Nuvessa

Drug overview for NUVESSA (metronidazole):

Generic name: METRONIDAZOLE (MET-roe-NID-a-zole)
Drug class: Vaginal Anti-Infectives
Therapeutic class: Vaginal Products

Metronidazole is a synthetic, nitroimidazole-derivative antibacterial and antiprotozoal agent and also has direct anti-inflammatory effects and effects on neutrophil motility, lymphocyte transformation, and some aspects of cell-mediated immunity.

No enhanced Uses information available for this drug.

DRUG IMAGES

NUVESSA VAGINAL 1.3% GEL

The following indications for NUVESSA (metronidazole) have been approved by the FDA:

Indications:
Bacterial vaginosis

Professional Synonyms:
Bacterial vaginitis

Dosing information for NUVESSA
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
NUVESSA VAGINAL 1.3% GEL	Maintenance	Adults insert 1 applicatorful (65 mg) by vaginal route once at bedtime

Generic dosing information for METRONIDAZOLE
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
METRONIDAZOLE VAGINAL 1.3% GEL	Maintenance	Adults insert 1 applicatorful (65 mg) by vaginal route once at bedtime

The following drug interaction information is available for NUVESSA (metronidazole):

Contraindicated
Severe
Moderate

There are 3 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Selected Nitroimidazole Antimicrobials/Disulfiram SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Since disulfiram has been associated with psychotic behavior in some patients, this interaction has been attributed to a combined toxicity with metronidazole or benznidazole.(1) CLINICAL EFFECTS: May observe psychotic reactions of confusional states. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturers of benznidazole,(2) fexinidazole,(3) metronidazole,(4) and tinidazole(5) state that these agents should not be administered to patients who have received disulfiram in the previous two weeks. DISCUSSION: In a study in hospitalized alcoholics, six of 29 patients receiving concurrent disulfiram and metronidazole developed acute psychosis or confusion. Of these six, five had paranoid delusions and three experienced visual and auditory hallucinations. These reactions were not reported in any of the 29 patients who received placebo with disulfiram.(6,7) An increased central effect of ethyl alcohol was observed in a single patient during concurrent disulfiram and metronidazole.(8) Psychotic symptoms were reported during concurrent use in another case report.(9)	DISULFIRAM
Live Typhoid Vaccine/Antimicrobials SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: The antimicrobial may be active against the organism in the live-vaccine. Antimicrobial therapy may prevent the vaccine organism from replicating enough to trigger an immune response.(1) CLINICAL EFFECTS: Vaccination may be ineffective. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Do not give oral typhoid vaccine until 72 hours after the last dose of antimicrobial. If possible, to optimize vaccine effectiveness, do not start antibacterial drugs for 72 hours after the last dose of oral typhoid vaccine. A longer interval should be considered for long-acting antimicrobials, such as azithromycin.(3) DISCUSSION: Because antimicrobial therapy may prevent sufficient vaccine-organism replication to generate an immune response, the manufacturer of live-attenuated typhoid vaccine and the Centers for Disease Control (CDC) state that the vaccine should not be administered to patients receiving antimicrobial therapy.(1-3)	VIVOTIF
Propylene Glycol/Metronidazole; Tinidazole SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Metronidazole(1) and tinidazole(2) inhibit the alcohol and aldehyde dehydrogenase pathway, which is responsible for the metabolism of propylene glycol.(1,2) CLINICAL EFFECTS: The concurrent administration of metronidazole(1) and tinidazole(2) may result in the accumulation of propylene glycol, which may result in adverse effects such as seizures, stupor, tachycardia, hyperosmolality, lactic acidosis, renal toxicity, and hemolysis. PREDISPOSING FACTORS: Certain ethnic populations (Asians, Eskimos, and Native Americans) and women may have a decreased ability to metabolize propylene glycol.(1,2) PATIENT MANAGEMENT: Patients should be advised of the possible affects that may result from ingestion or application of products that contain propylene glycol while taking metronidazole or tinidazole.(1,2) Patients receiving metronidazole or tinidazole should be instructed to avoid products containing propylene glycol during and for 3 days after taking metronidazole or tinidazole.(1,2) Patients should be informed about unsuspected sources of propylene glycol such as elixirs and topical preparations. Caution is also warranted when using intravenous preparations containing propylene glycol solvents in patients receiving metronidazole or tinidazole. DISCUSSION: Concurrent use of products that contain propylene glycol may cause a disulfiram-like reaction to alcohol when used with metronidazole or tinidazole.	PROPYLENE GLYCOL

There are 4 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
Selected Anticoagulants (Vit K antagonists)/Metronidazole; Tinidazole SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Possible inhibition of anticoagulant metabolism by metronidazole or tinidazole. Metronidazole is a weak CYP2C9 inhibitor and may inhibit the metabolism of the more potent warfarin isomer, S-warfarin.(1) CLINICAL EFFECTS: Concurrent use of anticoagulants with metronidazole or tinidazole may increase the risk for bleeding. PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be most susceptible to this interaction. Patients with a pre-existing CYP2C9 poor metabolizer genotype would be less susceptible to this interaction. However, patients with reduced function genotypes (e.g. CYP2C9 1/3, 2/2, 2/3, and 3/3) have an inherently higher risk for bleeding at usual anticoagulant doses and thus generally require lower doses to achieve effective and safe anticoagulation. In addition, CYP2C9 poor metabolizers may require more time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP2C9 variants. PATIENT MANAGEMENT: INR values should be closely monitored during and for several days after the conclusion of concurrent metronidazole or tinidazole. Anticoagulant dosage may need to be adjusted up to 10 days after concurrent therapy ends. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. DISCUSSION: In two studies, metronidazole significantly enhanced the hypoprothrombinemic effect of warfarin.(2,3) The onset of the interaction occurred within four(2) to ten days(3) and appeared as excessive bruising of the legs. In eight normal subjects, metronidazole significantly increased the half-life of racemic warfarin and the S-enantiomer of warfarin. The R-enantiomer of warfarin, which is metabolized primarily by the reduction of side chains, was unaffected by metronidazole.(4) In an animal study, metronidazole preferentially inhibited the S-enantiomer of warfarin.(5) This interaction should also be considered during concurrent administration and for eight days after concurrent anticoagulants and tinidazole.(6)	ANISINDIONE, DICUMAROL, JANTOVEN, PHENINDIONE, WARFARIN SODIUM
Ethyl Alcohol/Fexinidazole;Metronidazole;Tinidazole SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: In vitro studies show that metronidazole produces an inhibition of aldehyde dehydrogenase and other alcohol-oxidizing enzymes.(1-5) This results in the accumulation of acetaldehyde, which is responsible for the disulfiram-like reaction. A similar process may occur with fexinidazole(6) and tinidazole.(7) CLINICAL EFFECTS: Concurrent use of oral metronidazole with alcohol has been associated with a disulfiram-type reaction resulting in symptoms of hypotension, tachycardia, nausea, sweating, facial flushing, headache, and vomiting.(7-10) It has been suggested that some patients find this combination of agents a pleasant experience, citing giddiness and excitement as rationale for abuse.(11) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patients receiving fexinidazole should be instructed to avoid alcohol during and for at least 48 hours after taking fexinidazole.(6) Patients should be advised of the possible affects that may result from ingestion or application of products that contain alcohol while taking metronidazole. Patients receiving tinidazole should be instructed to avoid alcohol during and for 3 days after taking tinidazole.(7) Patients should be informed about unsuspected sources of alcohol such as elixirs and topical preparations. Caution is also warranted when using intravenous preparations containing alcohol solvents in patients receiving metronidazole or tinidazole. Alcohol is used to improve docetaxel and paclitaxel solubility. - The quantity of alcohol in paclitaxel injection formulations (0.385-0.396 grams/mL) is similar across manufacturers. A paclitaxel 200 mg dose contains approximately 13 grams of alcohol. - The quantity of alcohol in docetaxel formulations varies approximately 3-fold depending upon the manufacturer. FDA data on alcohol content (22): Product Manufacturer Alcohol/200 mg dose Docetaxel Inj. Pfizer 6.4 grams Docetaxel Inj. Sandoz 5.5 grams Docetaxel Inj. Accord 4.0 grams Taxotere-one vial Sanofi 4.0 grams formulation Docetaxel Inj. Hospira 3.7 grams Docefrez Sun Pharma 2.9 grams Taxotere-two vial Sanofi 2.0 grams formulation DISCUSSION: In a case report,(13) a patient developed disulfiram-like reactions after receiving concurrent metronidazole and intravenous sulfamethoxazole-trimethoprim, which is solubilized in a 10% alcohol base. In another case report, a female patient using vaginal inserts containing metronidazole once daily at bedtime ingested two or three drinks containing 30ml of vodka on the fifth day of metronidazole therapy.(14) About a half hour later, the patient inserted the metronidazole vaginal tablet and awoke one hour later with a severe burning sensation in her stomach, a severe headache, and nausea accompanied by a cold sweat. These symptoms resolved in about four hours. Other studies have failed to observe a disulfiram-like reaction between alcohol and metronidazole.(15-21)	ALCOHOL,DEHYDRATED, DILUENT FOR BICNU, DILUENT FOR CARMUSTINE, DILUENT FOR ISTODAX, DILUENT FOR IXEMPRA, DILUENT FOR JEVTANA, DILUENT FOR MELPHALAN, DILUENT FOR ROMIDEPSIN, DILUENT FOR TEMSIROLIMUS
Busulfan/Metronidazole SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The exact mechanism is unknown. CLINICAL EFFECTS: Concurrent use of metronidazole may result in elevated levels of and toxicity from busulfan.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The concurrent use of metronidazole and high-dose busulfan is not recommended.(1) DISCUSSION: A study in stem-cell transplantation recipients examined 3 groups of patients. Group A (n=5) received concurrent metronidazole and busulfan. Group B (n=9) received busulfan alone for 2 days, then concurrent busulfan and metronidazole for 2 days. Group C (n=10) received busulfan without metronidazole. Busulfan levels were 87% higher in Group A compared Group C. In Group B, busulfan levels were 79% higher during metronidazole therapy than during busulfan alone. In Group A, elevated liver transaminases and bilirubin were seen in all patients, 1 patient died of multiorgan failure, 3 developed veno-occlusive disease, and 1 developed hemorrhagic cystitis. In Group B, 6 patients had elevated liver function tests, but there were no reports of veno-occlusive disease.(2)	BUSULFAN, BUSULFEX, MYLERAN
Mebendazole/Metronidazole SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: The exact mechanism is unknown. Both mebendazole and metronidazole have been documented to cause Stevens-Johnson syndrome/toxic epidermal necrolysis. Concurrent use may result in additive or synergistic risk.(1) CLINICAL EFFECTS: Concurrent use of mebendazole and metronidazole may increase the risk of Stevens-Johnson syndrome/toxic epidermal necrolysis.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The Canadian manufacturer of mebendazole states that concurrent use of metronidazole should be avoided.(2) If concurrent use is warranted, monitor patients closely for signs and symptoms of Stevens-Johnson syndrome/toxic epidermal necrolysis. Instruct patients to discontinue therapy and seek medical attention for any peeling skin rash or blisters. DISCUSSION: In a retrospective review, 46 cases of Stevens-Johnson syndrome/toxic epidermal necrolysis that were reported to the Taiwan Department of Health for the period between February, 1996 and February, 1997 were matched to 2 case controls each. The odds ratio for developing Stevens-Johnson syndrome/toxic epidermal necrolysis was 9.5 among subjects who had used both metronidazole and mebendazole in the preceding 6 weeks. All 46 workers were Filipino. Following a change in practice in the Philippines that stopped routine prescription of anthelmintic drugs to workers going abroad, no new cases were reported.(1)	EMVERM, MEBENDAZOLE

There are 1 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
Metronidazole/Barbiturates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The metabolism of metronidazole may be increased by barbiturate administration via induction of CYP2A6. Primidone is metabolized to phenobarbital. CLINICAL EFFECTS: Serum metronidazole concentrations may be reduced producing a decrease in the therapeutic effects of metronidazole. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Observe the patient for possible metronidazole treatment failure. Adjust the dose of metronidazole accordingly. DISCUSSION: Therapeutic failure with corresponding increases in metronidazole elimination rate has been reported with concurrent administration of phenobarbital.	ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, DONNATAL, FIORICET, FIORICET WITH CODEINE, MYSOLINE, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PRIMIDONE, SEZABY, TENCON

Drug Interaction

Drug Names

Metronidazole/Barbiturates

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The metabolism of metronidazole may be increased by barbiturate administration via induction of CYP2A6. Primidone is metabolized to phenobarbital.

CLINICAL EFFECTS: Serum metronidazole concentrations may be reduced producing a decrease in the therapeutic effects of metronidazole.

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Observe the patient for possible metronidazole treatment failure. Adjust the dose of metronidazole accordingly.

DISCUSSION: Therapeutic failure with corresponding increases in metronidazole elimination rate has been reported with concurrent administration of phenobarbital.

ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, DONNATAL, FIORICET, FIORICET WITH CODEINE, MYSOLINE, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PRIMIDONE, SEZABY, TENCON

Severe List
Alcohol intoxication
Alcohol use disorder
Peripheral neuropathy

Moderate List
Severe hepatic disease

The following adverse reaction information is available for NUVESSA (metronidazole):

Overview
Severe
Less Severe

Adverse reaction overview.

No enhanced Common Adverse Effects information available for this drug.

There are 3 severe adverse reactions.

More Frequent	Less Frequent
None.	Abdominal pain with cramps Increased urinary frequency

Rare/Very Rare
Seizure disorder

There are 14 less severe adverse reactions.

More Frequent	Less Frequent
Diarrhea Dysmenorrhea Genital organ pruritus Headache disorder Nausea Vulvovaginal candidiasis	Alcohol intolerance Anorexia Dizziness Dysgeusia Vaginitis Vomiting Xerostomia

Rare/Very Rare
Dyspareunia

The following precautions are available for NUVESSA (metronidazole):

Pediatric
Pregnant
Lactation
Geriatric

No enhanced Pediatric Use information available for this drug.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

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/m2 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.

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.

No enhanced Geriatric Use information available for this drug.