METRONIDAZOLE- metronidazole tablet 
Unit Dose Services

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METRONIDAZOLE TABLETS, USP
250 mg and 500 mg                                              Revised: September 2015
 
Rx Only

To reduce the development of drug-resistant bacteria and maintain the effectiveness of metronidazole tablets, USP and other antibacterial drugs, metronidazole tablets, USP 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 ). Unnecessary use of the drug should be avoided. Its use should be reserved for the conditions described in the  section below. PRECAUTIONS  INDICATIONS AND USAGE

DESCRIPTION

Metronidazole tablets, USP, 250 mg or 500 mg is an oral formulation of the synthetic nitroimidazole antimicrobial, 2-methyl-5-nitro-1H-imidazole-1-ethanol, which has the following structural formula:

    Chemical Structure

Metronidazole 250 mg and 500 mg tablets, USP, for oral administration, contain the inactive ingredients: colloidal silicon dioxide, hydroxypropyl cellulose, lactose (anhydrous), microcrystalline cellulose, sodium starch glycolate, and stearic acid.

CLINICAL PHARMACOLOGY

Absorption

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

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 antimicrobial activity. in vitro

Renal clearance of metronidazole is approximately 10 mL/min/1.73 m2. 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±9.1 mL/min) and who received a single intravenous infusion of metronidazole 500 mg had no significant change in metronidazole pharmacokinetics but had 2-fold higher C of hydroxy-metronidazole and 5-fold higher C of metronidazole acetate,compared to healthy subjects with normal renal function (CL =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 ). maxmaxCRPRECAUTIONS

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 ). 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. DOSAGE AND ADMINISTRATION

Hepatic Impairment

Following a single intravenous infusion of 500 mg metronidazole, the mean AUC 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 AUC of hydroxyl-metronidazole in these hepatically impaired patients. A reduction in metronidazole dosage by 50% is recommended in patients with severe (Child-Pugh C)hepatic impairment (see ). No dosage adjustment is needed for patients with mild to moderate hepatic impairment. Patients with mild to moderate hepatic impairment should be monitored for metronidazole associated adverse events (see  and ). 2424DOSAGE AND ADMINISTRATION  PRECAUTIONSDOSAGE AND ADMINISTRATION

Geriatric Patients

Following a single 500 mg oral or IV dose of metronidazole, subjects greater than 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 less than 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, a nitroimidazole, exerts antibacterial effects in an anaerobic environment against most obligate anaerobes. Once metronidazole enters the organism by passive diffusion and activated in the cytoplasm of susceptible anaerobic bacteria, it is reduced; this process includes intracellular electron transport proteins such as ferredoxin, transfer of an electron to the nitro group of the metronidazole, and formation of a short-lived nitroso free radical. Because of this alteration of the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug’s intracellular transport. The reduced form of metronidazole and free radicals can interact with DNA leading to inhibition of DNA synthesis and DNA degradation leading to death of the bacteria. The precise mechanism of action of metronidazole is unclear. 

A potential for development of resistance exists against metronidazole.  Drug Resistance

Resistance may be due to multiple mechanisms that include decreased uptake of the drug, altered reduction efficiency, overexpression of the efflux pumps, inactivation of the drug, and/or increased DNA damage repair. 

Metronidazole does not possess any clinically relevant activity against facultative anaerobes or obligate aerobes.

Activity and in Clinical Infections In Vitro

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

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

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

Protozoal parasites
Entamoeba histolytica
Trichomonas vaginalis

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

Metronidazole exhibits minimal inhibitory concentrations (MIC’s) of 8 mcg/mL or less against most (greater than or equal to 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. in vitro

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

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

in vitro

For Anaerobes:

Quantitative methods are used to determine antimicrobial inhibitory concentrations  (MICs). These MICs provide 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 method .   1,2

The MIC values should be interpreted according to the criteria provided in the following Table

Susceptibility Test Interpretive Criteria for Metronidazole against Anaerobes*†

MIC (mcg/mL)      Interpretation

  MIC (mcg/mL)    Interpretation
 ≤ 8  sceptible (S)
 16  Intermediate (I)
 ≥ 32  Resistant (R)
†Broth dilution method is recommended for testing of group only; for this group, MIC values by agar and broth dilution methods are considered equivalent

*Agar dilution method is recommended for all anaerobes

Bacteroides fragilis

A report of “Susceptible” (S) 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” (I) implies that an infection due to the isolate may be appropriately treated in the body sites where the drugs are physiologically concentrated or when a high dosage of drug is used. A report of “Resistant” (R)  indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration 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. Standard metronidazole powder should provide a value within the MIC ranges noted in the following table: 1,2

Acceptable Quality Control Ranges for Metronidazole against Anaerobes
Quality strain Minimum Inhibitory Concentration (mcg/mL)
  Agar   Broth
  ATCC 25285 Bacteroides fragilis  0.25–1.0  0.25-2.0
  ATCC 29741 Bacteroides thetaiotaomicron  0.5–2.0  0.5-4.0
  ATCC 700057 Clostridium difficile 0.125-0.5 
  ATCC 43055 Eggerthella lenta  - 0.125-0.5 

Standardized tests do not exist for use in clinical microbiology laboratories. For protozoal parasites:

INDICATIONS AND USAGE

Symptomatic Trichomoniasis

Metronidazole tablets, USP are indicated for the treatment of infection in females and males when the presence of the trichomonad has been confirmed by appropriate laboratory procedures (wet smears and/or cultures). T. vaginalis

Asymptomatic Trichomoniasis

Metronidazole tablets, USP are indicated in the treatment of asymptomatic infection in 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. T. vaginalis

Treatment of Asymptomatic Sexual Partners

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 sexual partner 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 sexual partner should be treated with metronidazole tablets, USP in cases of reinfection. T. vaginalis

Amebiasis

Metronidazole tablets, USP 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 USP 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, USP.

INTRA-ABDOMINAL INFECTIONS, including peritonitis, intra-abdominal abscess, and liver abscess, caused by species including the group ( species, species, and species. BacteroidesB. fragilisB. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus), ClostridiumEubacteriumPeptococcus species,Peptostreptococcus

SKIN AND SKIN STRUCTURE INFECTIONS caused by species including the group, species, species, and species. BacteroidesB. fragilisClostridiumPeptococcus species, PeptostreptococcusFusobacterium

GYNECOLOGIC INFECTIONS, including endometritis, endomyometritis, tubo-ovarian abscess, and postsurgical vaginal cuff infection, caused by species including the group, species, species, and species. BacteroidesB. fragilisClostridiumPeptococcus species, PeptostreptococcusFusobacterium

BACTERIAL SEPTICEMIA caused by species including the group and species. BacteroidesB. fragilisClostridium

BONE AND JOINT INFECTIONS, (as adjunctive therapy), caused by species including the group. BacteroidesB. fragilis

CENTRAL NERVOUS SYSTEM (CNS) INFECTIONS, including meningitis and brain abscess, caused by species including the group. BacteroidesB. fragilis

LOWER RESPIRATORY TRACT INFECTIONS, including pneumonia, empyema, and lung abscess, caused by species including the group. BacteroidesB. fragilis

ENDOCARDITIS caused by species including the group. BacteroidesB. fragilis

To reduce the development of drug-resistant bacteria and maintain the effectiveness of metronidazole tablets, USP and other antibacterial drugs, metronidazole tablets, USP 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

Metronidazole tablets are contraindicated in patients with a prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives. Hypersensitivity

In patients with trichomoniasis, metronidazole tablets are contraindicated during the first trimester of pregnancy (see ). PRECAUTIONS

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 ). Psychotic Reaction with Disulfiram

PRECAUTIONS, DrugInteractions

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 ). Interaction with Alcohol
PRECAUTIONS, Drug Interactions

WARNINGS

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

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

Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole in the plasma. For patients with severe hepatic impairment (Child-Pugh C), a reduced dose of metronidazole is recommended. For patients with mild to moderate hepatic impairment, no dosage adjustment is needed but these patients should be monitored for metronidazole associated adverse events (see  and ). Hepatic Impairment

CLINICAL PHARMACOLOGYDOSAGE AND ADMINISTRATION

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 ). Renal Impairment

CLINICAL PHARMACOLOGY

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

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. Use in Patients with Blood Dyscrasias

Prescribing metronidazole tablets in the absence of a proven or strongly suspected bacterial or parasitic 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. Drug-Resistant Bacteria and Parasites

Information for Patients

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

 and CONTRAINDICATIONSPRECAUTIONS,Drug Interactions

Patients should be counseled that metronidazole tablets should only be used to treat bacterial and parasitic infections. Metronidazole tablets do not treat viral infections ( 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 in the future. Treatment of Bacterial and Parasitic Infections

e.g.,

Drug Interactions

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 (see . Disulfiram

) CONTRAINDICATIONS

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 ). Alcoholic Beverages

CONTRAINDICATIONS

Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. When metronidazole tablets are prescribed for patients on this type of anticoagulant therapy, prothrombin time and INR should be carefully monitored. Warfarin and other Oral Anticoagulants

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.

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. Busulfan

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 Inhibit 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 also been reported. Drugs that Induce CYP450 Enzymes

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

Tumors affecting the liver, lungs, 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/m (similar to the maximum recommended daily dose, based on body surface area comparisons). Malignant lymphomas and pulmonary neoplasms were 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. 2

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

Metronidazole failed to produce any adverse effects on fertility or testicular function in male rats at doses up at 400 mg/kg/day (similar to the maximum recommended clinical 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 metronidazole 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 ; however, these findings 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. in-utero

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 similar to the maximum 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 elderly geriatric patients, monitoring for metronidazole associated adverse events is recommended (see ). Decreased liver function in geriatric patients can result in increased concentrations of metronidazole that may necessitate adjustment of metronidazole dosage (see ). , CLINICAL PHARMACOLOGYPRECAUTIONSDOSAGE AND ADMINISTRATION

Pediatric Use

Safety and effectiveness in pediatric patients have not been established, except for the treatment of amebiasis.

ADVERSE REACTIONS

The following reactions have been reported during treatment with metronidazole:

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 ). Central Nervous System:WARNINGS

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; and abdominal cramping and constipation. Gastrointestinal:

: A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of which may occur during therapy. MouthCandida

: Erythematous rash and pruritus. Dermatologic

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

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

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

: 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. Renal

: Proliferation of 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. OtherCandida

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 tablets.
To report SUSPECTED ADVERSE EVENTS, contact Actavis at
1-800-272-5525 or FDA at 1-800-FDA-1088 or http://www.fda.gov/ for voluntary reporting of adverse reactions.

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.

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

DOSAGE AND ADMINISTRATION

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. Trichomoniasis

In the Female

One-day 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 and signs and symptoms, may be higher after a seven-day course of treatment than after a one-day treatment regimen. Seven-day course of treatment

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 In pregnant patients for 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 ). CONTRAINDICATIONS. ) 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 it is for the female.

Amebiasis

Adults

750 mg orally three times daily for 5 to 10 days. For acute intestinal amebiasis (acute amebic dysentery):

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

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, intravenous 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.

Dosage Adjustments

Patients with Severe Hepatic Impairment

For patients with severe hepatic

impairment (Child-Pugh C), the dose of metronidazole should be reduced by 50% (see  ).  and CLINICAL PHARMACOLOGYPRECAUTIONS

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 the 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

NDC:50436-4033-1 in a BOTTLE of 14 TABLETS

NDC:50436-4033-5 in a BOTTLE of 20 TABLETS

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). . CLSI document M11-A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2012.  Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Eighth Edition

2. Clinical and Laboratory Standards Institute (CLSI). , CLSI document M100-S25. CLSI, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.  Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fifth Informational Supplement

Manufactured by: Watson Pharma Private Limited Verna, Salcette Goa 403 722 INDIA 

Distributed by: Actavis Pharma, Inc. Parsippany, NJ  07054 USA 

Revised: September 2015          

METRONIDAZOLE TABLET

Label Image
METRONIDAZOLE 
metronidazole tablet
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50436-4033(NDC:0591-2522)
Route of Administration ORAL
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
METRONIDAZOLE (UNII: 140QMO216E) (METRONIDAZOLE - UNII:140QMO216E) METRONIDAZOLE 500 mg
Inactive Ingredients
Ingredient Name Strength
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
HYDROXYPROPYL CELLULOSE (TYPE H) (UNII: RFW2ET671P)  
ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)  
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)  
STEARIC ACID (UNII: 4ELV7Z65AP)  
Product Characteristics
Color WHITE Score 2 pieces
Shape BULLET (Oblong) Size 16mm
Flavor Imprint Code WPI;39;70
Contains     
Packaging
# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:50436-4033-1 14 in 1 BOTTLE; Type 0: Not a Combination Product 04/27/2016
2 NDC:50436-4033-5 20 in 1 BOTTLE; Type 0: Not a Combination Product 12/01/2015
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA070044 08/22/2011 08/31/2016
Labeler - Unit Dose Services (831995316)
Registrant - Unit Dose Services (831995316)
Establishment
Name Address ID/FEI Business Operations
Unit Dose Services 831995316 REPACK(50436-4033)

Revised: 9/2015
Document Id: 9c317ac5-bf0e-403a-9c4f-2ee4c2fa73bd
Set id: 566c68a0-50e6-4627-bb24-10ff4ce73181
Version: 3
Effective Time: 20150901
 
Unit Dose Services