times the

human dose and have revealed no evidence of impaired fertility or harm to the

fetus due to metronidazole. No fetotoxicity was observed when metronidazole

was administered orally to pregnant mice at 20 mg/kg/day approximately one

and a half times the most frequently recommended human dose (750 mg/day)

based on mg/kg body weight; however in a single small study where the drug

was administered intraperitoneally, some intrauterine deaths were observed.

The relationship of these findings to the drug is unknown. There are, however,

no adequate and well-controlled studies in pregnant women. Because animal

reproduction studies are not always predictive of human response, and because

metronidazole is a carcinogen in rodents, this drug should be used during

pregnancy only if clearly needed.

Use of metronidazole for trichomoniasis during pregnancy should be restricted to

those in whom alternative treatment has been inadequate. Use of metronidazole

for trichomoniasis in the first trimester of pregnancy should be carefully evaluated

because metronidazole crosses the placental barrier and its effects on the human

fetal organogenesis are not known (see above).

Nursing Mothers

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. Metronidazole is secreted in human milk in concentrations similar to

those found in plasma.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established, except for

the treatment of amebiasis.

GERIATRIC USE

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

metronidazole. However, plasma clearance of metronidazole is decreased in

patients with decreased liver function. Therefore, in elderly patients, monitoring of

serum levels may be necessary to adjust the metronidazole dosage accordingly

METRONIDAZOLE ADVERSE REACTIONS

Two serious adverse reactions reported in patients treated with metronidazole

have been convulsive seizures 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.

The most common adverse reactions reported have been referable to the

gastrointestinal tract, particularly nausea reported by about 12% of patients,

sometimes accompanied by headache, anorexia, and occasionally vomiting;

diarrhea; epigastric distress; and abdominal cramping. Constipation has also

been reported. The following reactions have also been reported during treatment with

metronidazole:

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.

Hematopoietic: Reversible neutropenia (leukopenia); rarely, reversible

thrombocytopenia.

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

electrocardiographic tracings.

Central Nervous

System:

Convulsive seizures, peripheral neuropathy, dizziness,

vertigo, incoordination, ataxia, confusion, irritability,

depression, weakness, and insomnia.

Hypersensitivity: Urticaria, erythematous rash, 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.” If patients

receiving metronidazole drink alcoholic beverages, they

may experience abdominal distress, nausea, vomiting,

flushing, or headache. A modification of the taste of

alcoholic beverages has also been reported. Rare cases

of pancreatitis, which generally abated on withdrawal of

the drug, have been reported.

Crohn’s disease patients 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.

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 to 10.4 g every

other day.

Treatment

There is no specific antidote for metronidazole overdose; therefore, management of

the patient should consist of symptomatic and supportive therapy.

METRONIDAZOLE DOSAGE AND ADMINISTRATION

In elderly patients, the pharmacokinetics of metronidazole may be altered,

and, therefore, monitoring of serum levels may be necessary to adjust the

metronidazole dosage accordingly.

Trichomoniasis

In the Female

One-day treatment — two grams of metronidazole tablets, given either as a single

dose or in two divided doses of one gram each given in the same day.

Seven-day course of treatment — 250 mg three times daily for seven consecutive

days. There is some indication from controlled comparative studies that cure rates

as determined by vaginal smears, signs and symptoms, may be higher after a

seven-day course of treatment than after a one day treatment regimen.

The dosage regimen should be individualized. Single-dose treatment can assure

compliance, especially if administered under supervision, in those patients who

cannot be relied on to continue the seven day regimen. A seven-day course of

treatment may minimize reinfection by protecting the patient long enough for

the sexual contacts to obtain appropriate treatment. Further, some patients may

tolerate one treatment regimen better than the other.

Pregnant patients should not be treated during the first trimester.

(See CONTRAINDICATIONS.) In pregnant patients in whom alternative treatment

has been inadequate, the one-day course of therapy should not be used,

as it results in higher serum levels which can reach the fetal circulation

(see PRECAUTIONS, Pregnancy).

When repeat courses of the drug are required, it is recommended that an

interval of four to six weeks elapse between courses and that the presence of

the trichomonad be reconfirmed by appropriate laboratory measures. Total and

differential leukocyte counts should be made before and after re-treatment.

In the Male

Treatment should be individualized as for the female.

Amebiasis

Adults

For acute intestinal amebiasis (acute amebic dysentery): 750 mg orally three times

daily for 5 to 10 days.

For amebic liver abscess: 500 mg or 750 mg orally three times daily for 5 to 10 days.

Pediatric Patients

35 to 50 mg/kg/24 hours, divided into three doses, orally for 10 days.

Anaerobic Bacterial Infections

In the treatment of most serious anaerobic infections, the intravenous form of

metronidazole is usually administered initially.

The usual adult oral dosage is 7.5 mg/kg every six hours (approx. 500 mg for a

70 kg adult). A maximum of 4 g should not be exceeded during a 24 hour period.

The usual duration of therapy is 7 to 10 days; however, infections of the bone and

joint, lower respiratory tract, and endocardium may require longer treatment.

Patients with severe hepatic disease metabolize metronidazole slowly, with

resultant accumulation of metronidazole and its metabolites in the plasma.

Accordingly, for such patients, doses below those usually recommended should

be administered cautiously. Close monitoring of plasma metronidazole levels2

and toxicity is recommended.

The dose of metronidazole tablets should not be specifically reduced in anuric

patients since accumulated metabolites may be rapidly removed by dialysis.

HOW SUPPLIED

Metronidazole tablets, 250 mg are available as round, convex, white compressed tablets

debossed with “93” and “851” and are packaged in blisterpacks of 30.

Metronidazole tablets, 500 mg are available as oblong, scored, white compressed

tablets debossed with “93-93” and “852” and are packaged in blisterpacks of 30. 

Dispense in a tight, light-resistant container as defined in the USP with a child-resistant

closure (as required).

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]

REFERENCES

1. Proposed standard: PSM-11 -- Proposed Reference Dilution Procedure for

Antimicrobic Susceptibility Testing of Anaerobic Bacteria, National Committee

for Clinical Laboratory Standards; and Sutter, et al: Collaborative Evaluation of

a Proposed Reference Dilution Method of Susceptibility Testing of Anaerobic

Bacteria, Antimicrob. Agents Chemother. 16: 495-502 (Oct.) 1979; and Tally, et

al.: In Vitro Activity of Thienamycin, Antimicrob. Agents Chemother. 14:436-438

(Sept.) 1978.

2. Ralph, E.D., and Kirby, W.M.M.: Bioassay of Metronidazole With Either Anaerobic

or Aerobic Incubation, J. Infect. Dis. 132:587-591 (Nov.) 1975; or Gulaid,

et al.: Determination of Metronidazole and Its Major Metabolites in Biological

Fluids by High Pressure Liquid Chromatography, Br. J. Clin. Pharmacol.

6:430-432, 1978.

Manufactured By:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Distributed By:

Watson Pharma, Inc.

Corona, CA 92880 USA

Rev. N 6/2004

PRINCIPAL DISPLAY PANEL

Metronidazole Tablets,

USP 250mg

PRINCIPAL DISPLAY PANEL

Metronidazole Tablets,

USP 500mg