Drugs Details

Drugs Info of Flagyl, Flagyl 375, Flagyl ER
Drugs Details
  • Drugs Type  : Multum
  • Date : 10th Mar 2015 05:31 am
  • Brand Name : Flagyl, Flagyl 375, Flagyl ER
  • Generic Name : metronidazole (Pronunciation: me troe NI da zole)
Descriptions

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:

 

FLAGYL® (metronidazole) Structural Formula Illustration

 

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.

 

What are the possible side effects of metronidazole (Flagyl, Flagyl 375, Flagyl ER)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any of these serious side effects:

  • numbness or tingling in your hands or feet;
  • white patches or sores inside your mouth or on your lips;
  • pain or burning when you urinate;
  • diarrhea that is watery or bloody;
  • vision problems, pain behind your eyes;
  • trouble concentrating, slurred speech, mood or behavior changes,...

Read All Potential Side Effects and See Pictures of Flagyl ER »

What are the precautions when taking metronidazole extended release tablets (Flagyl ER)?

Before taking metronidazole, tell your doctor or pharmacist if you are allergic to it; or to other nitroimidazoles such as tinidazole; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver problems, nervous system disorders (e.g., seizures), blood disorders, Crohn's disease.

Avoid alcoholic beverages while taking this medication and for at least 3 days after finishing this medicine because severe stomach upset, nausea, vomiting, headache and flushing may occur.

This drug may make you dizzy. Do not drive, use machinery, or do any activity...

Read All Potential Precautions of Flagyl ER »

 

This monograph has been modified to include the generic and brand name in many instances.

Indications

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.

 
 

Dosage 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
0025–1961–30 Bottle 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.

Distributed by: G.D. Searle, Division of Pfizer Inc., NY, NY 10017. Revised June 2013

This monograph has been modified to include the generic and brand name in many instances.

 
 

Side Effects

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 (SeeClinical 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)
Headache 48 (18%) 44 (15%)
Vaginitis 39 (15%) 32 (12%)
Nausea 28 (10%) 8 (3%)
Taste Perversion (metallic taste) 23 (9%) 1 (0%)
Infection Bacterial 19 (7%) 17 (6%)
Influenza-like Symptoms 17 (6%) 20 (7%)
Pruritus Genital 14 (5%) 25 (9%)
Abdominal Pain 10 (4%) 13 (5%)
Dizziness 11 (4%) 3 (1%)
Diarrhea 11 (4%) 3 (1%)
Upper Respiratory Tract Infection 11 (4%) 10 (4%)
Rhinitis 12 (4%) 10 (4%)
Sinusitis 7 (3%) 6 (2%)
Urine Abnormal 7 (3%) 4 (1%)
Pharyngitis 8 (3%) 4 (1%)
Dysmenorrhea 9 (3%) 7 (2%)
Moniliasis 9 (3%) 8 (3%)
Mouth Dry 5 (2%) 2 (1%)
Urinary Tract Infection 6 (2%) 16 (6%)

 

Vulvovaginal candidiasis is a recognized consequence of treatment with many anti-infective agents. In these multicenter clinical trials, there were no statistically significant differences in the incidence rates of yeast vaginitis for groups of patients treated with 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, reversiblethrombocytopenia.

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 oflibido, 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 ofgastrointestinal 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.

REFERENCES

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.

Read the Flagyl ER (metronidazole extended release tablets) Side Effects Center for a complete guide to possible side effects

Learn More »
 
 
 

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 (seeCONTRAINDICATIONS).

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

Read the Flagyl ER Drug Interactions Center for a complete guide to possible interactions

Learn More »
 

This monograph has been modified to include the generic and brand name in many instances.

 
 

Warnings

Central and Peripheral Nervous System Effects

Encephalopathy and peripheral neuropathy: Cases of encephalopathyand 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 MRIhave 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 (seeADVERSE 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.

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 wereinfertile 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). 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.

This monograph has been modified to include the generic and brand name in many instances.

 
 

OverDose

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 andperipheral 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.

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).

This monograph has been modified to include the generic and brand name in many instances.

Clinical Pharamacology

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

PARAMETER FLAGYL ER 750 MG DAILY 
MEAN ± SD 
(N=24)
FED FASTED
AUC(0–24) (μg•hr/mL) 211±60.0 198±75.3
Cmax (μg/mL) 19.4±4.7 12.5±4.8
Cmin (μg/mL) 3.4±2.0 4.2±2.2
Tmax (hrs) 4.6±2.4 6.8±2.8
T½ (hrs) 7.4±1.6 8.7±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 incerebrospinal 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-(ßhydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-ylacetic 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 peritonealdialysis 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 ofin vitro susceptibility test results for antimicrobial drug products used inresident 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
≤ 8 Susceptible (S)
16 Intermediate (I)
≥ 32 Resistant (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 STRAIN MINIMUM INHIBITORY CONCENTRATION (MCG/ML)
AGAR BROTH
Bacteroides fragilis ATCC 25285 0.25–1.0 0.25-2.0
Bacteroides thetaiotaomicron ATCC 29741 0.5–2.0 0.5-4.0

 

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” amineodor, 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)
Study 1 61% (77/126) 59% (80/135)
Study 2 62% (74/119)* 43% (50/117)
*p < 0.05 versus clindamycin cream

 

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. S13-95-06014, 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.

This monograph has been modified to include the generic and brand name in many instances.

Patient Information

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., thecommon 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.

This monograph has been modified to include the generic and brand name in many instances.

Consumer Overview Uses

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

 

METRONIDAZOLE SUSTAINED-ACTION - ORAL

 

(MET-roe-NYE-da-zole)

 

COMMON BRAND NAME(S): Flagyl ER

 

USES: This form of metronidazole is used for vaginal infections. It belongs to a class of antibiotics known as nitroimidazoles. It works by stopping the growth of bacteria and protozoa.

This antibiotic only treats bacterial and protozoal infections. It will not work for viral infections (e.g., common cold, flu). Unnecessary use or overuse of any antibiotic can lead to its decreased effectiveness.

 

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This drug may also be used for other infections.

 

HOW TO USE: Take this medication by mouth once daily or as directed by your doctor. To help this drug be absorbed by your body, it is best to take this on an empty stomach at least one hour before or two hours after a meal.

Do not crush or chew this medication. Doing so can release all of the drug at once, increasing the risk of side effects. Also, do not split the tablets unless they have a score line and your doctor or pharmacist tells you to do so. Swallow the whole or split tablet without crushing or chewing.

Antibiotics work best when the amount of medicine in your body is kept at a constant level. Therefore, take this drug at evenly spaced intervals.

Continue to take this medication until the full prescribed amount is finished, even if symptoms disappear after a few days. Stopping the medication too early may allow bacteria/protozoa to continue to grow, which may result in a relapse of the infection.

Inform your doctor if your condition persists or worsens.

Consumer Overview Side Effect

SIDE EFFECTS: Dizziness, headache, diarrhea, nausea, stomach pain, loss of appetite, constipation, changes in taste, furry tongue, and dry mouth may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

This drug may cause urine to darken in color. This is harmless.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: unsteadiness, seizures, mental/mood changes (such as confusion), numbness/tingling of hands/feet, painful urination.

Tell your doctor immediately if any of these rare but very serious side effects occur: eye pain, severe/persistent headache, stiff/painful neck, sudden vision changes, sore throat, persistent fever, unusual bleeding/bruising, severe stomach pain, persistent nausea/vomiting.

Use of this medication for prolonged or repeated periods may result in oral thrush or a new vaginal yeast infection (oral or vaginal fungal infection). Contact your doctor if you notice white patches in your mouth, a change in vaginal discharge, or other new symptoms.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

 

Read the Flagyl ER (metronidazole extended release tablets) Side Effects Center for a complete guide to possible side effects

Learn More »
 

PRECAUTIONS: Before taking metronidazole, tell your doctor or pharmacist if you are allergic to it; or to other nitroimidazoles such as tinidazole; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver problems, nervous system disorders (e.g., seizures), blood disorders, Crohn's disease.

Avoid alcoholic beverages while taking this medication and for at least 3 days after finishing this medicine because severe stomach upset, nausea, vomiting, headache and flushing may occur.

This drug may make you dizzy. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely.

The elderly may be at greater risk for side effects while using this drug.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

This medication passes into breast milk. Discuss the risks and benefits with your doctor before breast-feeding.

Consumer Overview Missed Dose

DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug include: alcohol-containing products (e.g., cough and cold syrups, aftershave), lopinavir/ritonavir oral solution, "blood thinners" (such as warfarin), busulfan, cimetidine, fluorouracil, lithium, mebendazole, live vaccines, drugs for seizures (such as phenobarbital, phenytoin).

Avoid disulfiram for 2 weeks before and during treatment with this medication.

Although most antibiotics probably do not affect hormonal birth control such as pills, patch, or ring, some antibiotics may decrease their effectiveness. This could cause pregnancy. Examples include rifamycins such as rifampin or rifabutin. Be sure to ask your doctor or pharmacist if you should use additional reliable birth control methods while using this antibiotic.

This medication may interfere with certain laboratory tests (including liver function tests, blood triglyceride levels), possibly causing false test results. Make sure laboratory personnel and your doctors know you use this drug.

 

OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include nausea, vomiting, severe dizziness, and seizures.

 

NOTES: Do not share this medication with others.

Treatment of certain infections (trichomoniasis) may require that sexual partners be treated as well to avoid re-infection. During therapy, refrain from sexual intercourse or always use a condom.

This medication has been prescribed for your current condition only. Do not use it later for another infection unless told to do so by your doctor. A different medication may be necessary in those cases.

Laboratory and/or medical tests (e.g., blood counts) should be performed from time to time to monitor your progress or check for side effects. Consult your doctor for more details.

 

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

 

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from moisture and sunlight. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

 

Information last revised August 2013. Copyright(c) 2013 First Databank, Inc.

Patient Detailed Side Effect

Brand Names: Flagyl, Flagyl 375, Flagyl ER

Generic Name: metronidazole (Pronunciation: me troe NI da zole)

  • What is metronidazole (Flagyl ER)?
  • What are the possible side effects of metronidazole (Flagyl ER)?
  • What is the most important information I should know about metronidazole (Flagyl ER)?
  • What should I discuss with my healthcare provider before taking metronidazole (Flagyl ER)?
  • How should I take metronidazole (Flagyl ER)?
  • What happens if I miss a dose (Flagyl ER)?
  • What happens if I overdose (Flagyl ER)?
  • What should I avoid while taking metronidazole (Flagyl ER)?
  • What other drugs will affect metronidazole (Flagyl ER)?
  • Where can I get more information?

What is metronidazole (Flagyl ER)?

 

Metronidazole is an antibiotic. It fights bacteria in your body.

Metronidazole is used to treat bacterial infections of the vagina, stomach, skin, joints, and respiratory tract. This medication will not treat a vaginal yeast infection.

Metronidazole may also be used for purposes not listed in this medication guide.

Flagyl 500 mg

oblong, blue, imprinted with 500, FLAGYL

What are the possible side effects of metronidazole (Flagyl ER)?

 

Get emergency medical help if you have any of thesesigns of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any of these serious side effects:

  • numbness or tingling in your hands or feet;
  • white patches or sores inside your mouth or on your lips;
  • pain or burning when you urinate;
  • diarrhea that is watery or bloody;
  • vision problems, pain behind your eyes;
  • trouble concentrating, slurred speech, mood or behavior changes, tremors, muscle twitching, seizure (convulsions);
  • fever, chills, muscle pain, confusion, headache, sore throat, neck stiffness, increased sensitivity to light, drowsiness, nausea and vomiting; or
  • severe skin reaction -- fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Less serious side effects may include:

  • stomach pain, diarrhea;
  • dizziness, loss of balance;
  • vaginal itching or discharge;
  • dry mouth or unpleasant metallic taste;
  • cough, sneezing, runny or stuffy nose; or
  • swollen or sore tongue.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Flagyl ER (metronidazole extended release tablets) Side Effects Center for a complete guide to possible side effects

Learn More »
 

What is the most important information I should know about metronidazole (Flagyl ER)?

 

Take this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antibiotics. Metronidazole will not treat a viral infection such as the common cold or flu.

Do not drink alcohol while you are taking metronidazole and for at least 3 days after you stop taking it. You may have unpleasant side effects such as fast heartbeats, warmth or redness under your skin, tingly feeling, nausea, and vomiting.

Side Effects Centers
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  • Flagyl ER

Patient Detailed How Take

What should I discuss with my healthcare provider before taking metronidazole (Flagyl ER)?

 

You should not use this medication if you are allergic to metronidazole, or if you are in the first trimester of pregnancy. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

Before taking metronidazole, tell your doctor if you are allergic to any drugs, or if you have:

  • liver disease;
  • a stomach or intestinal disease such as Crohn's disease;
  • a blood cell disorder such as anemia (lack of red blood cells) or leukopenia (lack of white blood cells);
  • epilepsy or other seizure disorder; or
  • nerve disorders.

If you have any of these conditions, you may need a dose adjustment or special tests to safely take this medication.

Metronidazole can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I take metronidazole (Flagyl ER)?

 

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Take the extended-release metronidazole tablet (Flagyl ER) on an empty stomach, at least 1 hour before or 2 hours after eating a meal.

Do not crush, chew, or break an extended-release tablet. Swallow it whole. Breaking the pill may cause too much of the drug to be released at one time.

Take this medication for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antibiotics. Metronidazole will not treat a viral infection such as the common cold or flu.

To be sure this medication is not causing harmful effects, your blood may need to be tested often. Your liver function may also need to be tested. Visit your doctor regularly.

This medication can cause unusual results with certain medical tests. Tell any doctor who treats you that you are using metronidazole.

Store at room temperature away from moisture and heat.

Side Effects Centers
  • Flagyl
  • Flagyl ER

Patient Detailed Avoid Taking

What happens if I miss a dose (Flagyl ER)?

 

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Flagyl ER)?

 

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include nausea, vomiting, dizziness, loss of balance or coordination, numbness and tingling, or seizures (convulsions).

What should I avoid while taking metronidazole (Flagyl ER)?

 

Do not drink alcohol while you are taking metronidazole and for at least 3 days after you stop taking it. You may have unpleasant side effects such as fast heartbeats, warmth or redness under your skin, tingly feeling, nausea, and vomiting.

Check the labels of any medicines or food products you use to make sure they do not contain alcohol.

Antibiotic medicines can cause diarrhea, which may be a sign of a new infection. If you have diarrhea that is watery or bloody, stop taking metronidazole and call your doctor. Do not use anti-diarrhea medicine unless your doctor tells you to.

What other drugs will affect metronidazole (Flagyl ER)?

 

Tell your doctor about all other medicines you use, especially:

  • cimetidine (Tagamet);
  • seizure medication such as phenytoin (Dilantin) or phenobarbital (Luminal, Solfoton);
  • a blood thinner such as warfarin (Coumadin, Jantoven);
  • lithium (Lithobid, Eskalith, others); or
  • disulfiram (Antabuse).

This list is not complete and other drugs may interact with metronidazole. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

 

Your pharmacist can provide more information about metronidazole.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2013 Cerner Multum, Inc. Version: 10.01. Revision date: 2/14/2011.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

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