Metronidazole - Metronidazole tablet, Film Coated, Extended Release

Metronidazole has been shown to be carcinogenic in mice and rats (see

). Unnecessary use of the drug should be avoided. Its use should be reserved for conditions described in the section below. 

Metronidazole extended-release 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 metronidazole extended-release tablets and other antibacterial drugs, metronidazole extended-release tablets 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.

Bacterial Vaginosis: 750 mg once daily by mouth for seven consecutive days.

Metronidazole extended-release 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 metronidazole extended-release tablets 750 mg are obtained when the drug is taken under fasting conditions (See

Absorption).

 

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

).

  

In two multicenter clinical trials, a total of 270 patients received 750 mg metronidazole extended-release tablets orally once daily for 7 days, and 287 were treated with a comparator agent administered intravaginally once daily for 7 days (See

^3,4 

Most adverse events were described as being of mild or moderate severity. Among patients taking metronidazole extended-release tablets 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 metronidazole extended-release tablets.

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

                                                                                                        

	Metronidazole Extended-Release Tablets 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 metronidazole extended-release tablets or the vaginal comparator.

The following reactions have been reported during treatment with metronidazole:

The most serious adverse reactions reported in patients treated with metronidazole have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. Since persistent peripheral neuropathy has been reported in some patients receiving prolonged administration of metronidazole, patients should be specifically warned about these reactions and should be told to stop the drug and report immediately to their physicians if any neurologic symptoms occur. In addition, patients have reported headache, syncope, dizziness, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia (See ).

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.

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

Erythematous rash and pruritus.

Reversible neutropenia (leukopenia); rarely, reversible thrombocytopenia.

QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval. Flattening of the T-wave may be seen in electrocardiographic tracings.

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

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.

Cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole, have been reported in patients with Cockayne Syndrome (latency from drug start to signs of liver failure as short as 2 days) ( ).

Proliferation of in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling “serum sickness.” Rare cases of pancreatitis, which generally abated on withdrawal of the drug, have been reported. 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 extended-release 750 mg tablets.

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 (see

).  

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

).

Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. When metronidazole 375 capsules is prescribed for patients on this type of anticoagulant therapy, prothrombin time and INR should be carefully monitored.

In patients stabilized on relatively high doses of lithium, short-term metronidazole therapy has been associated with elevation of serum lithium and, in a few cases, signs of lithium toxicity. Serum lithium and serum creatinine levels should be obtained several days after beginning metronidazole to detect any increase that may precede clinical symptoms of lithium intoxication.

Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Metronidazole should not be administered concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to metronidazole are available, and concomitant administration with busulfan is medically needed, frequent monitoring of busulfan plasma concentration should be performed and the busulfan dose should be adjusted accordingly.

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.

 

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.

QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval.