metronidazole 0.75% cream generic metrocream, rosadan

Uses

Rosacea

Metronidazole is used topically for the treatment of inflammatory lesions (papules and pustules) associated with rosacea (acne rosacea). Topical metronidazole has been designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this condition. Although periods of remission may be induced, metronidazole, like other currently available therapies, appears to be only palliative in the treatment of rosacea and does not appear to alter the underlying disease process; when the drug is withdrawn, manifestations appear to recur commonly. In addition, chronic therapy (usually intermittent) may be necessary, particularly for moderate to severe disease.

Rosacea is a chronic, progressive, dermatologic syndrome of unknown etiology generally characterized by recurrent inflammatory papules and pustules on the face, facial flushing, erythema, and telangiectasia. Ocular manifestations such as blepharitis, conjunctivitis, keratitis, and corneal scarring also may be present; in some patients (usually males), rhinophyma also may develop (secondary to soft tissue hypertrophy of the nose). Optimum treatment of rosacea has not been determined, although the inflammatory lesions may respond to long-term therapy with oral anti-infective agents (e.g., doxycycline, tetracycline, erythromycin, ampicillin, metronidazole) or topical anti-infective agents (e.g., metronidazole). In addition to anti-infective therapy, adjunctive measures often are recommended to decrease exposure to factors that may provoke the inflammatory and vascular manifestations of rosacea (e.g., excessive sunlight, wind, hot liquids, spicy food, alcohol, extremes of heat and cold). Other agents (e.g., isotretinoin for severe recalcitrant rosacea, sulfur) also have been used with some success.

In a placebo-controlled clinical study in adults with moderate rosacea, once-daily application of metronidazole 1% topical gel or vehicle alone resulted in a 50.7 or 32.6% reduction in the number of inflammatory lesions at 10 weeks of therapy, respectively; 38.42 or 27.51% of patients, respectively, met the criteria of clear or almost clear on the Investigator Global Assessment Scale at week 10.

In clinical studies in adults with rosacea, therapy with metronidazole 1% topical cream, metronidazole 0.75% topical lotion, or metronidazole 0.75% topical gel (no longer commercially available in the US) resulted in clinical improvement in inflammatory lesions in 68-96% of patients based on objective clinical assessment and photographic evaluation. A controlled study using metronidazole 1% topical cream indicates that topical metronidazole therapy is as effective as oral tetracycline (250 mg twice daily) in reducing the number of inflammatory lesions and improving erythema associated with rosacea. In 2 placebo-controlled clinical studies in adults with rosacea (excluding patients with nodules, moderate or severe rhinophyma, dense telangiectases, plaque-like facial edema, ocular involvement, or those whose infection did not respond to previous metronidazole therapy), once-daily application of metronidazole 1% topical cream or vehicle alone resulted in a 49-58 or 17-30% reduction in number of papules and pustules at 10 weeks of therapy, respectively; the erythema severity scores were reduced by 40-42 or 19-25% at 10 weeks of therapy, respectively, in patients receiving the cream or vehicle alone. Topical metronidazole has been effective in patients whose rosacea failed to respond adequately to, or relapsed with, other therapies (e.g., tetracycline).

In a controlled study in adults with moderate to severe rosacea, twice-daily application of metronidazole 0.75% topical lotion or vehicle alone for 12 weeks resulted in definite improvement in 32 or 15%, marked improvement in 32 or 20%, and clearing of lesions in 8 or 0% of patients, respectively, based on investigator's global assessment of improvement. There was worsening of rosacea in 5 or 15%, no change in 12 or 27%, and minimal improvement in 11 or 23% of patients, respectively, applying metronidazole lotion or vehicle alone. Treatment with metronidazole lotion or the vehicle alone resulted in a mean 55 or 20% reduction, respectively, in the number of inflammatory papules and pustules at 12 weeks of therapy.

Relapse rates 3-6 months after discontinuance of 2 or 4 months of daily therapy with metronidazole 1% cream were about 50 or 25%, respectively, in a study in a limited number of patients with varying degrees of severity of rosacea. Further study is needed to determine the rate of relapse after therapy with metronidazole 0.75% topical lotion. Topical metronidazole therapy has no effect on telangiectasia, rhinophyma, or ocular manifestations of rosacea.

Oral metronidazole also has been used with some success in the treatment of rosacea and has decreased total numbers of inflammatory lesions associated with the disease. However, long-term therapy generally is required to control the inflammatory lesions of rosacea, and use of oral metronidazole in the disease has been limited by concerns over adverse systemic effects and toxicity of the drug. There are no studies to date comparing efficacy and safety of topical and oral metronidazole therapy in the treatment of rosacea.

Bacterial Vaginosis

Metronidazole is used intravaginally (e.g., as a vaginal gel) or orally, administered as immediate-release tablets or as extended-release tablets, for the treatment of bacterial vaginosis (formerly called Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, Corynebacterium vaginitis, or anaerobic vaginosis).

Bacterial vaginosis is a noninflammatory vaginal syndrome characterized by replacement of the normal vaginal flora (predominantly hydrogen peroxide-producing Lactobacillus) with a mixed flora including Gardnerella vaginalis, anaerobes (e.g., Bacteroides ureolyticus, Prevotella, Porphyromonas, Peptostreptococcus, Mobiluncus), and Mycoplasma hominis; vaginal discharge may be an unreliable indicator of infection since many women are asymptomatic. While Gardnerella previously was thought to be the sole causative agent of this syndrome, it currently is thought that bacterial vaginosis is a polymicrobial condition in which Gardnerella acts synergistically with anaerobic bacteria and genital mycoplasmas. Clinical diagnosis of the syndrome generally is established by characteristic vaginal manifestations rather than bacteriologic determinations. The presence of at least 3 of the following manifestations is considered diagnostic for bacterial vaginosis: a nonirritating, odoriferous, thin, homogeneous, grayish-white, noninflammatory vaginal discharge that smoothly coats the vaginal walls; a vaginal pH exceeding 4.5; the elaboration of malodorous amines (''fishy'' odor) from discharge fluid after alkalinization with potassium hydroxide 10% (''whiff test''); and/or microscopic smears containing small coccobacillary organisms adherent to epithelial cells (''clue cells''). The presence of clue cells on wet mount examination of vaginal secretions is one of the most reliable indicators of bacterial vaginosis.

Gram stain results consistent with a diagnosis of bacterial vaginosis include markedly reduced or absent Lactobacillus morphology and predominance of Gardnerella morphotype. Although Gram stain of vaginal secretions also has been employed as a diagnostic test for bacterial vaginosis, accuracy of this method depends on evaluation by an experienced microbiologist; thus, this technique is used more often in research and hospital settings whereas diagnosis by clinical criteria typically is performed in an office setting.Gardnerella can be isolated from vaginal cultures in a large proportion of healthy women; because of this lack of specificity, culture for the organism is not recommended as a diagnostic method for bacterial vaginosis, and it is not used to guide therapy. The possibility of other pathogens commonly associated with vulvovaginitis or cervicitis (e.g., Trichomonas vaginalis, Chlamydia trachomatis, Neisseria gonorrhoeae, Candida albicans, herpes simplex viruses) generally should be ruled out, particularly since coinfection with these organisms may occur.

Goals of treatment and recommended therapy for bacterial vaginosis differ for nonpregnant versus pregnant women. However, relief of signs and symptoms of infection is a principal goal of therapy, and all women with symptomatic bacterial vaginosis should be treated regardless of pregnancy status.

Nonpregnant Women

The principal goal in the treatment of bacterial vaginosis in nonpregnant women is to provide relief of vaginal manifestations and signs of infection. Other potential benefits include a reduction in other infectious complications (e.g., human immunodeficiency virus [HIV] infection) or other sexually transmitted diseases.

The US Centers for Disease Control and Prevention (CDC) states that treatment of bacterial vaginosis is indicated in all nonpregnant women who are symptomatic. The regimens recommended by the CDC for the treatment of bacterial vaginosis in nonpregnant women are a 7-day regimen of oral metronidazole (500 mg twice daily), a 5-day regimen of intravaginal metronidazole gel, or a 7-day regimen of intravaginal clindamycin cream. Alternative regimens recommended by the CDC for these women are a 7-day regimen of oral clindamycin or a 3-day regimen of intravaginal clindamycin suppositories.

Intravaginal metronidazole therapy results in clinical cure rates comparable to those reported with a 7-day oral metronidazole regimen; intravaginal clindamycin cream appears to be less effective than the metronidazole regimens. Regardless of the therapy chosen, relapse or recurrence of bacterial vaginosis is common, and some clinicians suggest that an alternative regimen (e.g., oral therapy when intravaginal therapy was used initially) can be employed in such infections.

Results of controlled studies indicate that metronidazole vaginal gel is more effective than placebo for the treatment of bacterial vaginosis. Patients with bacterial vaginosis who were treated with 5 g of metronidazole 0.75% vaginal gel (approximately 37.5 mg of the drug) twice daily for 5 days had clinical cure rates of 78-87% at the first follow-up visit (1-3 weeks after completion of treatment); microbiologic response to therapy paralleled clinical response. In a randomized, single-blind, comparative study in nonpregnant patients with bacterial vaginosis, clinical cure rates at 4 weeks following completion of therapy were 53 or 57% in patients receiving 5-day therapy with metronidazole vaginal gel once or twice daily, respectively. In one placebo-controlled study with a limited number of patients, the recurrence rate (15%) with metronidazole vaginal gel 1 month after treatment was comparable to that reported for oral metronidazole. In a randomized controlled trial, similar cure rates were obtained with intravaginal metronidazole (75%), oral metronidazole (84%), or intravaginal clindamycin (86%) at 7-14 days following completion of therapy; interpretation of these results is limited by the statistical limitations of this study (i.e., small sample size, inadequate power, short-term follow-up). Long-term follow-up of patients suggests high recurrence rates for bacterial vaginosis regardless of initial therapy.

Pregnant Women

An increased risk of obstetric complications, including intraamniotic infection, chorioamnionitis, premature rupture of membranes, preterm delivery, and low-birthweight infants, is associated with the presence of bacterial vaginosis in pregnant women, and the organisms found in increased concentrations in the genital flora of women with bacterial vaginosis are frequently found in patients with postpartum or postcesarean endometritis. Evidence from randomized, controlled trials indicates that systemic treatment of bacterial vaginosis reduces the rate of preterm birth in pregnant women at high risk for complications of pregnancy.

Because of an increased risk of adverse pregnancy outcomes associated with the presence of bacterial vaginosis, the CDC recommends that all symptomatic pregnant women be tested and treated for bacterial vaginosis. In addition, because there is evidence from randomized studies that treatment of bacterial vaginosis in asymptomatic pregnant women at high risk for complications of pregnancy (e.g., those who previously delivered a premature infant) has reduced preterm delivery, some experts recommend that all women at high risk be screened and treated for bacterial vaginosis. The CDC recommends that screening for bacterial vaginosis (if conducted) should be performed at the first prenatal visit and treatment initiated if needed. for a complete discussion of screening and treatment for bacterial vaginosis in pregnant women.)

The preferred regimens for the treatment of symptomatic bacterial vaginosis in pregnant women and for the treatment of asymptomatic women at high risk for complications of pregnancy are a 7-day regimen of oral metronidazole (500 mg twice daily or 250 mg 3 times daily) or a 7-day regimen of oral clindamycin (300 mg twice daily). Although some experts state that intravaginal therapy may be used solely for symptomatic relief (and not for prevention of adverse pregnancy outcomes) in women at low risk for preterm delivery, other experts prefer use of systemic therapy for all pregnant women, regardless of degree of risk for complications of pregnancy, because systemic treatment may be required to eradicate upper genital tract infection that may be associated with bacterial vaginosis. No adequate and controlled studies have been performed to date to establish the safety and efficacy of intravaginal metronidazole for the treatment of bacterial vaginosis in pregnant women.(See Cautions: Pregnancy, Fertility, and Lactation.) Because recurrence of bacterial vaginosis is not unusual, and the treatment of this condition may prevent adverse pregnancy outcomes, particularly in women at high risk for complications of pregnancy, follow-up at 1 month to assess for cure and evaluate the need for additional treatment should be considered.

Women Undergoing Gynecologic Procedures and Surgery

The goal of treatment of symptomatic bacterial vaginosis in women undergoing hysterectomy or abortion is to reduce the risk of infectious complications (e.g., pelvic inflammatory disease [PID]) following these procedures.

Treatment of asymptomatic bacterial vaginosis in patients who are about to undergo an invasive gynecologic procedure (e.g., endometrial biopsy, hysteroscopy, hysterosalpingography, hysterectomy, placement of an intrauterine device, uterine curettage), abortion, vaginal surgery, or abdominal surgery may be a reasonable consideration because of the association between this condition and various gynecologic infections (e.g., endometritis, PID, vaginal cuff cellulitis). While a reduction in postoperative pelvic inflammatory disease in women with bacterial vaginosis undergoing first-trimester elective abortion has been established in at least one study employing oral metronidazole, further study is needed to determine the value of treating asymptomatic bacterial vaginosis in patients who are about to undergo other invasive procedures.

HIV-infected Women

Recommendations for treatment and preferred regimens for treatment of bacterial vaginosis in patients with concurrent human immunodeficiency virus (HIV) infection are the same as those for patients without HIV infection.

Sexual Contacts

Results of several randomized, double-blind, placebo-controlled trials indicate that concurrent treatment of male sexual contacts of a woman with symptomatic bacterial vaginosis generally does not affect the clinical cure rate, including the risk of relapse or recurrence of the syndrome, in the woman. Therefore, routine treatment of male sexual contacts currently is not recommended. However, despite the lack of controlled studies showing any benefit, some clinicians believe that treatment of male sexual contacts (with similar oral dosages) of women who have relapsing or recurrent bacterial vaginosis may be reasonable. Further study is needed to elucidate the possible role, if any, of sexual transmission in bacterial vaginosis.

Decubitus and Other Ulcers

Metronidazole has been used topically as a 0.75% gel (no longer commercially available in the US) or a 1% aqueous solution or suspension (not commercially available in the US) for the treatment of infected decubitus ulcers, and has been designated an orphan drug by the FDA for use in the treatment of grade III or IV, anaerobically infected, decubitus ulcers. Metronidazole also has been used with some success in a limited number of patients for the topical treatment of infected ulcers of the feet associated with diabetes mellitus, ulcers associated with varicose veins, and postirradiation ulcers. In several uncontrolled studies in nonambulatory geriatric patients, a 1% aqueous solution or suspension of metronidazole applied topically to infected decubitus ulcers 3 times daily resulted in clinically apparent improvement, including decreased odor and drainage, clearing of surrounding cellulitis, and development of clean granulation within 48-72 hours. Topical administration of metronidazole gel to malodorous decubitus ulcers has decreased or eliminated odor. The drug also has been used orally for the treatment of infected decubitus ulcers and of malodorous (presumably anaerobically infected) ulcers associated with breast tumors.

Dental Conditions

Metronidazole has been used topically with some success in the treatment of dry socket (alveolar osteitis) after routine dental extraction. In one placebo-controlled study in patients with a painful tooth socket (alveolalgia) following recent tooth extraction and partial or total loss of the blood clot, a dressing containing metronidazole 10% in a carboxymethylcellulose gelatin vehicle (Orabase) applied to affected sockets appeared to decrease pain and shorten the treatment period when compared with the vehicle alone. Metronidazole also has been used topically as a 25% gel (not commercially available in the US) as an adjunct to conventional mechanical therapy in the treatment of periodontitis, but such topical anti-infective therapy may not provide any substantial clinical benefit compared with use of mechanical therapy alone. However, there is some evidence that adjunctive use of oral metronidazole alone or in conjunction with oral amoxicillin in patients with periodontitis may result in better clinical and microbiologic results than use of mechanical therapy alone.

Trichomoniasis

Intravaginal metronidazole is unlikely to achieve therapeutic concentrations in the urethra and perivaginal glands and therefore is considerably less effective than oral metronidazole for the treatment of trichomoniasis caused by Trichomonas vaginalis.T. vaginalis infection usually extends beyond the vagina (e.g., to the urethra, cervical glands, and/or Skene's and Bartholin's glands) and systemic therapy is necessary. In a study comparing intravaginal metronidazole 0.75% gel twice daily for 7 days with oral metronidazole 250 mg 3 times daily for 7 days, microbiologic cure occurred in only 44% of women treated intravaginally versus in 100% of women treated orally. The CDC and other clinicians currently recommend oral metronidazole or oral tinidazole as the treatment of choice for trichomoniasis.

While intravaginal metronidazole has been used as an adjunct to oral metronidazole for the treatment of trichomoniasis in selected cases, substantial evidence that such concurrent therapy is superior to oral therapy alone is lacking. There is limited anecdotal evidence that adjunctive intravaginal metronidazole therapy combined with extended and/or high-dose oral therapy (with or without acetic acid vaginal douches) may be useful in treating certain intractable cases of trichomoniasis; however, the preparations of metronidazole used intravaginally in these studies (i.e., 500-mg suppositories [not commercially available in the US], 1-g extemporaneously prepared suppositories, 250- or 500-mg intravaginally inserted oral tablets) contained the drug in concentrations substantially higher than that in the currently available vaginal gel (i.e., 37.5 mg of drug per dose). Therefore, while some clinicians have suggested that metronidazole 0.75% vaginal gel may be useful as an adjunct to oral metronidazole in refractory cases of trichomoniasis, the role, if any, of the commercially available gel in the treatment of this infection remains to be established.

Other Uses

Metronidazole topical cream or gel has been used for the treatment of perioral dermatitis, and the gel has been designated an orphan drug by the US Food and Drug Administration (FDA) for the treatment of this condition.

Dosage and Administration

Administration

Metronidazole is applied topically to the skin or intravaginally in appropriate formulations.

Topical Administration

Metronidazole is applied topically to the skin as a 0.75 or 1% cream, 1% gel, or 0.75% lotion. The drug also has been applied topically to the skin as a 1% aqueous solution or suspension (not commercially available in the US).

Metronidazole topical preparations are for external use only and should not be used orally or intravaginally and contact with the eyes should be avoided.

Prior to application of metronidazole 1% topical gel, 0.75 or 1% topical cream, or 0.75% lotion, affected areas should be washed with a mild, nonirritating cleanser. A thin film of the drug should then be applied; the gel or cream should be rubbed into the affected areas. To minimize the risk of local irritation, some clinicians suggest that application of the drug be delayed for about 15-20 minutes after cleansing the skin. Cosmetics may be applied to the skin after application of metronidazole 1% topical gel, 0.75 or 1% topical cream, or 0.75% topical lotion; the lotion should be allowed to dry for at least 5 minutes before applying cosmetics. A moisturizer also can be used if the skin is dry.

Intravaginal Administration

Metronidazole is administered intravaginally as an intravaginal gel containing 0.75% of the drug. Patients should be instructed in the use of the vaginal applicator. Metronidazole also has been administered intravaginally as a vaginal cream, suppository, sponge, or tablet, but such preparations currently are not commercially available in the US.

Metronidazole vaginal preparations are for intravaginal administration only and should not be used orally, topically on the skin, or near or in the eyes.

Dosage

Rosacea

For the treatment of inflammatory lesions (papules and pustules) and erythema of rosacea, a thin film of metronidazole 0.75% cream or 0.75% lotion should be applied and rubbed into the cleansed, affected areas twice daily, in the morning and evening. Alternatively, metronidazole 1% topical cream or 1% topical gel should be applied and rubbed in the cleansed, affected area once daily.

Clinical improvement usually occurs within 3 weeks. Once an adequate response is obtained, the frequency and duration of therapy should be adjusted according to the course of the disease. Although periods of remission may be induced, the optimum duration of topical metronidazole therapy has not been established, and relapse appears to occur commonly following discontinuance of the drug. In clinical studies, topical metronidazole therapy for rosacea has been continued for up to at least 21 weeks.

Bacterial Vaginosis

For the treatment of bacterial vaginosis in nonpregnant women, one applicatorful (approximately 5 g) of metronidazole 0.75% vaginal gel (approximately 37.5 mg of the drug) is administered intravaginally once (at bedtime) or twice daily (in the morning and in the evening), for 5 consecutive days.

No adequate and controlled studies have been performed to date to establish the safety and efficacy of intravaginal metronidazole for the treatment of bacterial vaginosis in pregnant women and intravaginal metronidazole is not included in current CDC recommendations for the treatment of bacterial vaginosis in pregnant women.(See Uses: Bacterial Vaginosis.)

Decubitus Ulcers

For the treatment of infected decubitus ulcers, metronidazole 0.75% topical gel (no longer commercially available in the US) has been applied to the ulcers. Alternatively, a 1% aqueous solution or suspension of metronidazole has been prepared extemporaneously from crushed metronidazole tablets, sterilized, and applied 3 times daily.

Dosage in Hepatic Impairment

Patients with severe hepatic disease metabolize metronidazole slowly, which can result in the accumulation of the drug and its metabolites in plasma. Therefore, the manufacturers recommend that metronidazole vaginal gel be used with caution in patients with severe hepatic disease.

Cautions

Adverse Effects

Topical Preparations

Local Effects

Topically applied metronidazole appears to have a low order of toxicity and generally is well tolerated.

The principal adverse effects of topical metronidazole preparations are local reactions, including transient redness and mild dryness, pruritus, aggravated rosacea or acne, burning, irritation, and stinging, which have occurred in less than 3% of patients. Topical metronidazole preparations have caused watery or tearing eyes when applied too close to the eyes, and conjunctivitis (associated with topical use of metronidazole on the face) has been reported.

Assessment of local reactions to topical metronidazole may be difficult in patients with rosacea since the disease is an inflammatory disorder characterized by facial papules, pustules, erythema, edema, pruritus, burning, and stinging.

Contact dermatitis has not been reported to date in patients receiving metronidazole 0.75% topical gel (no longer commercially available in the US) or the gel vehicle alone, and dermatotoxicity studies in rabbits and adults have not revealed evidence of local irritation, contact sensitization, phototoxicity, or photoallergic dermatitis with either metronidazole 0.75% topical gel or the gel vehicle alone. In one study, no contact or photocontact sensitization or phototoxicity was reported in individuals receiving metronidazole 1% cream. Slight irritant reactions have occurred when patch tests were done in adults with rosacea using metronidazole 1% cream, but it was unclear whether these reactions were caused by the drug or the vehicle. In a controlled study in adults with rosacea, contact dermatitis occurred in 3 or 1%, local allergic reaction in 3 or 0%, and erythema in 6 or 0%, of patients using metronidazole 0.75% topical lotion or the lotion vehicle alone, respectively.

Systemic Effects

Topically applied metronidazole does not have an appreciable effect on the microflora of the skin or feces of patients with rosacea. In one study in adults with rosacea who received topical metronidazole 1% cream twice daily for 30 days, there were no substantial alterations in aerobic or anaerobic skin or fecal microflora during or after treatment with the drug.

Since only minimal amounts of topical metronidazole preparations are absorbed systematically following application to the skin, abnormal hematologic, renal, or hepatic function test results have not been reported with the use of topical metronidazole preparations. However, other adverse systemic effects, including metallic taste, nausea, paresthesia, and tingling or numbness of the extremities, have been reported in patients receiving topical preparations of metronidazole.

Intravaginal Preparations

Intravaginally applied metronidazole generally is well tolerated. Adverse effects occurred in about 39% of nonpregnant patients receiving metronidazole vaginal gel during clinical trials; discontinuance (occasionally because of abdominal/pelvic cramps, loose stools, or mild vaginal burning) of the drug because of adverse effects was required in about 0.4-1% of patients. These symptoms resolved following discontinuance of the drug. Incidence of adverse effects was similar in patients receiving metronidazole vaginal gel once or twice daily. While systemically achieved concentrations of the drug generally are low at usual intravaginal dosages, this route of administration is not devoid of adverse systemic effects.

Local and Genitourinary Effects

The most common adverse effects of therapy with metronidazole vaginal gel are vaginal discharge, symptomatic Candida cervicitis/vaginitis, and vulvovaginal irritation occurring in 12, 10, and 9% of patients receiving the drug, respectively.

Known or previously unrecognized vaginal candidiasis may become prominently symptomatic during therapy with metronidazole vaginal gel. However, metronidazole is inactive against most lactobacilli normally resident in the vagina, even at the high concentrations achieved with local application, and in vitro data suggest that intravaginal application of metronidazole at usual concentrations may be less likely than intravaginal application of clindamycin to disrupt this flora. Limited evidence from a comparative study suggests that similar rates of vulvovaginal candidiasis occur following treatment with intravaginal metronidazole, intravaginal clindamycin, or oral metronidazole; however, further study is needed to establish the relative risk of this effect. Approximately 6-10% of patients have been reported to develop symptomatic candidal vaginitis during or immediately following therapy with metronidazole vaginal gel, although a higher rate of 30% was recorded in one small comparative study. Abdominal or pelvic discomfort/cramps reportedly occur in about 3% and dark urine occurs in less than 1% of patients receiving intravaginal metronidazole therapy with the gel.

Vaginal candidiasis, dyspareunia, decreased libido, proctitis, dysuria, urinary tract infections (cystitis), polyuria, incontinence, dryness of the vagina or vulva, dark urine, and pelvic pressure have been reported in patients receiving oral or parenteral metronidazole.

GI Effects

GI effects including GI discomfort, nausea/vomiting, and unusual taste have been reported in 7, 4, and 2% of patients receiving metronidazole vaginal gel. Diarrhea/loose stools and decreased appetite occurred in 1% of patients while abdominal bloating/gas, thirst, and dry mouth were reported in less than 1% of patients receiving intravaginal metronidazole as the gel.

Abdominal discomfort/cramping, nausea, vomiting, diarrhea, unpleasant metallic taste, anorexia, epigastric distress, constipation, furry tongue, dry mouth, glossitis, stomatitis, pancreatitis, and changes in taste perception of alcoholic beverages have been reported in patients receiving oral or parenteral metronidazole.

Nervous System Effects

Headache and dizziness have been reported in 5 and 2% of patients receiving metronidazole vaginal gel, respectively, while depression and fatigue occurred in less than 1% of patients.

Headache, dizziness, syncope, ataxia, confusion, seizures, peripheral neuropathy, vertigo, incoordination, irritability, depression, weakness, and insomnia have been reported in patients receiving oral or parenteral metronidazole.

Dermatologic and Sensitivity Reactions

Generalized pruritus or rash occurred in less than 1% of patients receiving metronidazole vaginal gel.

Hypersensitivity reactions including urticaria, pruritus, erythematous rash, flushing, nasal congestion, fever, and fleeting joint pains have been reported in patients receiving oral or parenteral metronidazole.

Other Adverse Effects

Leukopenia or leukocytosis has been reported in about 1.7% of patients receiving metronidazole vaginal gel while unspecified cramping occurred in 1% of patients receiving metronidazole intravaginally as the gel.

Flattening of the T-wave has been reported rarely in ECG tracings of patients receiving oral or parenteral metronidazole. Reversible neutropenia and reversible thrombocytopenia have been reported in patients receiving oral or parenteral metronidazole.

The possibility that other adverse effects associated with topical (e.g., local irritation, transient local erythema, local dryness and burning) or systemic metronidazole therapy could occur with intravaginal therapy should be considered.

Precautions and Contraindications

Patients receiving metronidazole 0.75 or 1% topical cream, 1% topical gel, or 0.75% topical lotion should be instructed to use the drug only as directed by their physician and only for the disorder for which it was prescribed. Commercially available topical metronidazole preparations are for external use only. Because the topical preparations have caused ocular irritation, contact with the eyes should be avoided. If a reaction suggesting local irritation occurs, patients should be directed to use topical metronidazole preparations less frequently or discontinue use. Patients should be advised to report any adverse effects to their clinician.

Although adverse hematologic effects have not been reported to date with topical metronidazole, the manufacturers state that the drug is a nitroimidazole and should be used with caution in patients with evidence or history of blood dyscrasia.

Patients should be instructed to not engage in vaginal intercourse and to refrain from use of other vaginal products (tampons, douches) during the entire course of therapy with metronidazole vaginal gel since vaginal intercourse or vaginal products could reduce the efficacy of the gel (e.g., by dislodgement and/or dilution, by increased vaginal pH secondary to deposition of semen). In addition, although serum metronidazole concentrations are substantially lower with usual intravaginal doses of the 0.75% vaginal gel compared with usual oral doses, patients should be cautioned about the use of alcohol during therapy with metronidazole vaginal gel.(See Drug Interactions: Alcohol.)

Because the vaginal gel may cause ocular burning and irritation, contact with the eyes should be avoided. If such contact occurs, the eyes may be irrigated with copious amounts of cool water.

Convulsive seizures and peripheral neuropathy (characterized by numbness or paresthesia of an extremity) have been reported in patients receiving oral or IV metronidazole. If abnormal neurologic manifestations occur during intravaginal metronidazole therapy, the drug should be discontinued promptly. In addition, the vaginal gel should be used cautiously in patients with a history of CNS disease.

Metronidazole topical or vaginal preparations are contraindicated in patients with known hypersensitivity to metronidazole, other nitroimidazole derivatives, parabens, or any other ingredient in the formulation.

Pediatric Precautions

Safety and efficacy of topical preparations of metronidazole in pediatric patients have not been established.

Safety and efficacy of metronidazole vaginal gel (Vandazole) in postmenarchal females have been established based on extrapolation of clinical trial data from adult women; safety and efficacy of this preparation in premenarchal females have not been established.

Geriatric Precautions

While safety and efficacy of metronidazole 1% topical gel (MetroGel) in geriatric patients have not been established specifically, safety and efficacy of this preparation in the 66 patients 65 years of age or older included in the clinical studies were comparable to the study population.

Clinical studies of metronidazole vaginal gel (Vandazole) did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger patients.

Mutagenicity and Carcinogenicity

Metronidazole has shown mutagenic activity in several in vitro microbial studies, and has caused chromosomal aberrations in mammalian cells cultured with the drug under anaerobic conditions. In addition, dose-response increases in the frequency of micronuclei were observed in mice receiving intraperitoneal administration of metronidazole. There was no evidence of mutagenic effects in in vivo studies using metronidazole in mammals. No excess chromosomal aberrations were observed in circulating human lymphocytes in patients receiving metronidazole therapy for 8 months. However, increases in chromosomal aberrations have been reported in patients with Crohn's disease receiving 200-1200 mg of metronidazole daily for 1-24 months. Oral metronidazole was carcinogenic in mice and rats in chronic studies. In several long-term studies in mice, oral administration of metronidazole at dosages of 225 mg/m daily or more (about 37 times the recommended human topical dosage on a mg/m basis) was associated with increases in the incidence of pulmonary tumors and lymphomas. In other long-term studies, increases in the incidence of pulmonary tumors in male mice and lymphomas in female mice were observed in mice receiving oral metronidazole at dosages of 198 mg/m daily or more (about 29-71 times the recommended human topical dosage on a mg/m basis). In other long-term studies, statistically significant increases in the incidence of hepatic and mammary tumors were observed in rats receiving oral metronidazole at dosages exceeding 885 mg/m daily (about 144 times the recommended human topical dosage). Similar studies in hamsters did not reveal evidence of carcinogenicity. In other studies, the incidence of hepatic and mammary tumors in female rats and the incidence of testicular tumors and pituitary adenomas in male rats was increased in those receiving oral metronidazole at dosages of 1593 mg/m daily or greater (about 230-573 times the recommended human topical dosage on a mg/m basis). In another study, mammary tumors were reported in rats receiving metronidazole by oral gavage at a dosage of 177 mg/m daily (about 26-64 times the human topical dosage on a mg/m basis). In addition, in studies in albino, hairless mice, intraperitoneal administration of metronidazole at dosages of 45 mg/m daily (about 7 times the recommended human topical dosage on a mg/m basis) was associated with increased incidence or enhancement (as demonstrated by a decreased latency period to the development of skin neoplasms) of ultraviolet radiation-induced skin carcinogenesis. However, one manufacturer states that concentration of metronidazole in the skin was not determined, and the study did not differentiate whether metronidazole must be present during ultraviolet radiation exposure to enhance tumor formation or might promote tumor formation from preexisting ultraviolet radiation-initiated cells. Carcinogenicity (including dermal or photocarcinogenicity) studies have not been performed using topical or intravaginal metronidazole. Although there is no evidence to date that long-term use of metronidazole in humans is associated with an increased risk of mutagenicity or carcinogenicity, some clinicians suggest that further studies with longer-term follow-up are necessary before the risks of chronic systemic or topical metronidazole therapy can be fully determined.

Pregnancy, Fertility, and Lactation

Pregnancy

No fetotoxicity was observed in rats or mice receiving oral administration of metronidazole at dosages 200 or 20 times the usual dosage, respectively. In addition, reproduction studies in pregnant mice using oral metronidazole doses about 6 times the maximum recommended human dose (on a mg/m basis) have not revealed evidence of fetotoxicity or teratogenicity; however, intrauterine deaths have occurred following intraperitoneal administration of the drug. The fetal risk, if any, with the use of topical or vaginal metronidazole gel in pregnant women currently is not known. Metronidazole crosses the placenta and is rapidly distributed into fetal circulation. There have been no adequate and controlled studies to date using oral, IV, topical, or intravaginal metronidazole in pregnant women. Because animal reproduction studies are not always predictive of human response and because oral metronidazole has been shown to be carcinogenic in some rodents, topical metronidazole preparations or the vaginal gel should be used in pregnant women only when clearly needed.

Screening and/or treatment for bacterial vaginosis in pregnant women as clinically indicated should be conducted during the first prenatal visit. Although some experts state that intravaginal therapy may be used solely for symptomatic relief (and not for prevention of adverse pregnancy outcomes) in women at low risk for preterm delivery, other experts prefer use of systemic therapy for all pregnant women, regardless of degree of risk for complications of pregnancy, because systemic treatment may be required to eradicate upper genital tract infection that may be associated with bacterial vaginosis. For the treatment of bacterial vaginosis and reduction in the incidence of adverse pregnancy outcomes associated with bacterial vaginosis (e.g., preterm birth), particularly in pregnant women at high risk for complications of pregnancy, a 7-day regimen of oral metronidazole or a 7-day regimen of oral clindamycin is recommended.

Fertility

Reproduction studies in mice using oral metronidazole doses about 6 times the maximum recommended human dose (on a mg/m basis), have not revealed evidence of impaired fertility. Induced inhibition of spermatogenesis and severe testicular degeneration were observed in rats receiving oral metronidazole at a dosage of 1,770 mg/m daily (about 255-637 times the human topical dose on a mg/m basis). Conflicting results (either no effect or a similar effect to that in rats) were reported in 2 strains of mice (ICR and CF1).

Lactation

Following oral administration, metronidazole is distributed into milk in concentrations similar to those attained in plasma. Although plasma concentrations of metronidazole following topical or intravaginal administration are lower than those achieved after oral administration of the drug, it is not known whether metronidazole distributes into milk following topical or intravaginal application. Therefore, because oral metronidazole has been shown to be carcinogenic in some rodents, a decision should be made whether to discontinue nursing or topical or intravaginal metronidazole, taking into account the importance of the drug to the woman.

Drug Interactions

Because metronidazole can be absorbed systemically following intravaginal application (see Pharmacokinetics: Absorption), the possibility that drug interactions could occur with this route of administration should be considered. Small amounts of metronidazole may be absorbed systemically following topical application to the skin (see Pharmacokinetics: Absorption), but the likelihood of systemic interactions following topical administration of the drug is less than with oral or parenteral administration. For additional information on potential interactions with the drug, .

Coumarin Anticoagulants

Systemic metronidazole potentiates the effects of oral anticoagulants resulting in prolongation of the prothrombin time. While only small amounts of metronidazole are absorbed from topical preparations through the skin or mucous membranes during topical or intravaginal therapy at usual dosages, the possibility that anticoagulant effects may be potentiated should be considered when topical or intravaginal metronidazole is used in patients receiving oral anticoagulant therapy.

Alcohol

Disulfiram-like reactions have occurred in some patients who ingested alcohol while receiving oral or IV metronidazole. A disulfiram-like reaction also has occurred in at least one patient who ingested alcohol while receiving intravaginal metronidazole. Although serum metronidazole concentrations are substantially lower with usual intravaginal doses of the 0.75% vaginal gel compared with usual oral doses, the possibility of an interaction with alcohol exists during intravaginal metronidazole therapy. Patients should be cautioned about the use of alcohol during therapy with the vaginal gel.

These reactions have not been reported to date in patients receiving topical application of metronidazole to the skin.

Disulfiram

Administration of disulfiram and oral metronidazole has been associated with acute psychoses in some patients; therefore, the drugs should not be used concomitantly. The manufacturers recommend that 2 weeks elapse following discontinuance of disulfiram prior to initiating therapy with metronidazole vaginal gel.

Lithium

Initiation of short-term metronidazole therapy in patients stabilized on a relatively high dosages of lithium has been reported to increase serum lithium concentrations resulting in signs of lithium toxicity in several patients.

Cimetidine

Concomitant use of cimetidine with oral or IV metronidazole may prolong the plasma half-life and decrease the plasma clearance of metronidazole. In a study in healthy individuals, pretreatment with cimetidine reportedly increased the plasma half-life and decreased total plasma clearance of metronidazole following a single IV dose of the anti-infective, possibly by inhibiting hepatic metabolism of metronidazole.

Pharmacokinetics

Absorption

Topical Administration

Only small amounts of metronidazole are absorbed systemically following topical application to the skin; the extent of absorption varies depending on the topical formulation used.

In adults with rosacea who received once-daily application to the face of metronidazole 1% topical cream in doses averaging 3.75 mg (range: 2.2-6.8 mg) for 1 month, serum concentrations of the drug ranged from undetectable to 45 ng/mL; traces of the drug were detectable in the serum of 20% of patients. In another study, following topical application of 1 g of metronidazole 1% topical cream in a limited number of healthy individuals, the drug was detectable in serum of about 44% of patients; mean serum metronidazole concentrations ranged from 20.3-34.9 ng/mL and peak serum concentrations were achieved within 8-12 hours after topical application of the cream.

Following topical application of 1 g of metronidazole 0.75% lotion (7.5 mg of metronidazole) to the face of healthy individuals, the peak plasma concentration was 96 ng/mL and was about 80 times lower than peak plasma concentrations attained following oral administration of a single 250-mg dose of the drug; the drug was detectable in the plasma of all individuals.

In in vitro studies using human skin and hydroalcoholic solutions containing approximately 3.1 mg of metronidazole per mL with propylene glycol, approximately 3-10% of the metronidazole dose is absorbed within 20 hours. Hydration of the skin by occlusion appears to increase percutaneous absorption of metronidazole following topical application of the drug in a hydroalcoholic solution containing propylene glycol.

Intravaginal Administration

Metronidazole is absorbed systemically following intravaginal application of the drug as a vaginal gel, cream (not commercially available in the US), tablet (not commercially available in the US), or suppository (not commercially available in the US). The systemic bioavailability of intravaginally administered cream, tablet, or suppository is only about 20-25%; however, that of the commercially available vaginal gel (MetroGel) is increased substantially, averaging about 50-56% in healthy females. Despite the good systemic bioavailability of the vaginal gel, only small concentrations of the drug and its active 2-hydroxy metabolite are achieved systemically following application of usual intravaginal doses (e.g., 37.5 mg) relative to usual oral or parenteral doses (e.g., 500 mg). Following intravaginal administration of 5 g of metronidazole 0.75% vaginal gel (MetroGel; approximately 37.5 mg of the drug) in a limited number of healthy women, peak serum metronidazole concentrations 6-12 hours after administration averaged 237 ng/mL (range: 152-368 ng/mL). Following oral administration of a single 500-mg dose of the drug in these women, peak serum metronidazole concentrations 1-3 hours after administration averaged 12.8 mcg/mL (range: 10-17.4 mcg/mL). Thus, peak serum concentration of metronidazole after a single 37.5-mg intravaginal dose (5-g dose of the 0.75% vaginal gel MetroGel) was approximately 2% of that after a single 500-mg oral dose. Systemic bioavailability (as determined by area under the concentration-time curve [AUC]) of metronidazole after a single 37.5-mg intravaginal dose (5-g dose of the 0.75% vaginal gel) was approximately 4 and 53% of that after single 500- and 37.5-mg oral doses, respectively. Following intravaginal administration of single and multiple doses of 5 g of metronidazole 0.75% vaginal gel (MetroGel; approximately 37.5 mg of the drug) in several women with bacterial vaginosis, peak serum metronidazole concentrations approximately 6-12 hours after administration averaged 214 and 294 ng/mL (range: 228-349 ng/mL) on days 1 and 5 of therapy, respectively.

Distribution

The distribution of metronidazole following topical application to the skin or intravaginal application has not been determined. Metronidazole is less than 20% bound to plasma proteins.

The distribution of metronidazole across the placenta or into milk following topical application to the skin or intravaginal application is not known; however, the drug readily crosses the placenta and is rapidly distributed into fetal circulation, and it is distributed into milk following oral or IV administration.

Elimination

The metabolic fate and elimination of metronidazole following topical application to the skin or intravaginal application have not been determined. Because anaerobic conditions do not exist in dermal cells of healthy individuals or patients with rosacea, it is unlikely that metronidazole is reduced following topical application to the skin. Metronidazole probably is absorbed percutaneously as unchanged drug, and any systemically absorbed drug is metabolized in the liver and excreted in urine.

For information on absorption of oral or IV metronidazole and information on the distribution and elimination of systemically absorbed drug, .