Metronidazole Extended-Release Tablets

Name: Metronidazole Extended-Release Tablets

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 and peripheral neuropathy, have been reported after 5 to 7 days of doses of 6 g to 10.4 g every other day.

Treatment of Overdosage

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

Clinical pharmacology

Absorption

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

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

Steady State Pharmacokinetic Parameters of Metronidazole after 750 mg of FLAGYL ER Given Once a Day for 7 Days

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 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-(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 peritoneal dialysis session lasting for 7.5 hours removed approximately 10% of the administered metronidazole dose. No adjustment in metronidazole dose is needed in ESRD patients undergoing CAPD.

Hepatic Impairment

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

Geriatric Patients

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

Pediatric Patients

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

Microbiology

Mechanism of Action

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

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

Activity In Vitro and In Vivo

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

Gram-positive anaerobes

Clostridium species
Eubacterium
species
Peptococcus
species Peptostreptococcus species

Gram-negative anaerobes

Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus)
Fusobacterium
species
Porphyromonas
species

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

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

Gram-negative anaerobes

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

Susceptibility Test Methods

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

Anaerobic techniques

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

Susceptibility Test Interpretive Criteria for Metronidazole

MIC (mcg/mL) Interpretation
≤ 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” amine odor, and absence of clue cells.

The study results are presented in the table below:

Clinical Cure Rates at One Month

  FLAGYL ER
% (n/N)
2% clindamycin cream
% (n/N)
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.

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

What should i discuss with my healthcare provider before taking metronidazole (flagyl, flagyl 375, 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.

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 (See Clinical Studies).5,6

Most adverse events were described as being of mild or moderate severity. Among patients taking FLAGYL ER who reported headaches, 10% considered them severe, and less than 2% of reported episodes of nausea were considered severe. Metallic taste was reported by 9% of patients taking FLAGYL ER.

Adverse events reported at ≥ 2% incidence for either treatment group, irrespective of treatment causality, are summarized in the table below.

Adverse Events ( ≥ 2% Incidence Rate)-Irrespective of Treatment Causality

  FLAGYL ER 7 days
(N=267)
Vaginal Preparation
(N=285)
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, reversible thrombocytopenia.

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

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

Renal: Dysuria, cystitis, polyuria, incontinence, and a sense of pelvic pressure. Instances of darkened urine have been reported by approximately one patient in 100,000. Although the pigment which is probably responsible for this phenomenon has not been positively identified, it is almost certainly a metabolite of metronidazole and seems to have no clinical significance.

Other: Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling “serum sickness.” Rare cases of pancreatitis, which generally abated on withdrawal of the drug, have been reported.

Patients with Crohn's disease are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn's disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause and effect relationship has not been established. Crohn's disease is not an approved indication for FLAGYL ER 750 mg tablets.

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 entire FDA prescribing information for Flagyl ER (Metronidazole Extended Release Tablets)

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What do I need to tell my doctor BEFORE I take Metronidazole Extended-Release Tablets?

  • If you have an allergy to metronidazole or any other part of this medicine.
  • If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
  • If you have taken disulfiram within the past 2 weeks.
  • If you are less than 12 weeks pregnant. This medicine is not for use in certain patients who are less than 12 weeks pregnant.
  • If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with this medicine (metronidazole extended-release tablets).

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Change in balance.
  • Dizziness or passing out.
  • Trouble speaking.
  • Seizures.
  • Change in eyesight.
  • Feeling irritable.
  • Low mood (depression).
  • Feeling tired or weak.
  • Not able to sleep.
  • Redness or white patches in mouth or throat.
  • Some people who took this medicine (metronidazole extended-release tablets) for a long time have had nerve problems that lasted for a long time. Call your doctor right away if you have a burning, numbness, or tingling feeling that is not normal.
  • This medicine may raise the chance of a very bad brain problem called aseptic meningitis. Call your doctor right away if you have a headache, fever, chills, very upset stomach or throwing up, stiff neck, rash, bright lights bother your eyes, feeling sleepy, or feeling confused.
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