Metronidazole

Prescribing Metronidazole Injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

• •
  Interaction with Alcohol
  
  
  Discontinue consumption of alcoholic beverages or products containing propylene glycol while taking Metronidazole Injection and for at least three days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur (see CONTRAINDICATIONS
  ,
  PRECAUTIONS-Drug Interactions).
• •
  Treatment of Bacterial Infections
  
  
  Patients should be counseled that antibacterial drugs including Metronidazole Injection should only be used to treat bacterial infections. They do not treat viral infections (
  e.g.,
  the common cold). When Metronidazole Injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Metronidazole Injection or other antibacterial drugs in the future.
• •
  Severe Cutaneous Adverse Reactions
  
  
  Advise patients that Metronidazole Injection may increase the risk of serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS). Instruct the patient to be alert for skin rash, blisters, fever or other signs and symptoms of these hypersensitivity reactions. Advise patients to stop Metronidazole Injection immediately if they develop any type of rash and seek medical attention.

• •
  Disulfiram
  
  
  Psychotic reactions and confusion have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Do not administer Metronidazole Injection to patients who have taken disulfiram within the last two weeks (see CONTRAINDICATIONS).
• •
  Alcoholic Beverages
  
  
  Abdominal cramps, nausea, vomiting, headaches, tachycardia and flushing may occur if alcoholic beverages or products containing propylene glycol are consumed during or following metronidazole therapy. Discontinue consumption of alcohol or products containing propylene glycol before, during and up to 72 hours after therapy with Metronidazole Injection (see CONTRAINDICATIONS).
• •
  Warfarin and other Oral Anticoagulants
  
  
  Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time and increased risk of hemorrhages. When Metronidazole Injection is prescribed for patients on this type of anticoagulant therapy, prothrombin time and international normalized ratio (INR) should be carefully monitored and their anticoagulant dose adjusted accordingly. Monitor patients for signs and symptoms of bleeding.
• •
  Lithium
  
  
  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. Lithium toxicity may lead to renal damage. Frequent monitoring of serum lithium and serum creatinine levels is necessary.
• •
  Busulfan
  
  
  Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity such as sinusoidal obstruction syndrome, gastrointestinal mucositis, and hepatic veno-occlusive disease. Metronidazole Injection 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.
• •
  Drugs that Inhibit CYP450 Enzymes
  
  
  The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may decrease metabolism and reduce plasma clearance of metronidazole which may result in metronidazole toxicity.
• •
  Drugs that Induce CYP450 Enzymes
  
  
  The simultaneous administration of drugs that induce microsomal liver enzyme activity, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole and therefore decrease its efficacy.
• •
  Cytochrome P450 3A4 (CYP3A4) substrates
  
  
  Concomitant use of Metronidazole Injection and CYP3A4 substrates (e.g., amiodarone, tacrolimus, cyclosporine, carbamazepine, phenytoin, and quinidine) may increase respective CYP3A4-substrate plasma levels. Monitoring of plasma concentrations of CYP3A4 substrates may be necessary.
• •
  5-Fluorouracil
  
  
  Metronidazole Injection decreases the clearance of 5-fluorouracil and may therefore cause 5-fluorouracil toxicity.
• •
  Vecuronium
  
  
  Metronidazole Injection may potentiate the effects of vecuronium.
• •
  Drugs that Prolong the QT interval
  
  
  QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval.
• •
  Drug/Laboratory Test Interactions
  
  
  Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides and glucose hexokinase. Metronidazole causes an increase in ultraviolet absorbance at 340 nm resulting in falsely decreased values.

Tumors affecting the liver, lung, mammary and lymphatic tissues have been detected in several studies of metronidazole in rats and mice, but not hamsters.

Pulmonary tumors have been observed in all six reported studies in the mouse, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). Malignant tumors were increased in male mice treated at approximately 1500 mg/m²(similar to the maximum recommended daily dose, based on body surface area comparisons). Malignant lymphomas and pulmonary neoplasms were also increased with lifetime feeding of the drug to mice. Mammary and hepatic tumors were increased among female rats administered oral metronidazole compared to concurrent controls. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative.

Metronidazole has shown mutagenic activity in

Metronidazole failed to produce any adverse effects on fertility or testicular function in male rats at doses up to 400 mg/kg/day (approximately 2 times the maximum recommended daily dose based on body surface area comparison) for 28 days. However, rats treated at the same dose for 6 weeks, or longer were infertile and showed severe degeneration of the seminiferous epithelium in the testes as well as marked decreases in testicular spermatid counts and epididymal sperm counts. Fertility was restored in most rats after an eight week, drug-free recovery period.

Fertility studies have been performed in male mice at doses up to six times the maximum recommended human dose based on mg/m²and have revealed no evidence of impaired fertility. However, metronidazole was associated with reversible adverse effects on the male reproductive system (significantly decreased testes and epididymides weight, decreased sperm viability, and increased the incidence of abnormal sperm).

Metronidazole is present in human milk at concentrations similar to maternal serum levels, and infant serum levels can be close to or comparable to infant therapeutic levels. Because of the potential for tumorigenicity shown for metronidazole in mouse and rat studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Alternatively, a nursing mother may choose to pump and discard human milk for the duration of metronidazole therapy, and for 24 hours after therapy ends and feed her infant stored human milk or formula.

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

In geriatric patients, monitoring for metronidazole associated adverse events is recommended (see CLINICAL PHARMACOLOGY, PRECAUTIONS). Decreased liver function in geriatric patients can result in increased concentrations of metronidazole that may necessitate adjustment of metronidazole dosage (see DOSAGE AND ADMINISTRATION).

A partially randomized, open-label, phase 2/3 study of intravenous Metronidazole Injection in combination with other intravenous antibacterial drugs was conducted in 62 preterm infants (≤ 33 weeks gestational age at birth, and postnatal age <121 days) and 55 late pre-term and term infants (≥ 34 weeks gestational age at birth, and postnatal age <121 days), with complicated intra-abdominal infections. The primary objective of this study was to evaluate the safety of metronidazole-containing regimens, which were administered for up to 10 days. The adverse reactions reported in patients receiving metronidazole-containing regimens were comparable to patients receiving other antibacterial regimens in the study and generally similar to adverse reactions described in adults.

The safety and effectiveness of Metronidazole Injection in pediatric patients less than 4 months of age have not been established for (1) the treatment of anaerobic infections other than intra-abdominal infections or for (2) prophylaxis for postoperative infections (see INDICATIONS AND USAGE, CLINICAL PHARMACOLOGY, Pediatric Patientsand DOSAGE AND ADMINISTRATION).

Metronidazole Injection is indicated in the treatment of serious infections caused by susceptible anaerobic bacteria. Indicated surgical procedures should be performed in conjunction with Metronidazole Injection therapy. In a mixed aerobic and anaerobic infection, antibacterial drugs appropriate for the treatment of the aerobic infection should be used in addition to Metronidazole Injection.

Metronidazole Injection is effective in

• •
  Intra-Abdominal Infections,
  including peritonitis, intra-abdominal abscess and liver abscess, caused by
  Bacteroides
  species including the
  B. fragilis
  group (
  B. fragilis
  ,
  B. distasonis
  ,
  B. ovatus
  ,
  B. thetaiotaomicron
  ,
  B. vulgatus
  ),
  Clostridium
  species,
  Eubacterium
  species,
  Peptococcus
  species and
  Peptostreptococcus
  species in adults and pediatric patients less than 4 months of age.
• •
  Skin and Skin Structure Infections
  caused by
  Bacteroides
  species including the
  B. fragilis
  group,
  Clostridium
  species,
  Peptococcus
  species,
  Peptostreptococcus
  species and
  Fusobacterium
  species in adults.
• •
  Gynecologic Infections
  , including endometritis, endomyometritis, tubo-ovarian abscess and postsurgical vaginal cuff infection, caused by
  Bacteroides
  species including the
  B. fragilis
  group,
  Clostridium
  species,
  Peptococcus
  species,
  Peptostreptococcus
  species and
  Fusobacterium
  species in adults.
• •
  Bacterial Septicemia
  caused by
  Bacteroides
  species including the
  B. fragilis
  group and
  Clostridium
  species in adults.
• •
  Bone and Joint Infections
  , as adjunctive therapy, caused by
  Bacteroides
  species including the
  B. fragilis
  group in adults.
• •
  Central Nervous System (CNS) Infections
  , including meningitis and brain abscess, caused by
  Bacteroides
  species including the
  B. fragilis
  group in adults.
• •
  Lower Respiratory Tract Infections
  , including pneumonia, empyema and lung abscess, caused by
  Bacteroides
  species including the
  B. fragilis
  group in adults.
• •
  Endocarditis
  caused by
  Bacteroides
  species including the
  B. fragilis
  group in adults.

The prophylactic administration of Metronidazole Injection preoperatively, intraoperatively and postoperatively may reduce the incidence of postoperative infection in adult patients undergoing elective colorectal surgery which is classified as contaminated or potentially contaminated. Prophylactic use of Metronidazole Injection should be discontinued within 12 hours after surgery. If there are signs of infection, specimens for cultures should be obtained for the identification of the causative organism(s) so that appropriate therapy may be given (see DOSAGE AND ADMINISTRATION).

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Metronidazole Injection and other antibacterial drugs, Metronidazole Injection 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.