Nidagel (Metronidazole)

NIDAGEL™

3M Pharmaceuticals

Metronidazole

Antibacterial

Action And Clinical Pharmacology: Metronidazole demonstrates antibacterial activity against bacteria classified as obligate anaerobes including Bacteroides and to a lesser extent against anaerobic gram-positive rods. The nitro group of the drug is thought to be reduced in the target cell leading to the production of cytotoxic metabolites.

Bioavailability studies on the administration of a single 5 g dose of NidaGel into the vaginas of 12 normal subjects showed a mean maximum serum concentration of 237 ng/mL. This is approximately 2% of the mean maximum serum concentration afforded by a single 500 mg tablet of metronidazole taken orally (mean Cmax = 12 785 ng/mL). Therefore, under normal usage levels, the formulation affords minimal serum concentrations of metronidazole.

Indications And Clinical Uses: For the treatment of bacterial vaginosis (formerly called nonspecific vaginitis, G. vaginalis or Haemophilus vaginitis).

A clinical diagnosis of bacterial vaginosis is usually defined by the presence of a homogenous vaginal discharge that: has a pH of greater than 4.5; emits a fishy amine odor when mixed with a 10% KOH solution; contains clue cells on microscopic examination.

Other pathogens commonly associated with vulvovaginitis, e.g., T. vaginalis, C. trachomatis, N. gonorrhoeae, C. albicans and herpes simplex virus should be ruled out.

Use of metronidazole during menses is not recommended.

Contra-Indications: Patients with a prior history of hypersensitivity to metronidazole, parabens, other ingredients of the formulation or other nitroimidazole derivatives.

Pregnancy: Metronidazole is contraindicated during the first trimester of pregnancy (see Precautions).

Manufacturers’ Warnings In Clinical States: Convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been reported in patients treated with oral metronidazole. The appearance of abnormal neurologic signs demands the prompt discontinuation of metronidazole therapy. It should be administered with caution to patients with CNS diseases. Psychotic reactions to oral metronidazole have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently.

Precautions: NidaGel affords minimal serum levels of metronidazole compared to oral metronidazole therapy. Although these lower serum levels are less likely to produce the common reactions seen with oral metronidazole, the possibility of these and other reactions cannot be excluded.

General: Patients with severe hepatic disease metabolize metronidazole slowly, with resultant accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients, metronidazole should be administered cautiously.

Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with metronidazole and requires treatment with a candicidal agent.

No reports of alcohol interaction were received during clinical studies with metronidazole. Despite the relatively low serum levels of metronidazole afforded by NidaGel, the possibility of a disulfiram-like reaction to alcohol while on metronidazole therapy cannot be excluded. Patients should be advised to abstain from alcohol during therapy and for 1 day following therapy.

Hematologic Effects: Metronidazole is a nitroimidazole and should be used with care in patients with evidence of or history of blood dyscrasia. A mild transient leukopenia has been observed during oral metronidazole administration.

In clinical studies with 0.75% metronidazole vaginal gel a mild, clinically insignificant leukopenia was observed in some patients. Relationship to therapy could not be determined.

Drug Interactions: Oral metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other coumarin anticoagulants, resulting in a prolongation of prothrombin time. This possible drug interaction should be considered when metronidazole is prescribed for patients on this type of anticoagulant therapy.

Laboratory Test Interactions : Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), triglycerides and hexokinase glucose. These determinations are based on the decrease in ultraviolet absorbance which occurs when NADH is oxidized to NAD. Metronidazole causes an increase in absorbance at the peak of NADH (340 nm) resulting in falsely decreased values.

Carcinogenicity: Metronidazole has shown evidence of carcinogenic activity following chronic oral administration in mice and rats. Pulmonary tumorigenesis has been reported in mice, and significant increases in the incidence of mammary and hepatic tumors have been found in female rats. Lifetime tumorigenicity studies in hamsters have given negative results.

These studies were conducted with orally administered metronidazole which results in significantly higher systemic blood levels than those obtained after use of 0.75% metronidazole vaginal gel.

Pregnancy: There has been no experience to date with the use of NidaGel in pregnant patients. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. It should not be used during the first trimester of pregnancy. Use of metronidazole for bacterial vaginosis in the second and third trimesters should be restricted to those patients in whom local palliative treatment has been inadequate to control symptoms. No fetotoxicity was observed after oral metronidazole in pregnant rats or mice. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed (see Contraindications).

Lactation: NidaGel blood levels are significantly lower than those achieved with oral metronidazole. After oral administration metronidazole has been shown to be secreted in breast milk in concentrations similar to those found in plasma. If the use of metronidazole is considered to be necessary in nursing mothers, the potential benefits must be weighed against the possible risks to the infant.

Children: Safety and effectiveness in children have not been established.

Adverse Reactions: Based on a multicenter clinical trial involving 505 patients, comparing NidaGel twice-daily dosing to once-daily dosing, adverse event experiences are listed below, in descending order of frequency: vaginal discharge, descriptions of which varied in both color and consistency (12%), yeast infection (9%), vulva/vaginal irritative symptoms (9%), gastrointestinal discomfort which included patient descriptions of abdominal or stomach cramping, pain and discomfort (7%), headache (5%), nausea and vomiting (4%), pelvic discomfort (3%). The following reactions were seen at a frequency of 2%: unusual taste, dizziness, cramping, undocumented or self-diagnosed yeast infections. The following reactions were seen at a frequency of 1%: decreased appetite, diarrhea/loose stools, fatigue, medication leakage, urinary tract infection symptoms. The following reactions were seen at a frequency of
Other reactions noted with oral metronidazole therapy include anorexia, epigastric distress, nausea, vomiting, furry tongue, dry mouth, metallic taste, transient eosinophilia or neutropenia, convulsive seizures, peripheral neuropathy, vertigo, incoordination, ataxia, confusion, insomnia, flushing, headache, dryness of the vagina, dysuria, darkened urine, modification of taste of alcoholic beverages, rash, pruritus, palpitation and chest pain.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no human experience with overdosage of metronidazole. Massive ingestion may produce vomiting and slight disorientation. There is no specific antidote. Early gastric lavage may remove a large amount of the drug; otherwise, treatment should be symptomatic.

Dosage And Administration: One applicator full (approximately 5 g) of vaginal gel should be inserted into the vagina once daily at bedtime for 5 days, or twice daily at morning and bedtime for 5 days. Controlled studies with alternate dosage schedules have not been conducted. If patients do not respond to initial therapy, it is recommended that appropriate laboratory measures be used to rule out other conditions before retreating with metronidazole.

Pregnancy: Pregnant patients should not be treated during the first trimester of pregnancy (see Contraindications and Precautions).

Use during menses is not recommended.

Availability And Storage: Each g of colorless to straw-colored, slightly hazy gel contains: metronidazole 7.5 mg. Nonmedicinal ingredients: carbomer 934P, edetate disodium, methylparaben, propylene glycol, propylparaben, purified water and sodium hydroxide to adjust the pH to 4. Aluminum tubes of 40 and 70 g, packaged with a 5 g vaginal applicator. Store between 15 and 25°C.

NIDAGEL™ 3M Pharmaceuticals Metronidazole Antibacterial

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