Metronidazole Capsules

Metronidazole Capsules USP 375 mg is an oral formulation of the synthetic nitroimidazole antimicrobial agent, 2-methyl-5-nitro-1H-imidazole-1-ethanol, which has the following structural formula:

Metronidazole Capsules USP 375 mg contain 375 mg of metronidazole USP. Inactive ingredients include corn starch, magnesium stearate, gelatin, titanium dioxide, FD&C Yellow No. 5 and iron oxide black.

Absorption

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

Metronidazole Capsules 375 mg have been shown to have a rate and extent of absorption similar to metronidazole tablets and were bioequivalent at an equal single dose of 750 mg. In a study conducted with 23 adult, healthy, female volunteers, oral administration of two 375 mg Metronidazole Capsules under fasted conditions produced a mean (±1 SD) peak plasma concentration (Cmax) of 21.4 (±2.8) mcg/mL with a mean Tmax of 1.6 (± 0.7) hours and a mean area under the plasma concentration-time curve (AUC) of 223 (±44) mcg·hr/mL. In the same study, three 250 mg metronidazole tablets produced a mean Cmax of 20.4 (± 3.8) mcg/mL with a mean Tmax of 1.4 (± 0.4) hours and a mean AUC of 218 (± 50) mcg·hr/mL.

Administration of Metronidazole Capsules 375 mg with food does not affect the extent of absorption of metronidazole; however, the presence of food results in a lower Cmax and a delayed Tmax compared to fasted conditions. In a study of 14 healthy, adult, female volunteers, administration of Metronidazole Capsules 375 mg under fasting conditions produced a mean Cmax of 10.9 (± 1.5) mcg/mL, a mean Tmax of 1.5 (± 1.4) hours, and a mean AUC of 110 (± 34) mcg·hr/mL compared to a mean Cmax of 8.6 (± 1.6) mcg/mL, a mean Tmax of 4.2 (± 1.7) hours, and a mean AUC of 99 (± 14) mcg·hr/mL under fed conditions.

Distribution

Metronidazole is the major component appearing in the plasma, with lesser quantities of metabolites also being present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Metronidazole appears in cerebrospinal fluid, saliva, and breast milk in concentrations similar to those found in plasma. Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses.

Metabolism/Excretion

The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the dose), with fecal excretion accounting for 6% to 15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation [1-(ß-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Both the parent compound and the hydroxyl metabolite possess in vitro antimicrobial activity against most strains of anaerobic bacteria and in vitro trichomonacidal activity.

Renal clearance of metronidazole is approximately 10 mL/min/1.73 m2. The average elimination half-life of metronidazole in healthy subjects is eight hours.

Renal Impairment

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

Subjects with end-stage renal disease (ESRD; CLCR=8.1±9.1 mL/min) and who received a single intravenous infusion of metronidazole 500 mg had no significant change in metronidazole pharmacokinetics but had 2-fold higher 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 hydroxy-metronidazole in these hepatically impaired patients. Pharmacokinetic modeling and simulation indicates the metronidazole dosage in amebiasis should be reduced by 50% and the dosage interval for trichomoniasis should be increased from every 12 hours to every 24 hours in patients with severe (Child-Pugh C) hepatic impairment. No dosage adjustment is needed for patients with mild to moderate hepatic impairment. Patients with hepatic impairment 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, a nitroimidazole, exerts antibacterial effects in an anaerobic environment against most obligate anaerobes. Once metronidazole enters the organism by passive diffusion and activated in the cytoplasm of susceptible anaerobic bacteria, it is reduced; this process includes intra-cellular electron transport proteins such as ferredoxin, transfer of an electron to the nitro group of the metronidazole, and formation of a short-lived nitroso free radical. Because of this alteration of the metronidazole molecule, a concentration gradient is created and maintained which promotes the drug’s intracellular transport. The reduced form of metronidazole and free radicals can interact with DNA leading to inhibition of DNA synthesis and DNA degradation leading to death of the bacteria. The precise mechanism of action of metronidazole is unclear.

Drug Resistance

A potential for development of resistance exists against metronidazole.

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

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

Activity In Vitro and in Clinical Infections

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

Protozoal parasites:

Entamoeba histolytica

Trichomonas vaginalis

The following in vitro data are available, but their clinical significance is unknown. Metronidazole exhibits in vitro minimal inhibitory concentrations (MICs) 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 Tests:

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 or community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

For Anaerobes:

Quantitative methods are used to determine antimicrobial inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. For anaerobic bacteria, the susceptibility to metronidazole can be determined by the reference broth and/or agar method1,2.

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

Susceptibility Test Interpretive Criteria for Metronidazole against Anaerobes*†

A report of “Susceptible” (S) indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen.

A report of “Intermediate” (I) implies that an infection due to the isolate may be appropriately treated in the body sites where the drugs are physiologically concentrated or when a high dosage of drug is used.

A report of “Resistant” (R) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1,2 Standard metronidazole powder should provide a value within the MIC ranges noted in the following table:

Acceptable Quality Control Ranges for Metronidazole against Anaerobes

For protozoal parasites:

Standardized tests do not exist for use in clinical microbiology laboratories.

Central and Peripheral Nervous System Effects

Encephalopathy and peripheral neuropathy: Cases of encephalopathy and 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 MRI have been described in reports of encephalopathy. CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible.

Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity.

Convulsive seizures have been reported in patients treated with metronidazole.

Aseptic meningitis: Cases of aseptic meningitis have been reported with metronidazole. Symptoms can occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued.

The appearance of abnormal neurologic signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy (see ADVERSE REACTIONS).

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 Metronidazole Capsules 375 mg.

Single oral doses of metronidazole, up to 15 g, have been reported in suicide attempts and accidental overdoses. Symptoms reported include nausea, vomiting, and ataxia.

Oral metronidazole has been studied as a radiation sensitizer in the treatment of malignant tumors. Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 to 7 days of doses of 6 to 10.4 g every other day.

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

Metronidazole Capsules USP 375 mg have an opaque grey / opaque yellow size ‘1’ hard gelatin capsules, linearly imprinted with ‘HP66’ on body and ‘HP66’ on cap in black ink, filled with off-white to yellowish white powder.

NDC Number                           Size

62332-018-30                                    Bottle of 30
62332-018-50                                    Bottle of 50
62332-018-31                                    Bottle of 100
62332-018-71                                    Bottle of 500
62332-018-91                                    Bottle of 1000

Storage and Stability:Store at 20° - 25°C (68° - 77°F).  [See USP Controlled Room Temperature]. Dispense in a well-closed, child resistant container.

Call your doctor for medical advice about side effects. You may report side effects to Alembic Pharmaceuticals Limited at 1-866 210 9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch