1 ® Flagyl metronidazole tablets drug-resistant bacteria and maintain the effectiveness of To reduce the development of only to treat or prevent drugs, Flagyl should be used Flagyl and other antibacterial infections that are prove to be caused by bacteria. n or strongly suspected WARNING shown to be carcinogenic in mice and rats. (See Metronidazole has been ug should be avoided. Its use should be PRECAUTIONS.) Unnecessary use of the dr Indications and Usage section below. reserved for the conditions described in the DESCRIPTION Flagyl (metronidazole) is an oral synthetic antiprotozoal and antibacterial agent, 1-(ß­ hydroxyethyl)-2-methyl-5-nitroimidazole, which has the following structural formula: or 500 mg of metronidazole. Flagyl tablets contain 250 mg Inactive ingredients include cellulose, FD&C Blue No. 2 Lake, hydroxypropyl cellulose, hypromellose, polyethylene glycol, stearic acid, a nd titanium dioxide. CLINICAL PHARMACOLOGY similar for both oral and intravenous dosage Disposition of metronidazole in the body is 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-(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. Renal clea rance of metronidazole is approximately 10 2 . mL/min/1.73 m Metronidazole is the major component appearin g 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 1

2 strains of anaerobic bacteria and in vitro possess in vitro bactericidal activity against most trichomonacidal activity. Metronidazole appears in cereb rospinal 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. with peak plasma is well absorbed, Following oral administration, metronidazole e and two hours afte r administration. concentrations occurring between on Plasma concentrations of metronidazole are proportional to the administered dose. Oral oduced peak plasma concentrations of administration of 250 mg, 500 mg, or 2,000 mg pr 6 mcg/mL, 12 mcg/mL, and 40 mcg/mL, resp ectively. Studies reveal no significant bioavailability differences between males and females; however, because of weight differences, the resulting plasma leve ls in males are generally lower. Decreased renal function does not alte r the single-dose pharmacokinetics of metronidazole. However, plasma clearance of me tronidazole is decreased in patients with decreased liver function. Microbiology: Flagyl (metronidazole) possesses direct Trichomonas vaginalis, Entamoeba histolytica. trichomonacidal and amebacidal activity against in The E. histolytica. and T. vaginalis vitro minimal inhibitory concentration (MIC) fo r most strains of these organisms is 1 mcg/mL or less. Metronidazole is active against most obligate anaerobes but Anaerobic Bacteria. in vitro does not appear to possess any clinically rele vant activity against facultative anaerobes or obligate aerobes. Against susceptible organism s, metronidazole is generally bactericidal at concentrations equal to or slightly highe r than the minimal inhibitory concentrations. and clinical activity against the following in vitro Metronidazole has be en shown to have organisms: Anaerobic gram-negative bacilli, including: species including the Bacteroides fragilis group ( B. fragilis, B. Bacteroides 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; howev er, the rapid, routine 2

3 dual isolates of anaerobic bacteria is not always practical, susceptibility testing of indivi and therapy may be started while awaiting these results. ity to antibacterial timates of susceptibil Quantitative methods give the most precise es drugs. A standardized agar dilution me thod and a broth microdilution method are 1 recommended. sting. Each time the ized susceptibility te Control strains are recommended for standard test is performed, one or more of th e following strains should be included: Clostridium ATCC 25285, and Bacteroides perfringens ATCC 13124, Bacteroides fragilis thetaiotaomicron ATCC 29741. The mode metronidazole MI Cs for those three strains are reported to be 0.25, 0.25, and 0.5 mcg/mL, respectively. the results of the control A clinical laboratory is considered under acceptable control if strains are within one doubling dilution of the mode MICs reported for metronidazole. tible if the MIC value for metronidazole is A bacterial isolate may be considered suscep idered resistant if the MIC is greater than not more than 16 mcg/mL. An organism is cons that the infecting e laboratory indicates 16 mcg/mL. A report of “resistant” from th organism is not likely to respond to therapy. INDICATIONS AND USAGE Symptomatic Trichomoniasis. Flagyl is indicated for the treatment of symptomatic trichomoniasis in females and males when the presence of the trichomonad has been confirmed by appropriate laboratory pro cedures (wet smears and/or cultures). Flagyl is indicated in the treatment of asymptomatic Asymptomatic Trichomoniasis. ith endocervicitis, cervicitis, or cervical females when the organism is associated w ce of the trichomonad erosion. Since there is evidence that presen 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 to whether to treat an asymptomatic male reinfection of the partner. The decision as re or one for whom no culture has been attempted is an partner who has a negative cultu individual one. In making this decision, it shou ld be noted that there is evidence that a woman may become reinfected if her consor t is not treated. Also, since there can be considerable difficulty in isolating the organism from the asymptomatic male carrier, negative smears and cultures ca nnot be relied upon in this regard. In any event, the consort should be treated with Flagyl in cases of reinfection. of acute intestinal amebiasis (amebic Amebiasis. Flagyl is indicated in the treatment dysentery) and amebic liver abscess. 3

4 the need for aspiration or In amebic liver abscess, Flagyl therapy does not obviate drainage of pus. Anaerobic Bacterial Infections. eatment of serious infections Flagyl is indicated in the tr ndicated surgical procedures should be caused by susceptible anaerobic bacteria. I performed in conjunction with Flagyl therapy. In a mixed aerobic and anaerobic iate for the treatment of th infection, antimicrobials appropr on should be e aerobic infecti used in addition to Flagyl. In the treatment of most se rious anaerobic infections, Fl agyl I.V. (metronidazole ® hydrochloride) or Flagyl I.V. RTU (metronidazole) is usuall y administered initially. This may be followed by oral therapy with Fla gyl (metronidazole) at the discretion of the physician. INTRA-ABDOMINAL INFECTIONS, including pe ritonitis, intra-abdominal abscess, B. fragilis B. species including the and liver abscess, caused by Bacteroides group ( species, fragilis, B. distasonis, B. ovatus , B. thetaiotaomicron, B. vulgatus ), Clostridium species. Eubacterium species, Peptococcus niger, and Peptostreptococcus Bacteroides species including SKIN AND SKIN STRUCTURE INFECTIONS caused by B. fragilis the Peptococcus niger, Peptostreptococcus species, Clostridium group, species, and Fusobacterium species. GYNECOLOGIC INFECTIONS , including endometritis, endo myometritis, tubo-ovarian nal cuff infection, caused by abscess, and postsurgical vagi Bacteroides species including the Peptostreptococcus B. fragilis group, Clostridium species, Peptococcus niger, and species. B. fragilis species including the BACTERIAL SEPTICEMIA caused by Bacteroides group, and Clostridium species. adjunctive therapy, caused by species Bacteroides BONE AND JOINT INFECTIONS, as including the B. fragilis group. CENTRAL NERVOUS SYSTEM (CNS) INFECTIONS, including meningitis and brain species including the B. fragilis abscess, caused by Bacteroides group. LOWER RESPIRATORY TRACT INFECTIONS , including pneumonia, empyema, and lung abscess, caused by Bacteroides species including the B. fragilis group. group. ENDOCARDITIS caused by Bacteroides species including the B. fragilis To reduce the development of drug-resistant bacteria and maintain the effectiveness of Flagyl and other antibacterial drugs, Flagyl 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 ar e available, they should be considered in 4

5 selecting or modifying antibacterial therapy. In the absence of such data, local contribute to the empiric selection of epidemiology and susceptibility patterns may therapy. CONTRAINDICATIONS ted in patients with a prior history of hypersensitivity to Flagyl is contraindica metronidazole or other nitroimidazole derivatives. is, Flagyl is contraindicated during the first trimester of In patients with trichomonias ) pregnancy. (See Warnings. WARNINGS Convulsive seizures, encephalopathy, Central and Peripheral Nervous System Effects: aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been reported in patients treated with l neurologic signs demands the prompt metronidazole. The appearance of abnorma erapy. Flagyl should be administered with discontinuation of Flagyl (metronidazole) th caution to patients with central nervous system diseases. PRECAUTIONS General: metabolize metronidazole slowly, with Patients with severe hepatic disease its metabolites in the plasma. Accordingly, resultant accumulation of metronidazole and for such patients, doses below those us ually recommended should be administered cautiously. Known or previously unrecognized candidiasis may presen t more prominent symptoms etronidazole) and requires tr during therapy with Flagyl (m eatment with a candidacidal agent. Prescribing Flagyl in the abse nce of a proven or strongly susp ected bacterial infection or a prophylactic indication is unlik ely to provide benefit to th e patient and increases the risk of the development of drug-resistant bacteria. Information for patients: avoided while taking Flagyl Alcoholic beverages should be and for at least one day afterward. See Drug interactions. Patients should be counseled that antibacteria l drugs including Flagyl should only be used to treat bacterial inf ections. They do not treat viral in fections (e.g., the common cold). When Flagyl is prescribed to treat a bact erial infection, patients should be told that although it is common to feel be tter 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 an d will not be treatable by Flagyl or other antibacterial drugs in the future. 5

6 midazole and should be used with Flagyl (metronidazole) is a nitroi Laboratory tests: caution in patients with evidence of or hist ory of blood dyscrasia. A mild leukopenia has been observed during its administration; however, no persistent hematologic been observed in clinical studies. Total abnormalities attributable to metronidazole have mmended before and after therapy for and differential leukocyte counts are reco trichomoniasis and amebiasis, especially if a second course of therapy is necessary, and before and after therapy for anaerobic infections. to potentiate the anticoagulant Drug interactions: Metronidazole has been reported effect of warfarin and other oral coumarin anticoagulants, resulti ng in a prolongation of prothrombin time. This possible drug interaction should be considered when Flagyl (metronidazole) is prescribed for patien ts 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 also been reported. ce of phenytoin has reduced plasma levels; impaired clearan 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 Flagyl therapy has been associated with elevation of serum lithium and, in a few cases, signs of lithium toxicity. Serum lithium and serum creat inine 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 Flagyl therapy and for at least one usea, vomiting, headaches, and flushing may day afterward because abdominal cramps, na occur. s who are using metronidazole Psychotic reactions have been reported in alcoholic patient 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 i nvolve enzymatic coupling of the assay to + NADH). oxidation-reduction of nicotinamide adenine dinucleotide (NAD 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. 6

7 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 fre quently recommended human dose for a 50 kg statistically significant increase in the adult based on mg/kg body weight) there was a ished results of one of the mors in males. Also, the publ incidence of malignant liver tu mouse studies indicate an incr ease in the incidence of ma lignant lymphomas as well as e feeding of the drug. All these effects are pulmonary neoplasms associated with lifetim statistically significant. Several long-term, oral-dosi ng studies in the rat have been completed. There were statistically significant increases in the inci dence of various neoplas ms, particularly in ts administered metronidazole over those mammary and hepatic tumors, among female ra noted in the concurrent female control groups. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative. assay in vitro genic activity in a number of Although metronidazole has shown muta in vivo ) have failed to demonstrate a potential for genetic systems, studies in mammals ( damage. Fertility studies have been performed in mice at doses up to six times the maximum 2 recommended human dose based on mg/m and have revealed no evidence of impaired fertility. Pregnancy: Teratogenic Effects— Pregnancy Category B. Metronidazole crosses the placental barrier and enters the fetal circul ation rapidly. Reproduction studies have been performed in rats at doses up to five times the human dose and have revealed no evidence s due to metronidazole. No fetotoxicity was of impaired fertility or harm to the fetu observed when metronidazole was administered orally to pregnant mice at 20 mg/kg/day, approximately one and a half times the mo st frequently recommended human dose (750 mg/day) based on mg/kg body weight; however in a single small study where the drug intrauterine deaths were observed. The was administered intraperitoneally, some relationship of these findings to the drug is unknown. There are, however, no adequate and well-controlled studies in pregnant wo men. Because animal reproduction studies are not always predictive of human response, a nd because metronidazole is a carcinogen in rodents, this drug should be used dur ing pregnancy only if clearly needed. Use of Flagyl for trichomoniasis during pregna ncy should be restricted to those in whom alternative treatment has been inadequa te. Use of Flagyl (metronidazole) for trichomoniasis in pregnancy should be careful ly evaluated because metronidazole crosses the placental barrier and its effects on the human fetal organogenesis are not known (see above). 7

8 genicity, shown for metronidazole Because of the potential for tumori Nursing mothers: ontinue nursing or to in mouse and rat studies, a decision should be made whether to disc discontinue the drug, taking into account the importance of the drug to the mother. ons similar to those found in Metronidazole is secreted in human milk in concentrati plasma. r the single-dose pharmacokinetics Geriatric use: Decreased renal function does not alte of metronidazole is decreased in patients of metronidazole. However, plasma clearance monitoring of serum levels with decreased liver function. Therefore, in elderly patients, may be necessary to adjust the metronidazole dosage accordingly. Safety and effectiveness in pediatri Pediatric use: c patients have not been established, except for the treatment of amebiasis. ADVERSE REACTIONS The most serious adverse reactions repor ted in patients treated with Flagyl (metronidazole) have been convulsive seizures, encephalopathy, aseptic meningitis, optic e latter characterized mainly by numbness or paresthesia of and peripheral neuropathy, th an extremity. Since persistent peripheral neuropathy has been reported in some patients tion of Flagyl, patients shoul d be specifically warned receiving prolonged administra 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 reactio ns reported have been refera ble 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 Flagyl (metronidazole): Mouth: A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have occurred; these may be Candida associated with a sudden overgrowth of which may occur during therapy. Hematopoietic: Reversible neutropeni a (leukopenia); rarely, reversible thrombocytopenia. Cardiovascular: Flattening of the T-wave may be seen in electroc ardiographic tracings. Central Nervous System: Encephalopathy, asep tic meningitis, convulsive seizures, optic neuropathy, peripheral neuropat hy, dizziness, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depr ession, weakness, and insomnia. Hypersensitivity: Ur ticaria, erythematous rash, Stevens-Johnson Syndrome, toxic epidermal necrolysis, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever. 8

9 Renal: Dysuria, cystitis, polyuria, incontinence , and a sense of pelvic pressure. Instances of darkened urine have b een reported by approximately one patient in 100,000. Although for this phenomenon has not been positively the pigment which is probably responsible ite of metronidazole and seems to have no identified, it is almost certainly a metabol clinical significance. Other: Proliferation of decrease of li bido, proctitis, in the vagina, dyspareunia, Candida “serum sickness.” If patients receiving and fleeting joint pains sometimes resembling may experience abdominal distress, nausea, Flagyl drink alcoholic beverages, they of alcoholic beverages has A modification of the taste vomiting, flushing, or headache. y abated on withdrawal of of pancreatitis, which generall also been reported. Rare cases the drug, have been reported. increased incidence of Crohn’s disease patients are known to have an gastrointestinal and some reports in the medical literature of certain extraintestinal cancers. There have been patients who have been treated with breast and colon cancer in Crohn’s disease metronidazole at high doses for extended peri ods of time. A cause and effect relationship has not been established. Crohn’s disease is not an approved indication for Flagyl. OVERDOSAGE have been reported in suicide attempts and Single oral doses of metronidazole, up to 15 g, include nausea, vomiting, and ataxia. accidental overdoses. Symptoms reported Oral metronidazole has been studied as a radiation sensitizer in the treatment of malignant tumors. Neurotoxic effects, includ ing seizures and peri pheral 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 Flagyl overdose; therefore, management of Treatment: the patient should consist of sy mptomatic and supportive therapy. DOSAGE AND ADMINISTRATION In elderly patients, the pharm acokinetics of metronidazole may be altered, and, therefore, ry to adjust the metronidazole dosage monitoring of serum levels may be necessa accordingly. Trichomoniasis: In the Female: One-day treatment as a single dose or in two divided —two grams of Flagyl, given either 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 afte r a one-day treatment regimen. The dosage regimen should be individualiz ed. 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-da y course of treatment may 9

10 ent long enough for the sexual contacts to minimize reinfection by protecting the pati patients may tolerate one treatment regimen obtain appropriate treatment. Further, some better than the other. Contraindications. eated during the first trimester. (See Pregnant patients should not be tr ) In pregnant patients in whom alternative treatment has been inadequate, the one-day course of therapy should not be in higher serum levels which can reach used, as it results PRECAUTIONS, Pregnancy). the fetal circulation (see is recommended that an interval of four When repeat courses of the drug are required, it to six weeks elapse between courses and that the presence of the trichomonad be reconfirmed by appropriate laboratory measur es. Total and differential leukocyte counts should be made before and after re-treatment. Treatment should be individua In the Male: lized as for the female. Amebiasis: Adults: 750 mg orally three times daily For acute intestinal amebiasis (acute amebic dysentery): 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. In the treatment of most serious anaerobic infections, Anaerobic Bacterial Infections: ® Flagyl I.V. (metronidazole hydroc hloride) or Flagyl I.V. RTU (metronidazole) is usually administered initially. oral dosage is 7.5 mg/kg every six hours (approx. 500 mg for a 70-kg The usual adult 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, and endocardium may require longer treatment. lower respiratory tract, Patients with severe hepatic disease metabo lize metronidazole slowly, with resultant lites in the plasma. Accordingly, for such accumulation of metronidazole and its metabo nistered cautiously. patients, doses below those usually recommended should be admi 2 and toxicity is recommended. Close monitoring of plasma metronidazole levels The dose of Flagyl should not be specifi cally reduced in anuric patients since accumulated metabolites may be rapidly removed by dialysis. HOW SUPPLIED Flagyl 250-mg tablets are round, blue, film coated, with SEARLE and 1831 debossed on one side and FLAGYL and 250 on the other side; bottles of 50 and 100. 10

11 Flagyl 500-mg tablets are oblong, blue, film coated, with FLAGYL debossed on one side and 500 on the other side; bottles of 50 and 100. Store below 77°F (25°C) and protect from light. Storage and Stability: Reference Dilution Procedure for 1. Proposed standard: PSM-11—Proposed Antimicrobic Susceptibility Testing of Anaerobic Bacteria, National Committee for Clinical Laboratory Standards; and Sutter, et al.: Collaborative Eval uation of a Proposed Testing of Anaerobic Bacteria, Antimicrob. Reference Dilution Method of Susceptibility 495–502 (Oct.) 1979; and Tally, et al.: In Vitro Agents Chemother. 16: Activity of 436–438 (Sept.) 1978. 14: Thienamycin, Antimicrob. Agents Chemother. Metronidazole With Either Anaerobic or 2. Ralph, E.D., and Kirby, W.M.M.: Bioassay of 587–591 (Nov.) 1975; or Gulaid, et al.: 132: Aerobic Incubation, J. Infect. Dis. r Metabolites in Biological Fluids by High Determination of Metronidazole and Its Majo Pressure Liquid Chromatography, Br. J. Clin. Pharmacol. 430–432, 1978. 6: Rx only LAB-0162-5.0 Revised -August 2010 11

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