Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/933
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Metronidazole (Injection, Solution)
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In elderly patients the pharmacokinetics of metronidazole
may be altered and, therefore, monitoring of serum levels may be necessary
to adjust the metronidazole dosage accordingly. Treatment of Anaerobic Infections: The recommended dosage schedule for Adults is: Patients with severe hepatic disease metabolize
metronidazole slowly, with resultant accumulation of metronidazole
and its metabolites in the plasma. Accordingly, for such patients,
doses below those usually recommended should be administered cautiously.
Close monitoring of plasma metronidazole levels and toxicity is recommended. In patients receiving metronidazole
injection in whom gastric secretions are continuously removed by nasogastric
aspiration, sufficient metronidazole may be removed in the aspirate
to cause a reduction in serum levels. The dose
of metronidazole injection should not be specifically reduced in anuric
patients since accumulated metabolites may be rapidly removed by dialysis. The usual duration of therapy is 7 to 10 days; however,
infections of the bone and joint, lower respiratory tract, and endocardium
may require longer treatment. Prophylaxis: For
surgical prophylactic use, to prevent postoperative infection in contaminated
or potentially contaminated colorectal surgery, the recommended dosage
schedule for adults is: a. 15 mg/kg infused
over 30 to 60 minutes and completed approximately one hour before
surgery; followed by b. 7.5 mg/kg infused over
30 to 60 minutes at 6 and 12 hours after the initial dose. It is important that (1) administration of the initial
preoperative dose be completed approximately one hour before surgery
so that adequate drug levels are present in the serum and tissues
at the time of initial incision, and (2) Metronidazole Injection,
USP be administered, if necessary, at 6-hour intervals to maintain
effective drug levels. Prophylactic use of Metronidazole Injection,
USP should be limited to the day of surgery only, following the above
guidelines. Parenteral therapy may be changed
to oral metronidazole when conditions warrant, based upon the severity
of the disease and the response of the patient to treatment with metronidazole
injection. The usual adult oral dosage is 7.5 mg/kg every six hours. A maximum of 4 g should not be exceeded during a 24-hour
period. CAUTION:
Metronidazole Injection, USP is to be administered by slow intravenous
drip infusion only, either as a continuous or intermittent infusion.
I.V. admixtures containing metronidazole and other drugs should be
avoided. Additives should not be introduced into this solution. If
used with a primary intravenous fluid system, the primary solution
should be discontinued during metronidazole infusion. DO NOT USE EQUIPMENT
CONTAINING ALUMINUM (e.g., NEEDLES, CANNULAE) THAT WOULD COME IN CONTACT
WITH THE DRUG SOLUTION. Metronidazole
Injection, USP is a ready-to-use isotonic solution. NO DILUTION OR
BUFFERING IS REQUIRED. Do not refrigerate. Each container of Metronidazole
Injection contains 14 mEq of sodium. Do not
use if cloudy or precipitated or if the seal is not intact. Parenteral drug products should be inspected visually
for particulate matter and discoloration prior to administration,
whenever solution and container permit. Use
sterile equipment. It is recommended that the intravenous administration
apparatus be replaced at least once every 24 hours.
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Metronidazole Injection, USP is a sterile, nonpyrogenic,
isotonic, buffered parenteral dosage form of metronidazole in water
for injection. Each 100 mL contains metronidazole
500 mg (5 mg/mL) and sodium chloride 790 mg in water for injection;
with dibasic sodium phosphate (anhydrous) 48 mg and citric acid (anhydrous)
23 mg added as buffers. The osmolarity of this solution is 314 mOsmol/liter
(calc.). Each 100 mL contains 14 mEq sodium, pH 5.8 (4.5���7.0). Metronidazole is classified as a synthetic
antibacterial and antiprotozoal agent and is administered by the intravenous
route. Metronidazole, USP is chemically designated
2-methyl-5-nitroimidazole-1-ethanol (CHNO), a crystalline powder sparingly soluble in
water. It has the following structural formula: Sodium Chloride, USP is chemically designated
NaCl, a white crystalline powder freely soluble in water. Water for Injection, USP is chemically designated HO. The flexible plastic container is
fabricated from a specially formulated polyvinylchloride. Water can
permeate from inside the container into the overwrap but not in amounts
sufficient to affect the solution significantly. Solutions inside
the plastic container also can leach out certain of its chemical components
in very small amounts before the expiration period is attained. However,
thesafety of the plastic has been confirmed by tests in animals according
to USP biological standards for plastic containers.
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Metronidazole is a synthetic antibacterial compound.
Disposition of metronidazole in the body is similar for both oral
and intravenous dosage forms, with an average elimination half-life
in healthy humans of eight hours. The major
route of elimination of metronidazole and its metabolites is via the
urine (60 to 80% of the dose), with fecal excretion accounting for
6 to 15% of the dose. The metabolites that appear in the urine result
primarily from side-chain oxidation (1-[��-hydroxyethyl]-2-hydroxymethyl-
5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid) and
glucuronide conjugation, with unchanged metronidazole accounting for
approximately 20% of the total. Renal clearance of metronidazole is
approximately 10 mL/min/1.73 m. Metronidazole is the major component appearing in the plasma, with
lesser quantities of the 2-hydroxymethyl metabolite also being present.
Less than 20% of the circulating metronidazole is bound to plasma
proteins. Both the parent compound and the metabolite possess in vitro bactericidal activity against
most strains of anaerobic bacteria. Metronidazole
appears in cerebrospinal fluid, saliva, and breast milk in concentrations
similar to those found in plasma. Bactericidal concentrations of metronidazole
have also been detected in pus from hepatic abscesses. Plasma concentrations of metronidazole are proportional
to the administered dose. An eight-hour intravenous infusion of 100
to 4,000 mg of metronidazole in normal subjects showed a linear relationship
between dose and peak plasma concentration. In patients treated with metronidazole injection using a dosage regimen
of 15 mg/kg loading dose followed six hours later by 7.5 mg/kg every
six hours, peak steady-state concentrations of metronidazole averaged
25 mcg/mL with trough (minimum) concentrations averaging 18 mcg/mL. Decreased renal function does not alter the single-dose
pharmacokinetics of metronidazole. However, plasma clearance of metronidazole
is decreased in patients with decreased liver function. In one study newborn infants appeared to demonstrate diminished
capacity to eliminate metronidazole. The elimination half-life, measured
during the first three days of life, was inversely related to gestational
age. In infants whose gestational ages were between 28 and 40 weeks,
the corresponding elimination half-lives ranged from 109 to 22.5 hours.<br/>Microbiology:: Metronidazole is active in vitro against most obligate anaerobes, but does not
appear to possess any clinically relevant activity against facultative
anaerobes or obligate aerobes. Against susceptible organisms, metronidazole
is generally bactericidal at concentrations equal to or slightly higher
than the minimal inhibitory concentrations. Metronidazole has been
shown to have in vitro and
clinical activity against the following organisms: Anaerobic gram-negative bacilli, including: Bacteroides species, including
the Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron,
B. vulgatus) Fusobacterium species Anaerobic gram-positive bacilli, including: Clostridium species and
susceptible strains of Eubacterium Anaerobic gram-positive cocci, including: Peptococcus species Peptostreptococcus species Susceptibility
Tests: Bacteriologic studies should
be performed to determine the causative organisms and their susceptibility
to metronidazole; however, the rapid routine susceptibility testing
of individual isolates of anaerobic bacteria is not always practical,
and therapy may be started while awaiting these results. Quantitative methods give the most accurate estimates
of susceptibility to antibacterial drugs. A standardized agar dilution
method and a broth microdilution method are recommended. Control strains are recommended for standardized
susceptibility testing. Each time the test is performed, one or more
of the following strains should be included: Clostridium perfringensATCC 13124, Bacteroides fragilis ATCC 25285, and Bacteroides thetaiotaomicron ATCC 29741.
The mode metronidazole MICs for those three strains are reported to
be 0.25, 0.25 and 0.5 mcg/mL, respectively. A clinical laboratory test is considered under acceptable control
if the results of the control strains are within one doubling dilution
of the mode MICs reported for metronidazole. A bacterial isolate may be considered susceptible if the MIC value
for metronidazole is not more than 16 mcg/mL. An organism is considered
resistant if the MIC is greater than 16 mcg/mL. A report of���resistant���from the laboratory indicates that the infecting organism is not likely
to respond to therapy.
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Metronidazole Injection, USP is contraindicated in
patients with a prior history of hypersensitivity to metronidazole
or other nitroimidazole derivatives.
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Metronidazole Injection, USP, sterile, is supplied
in 100 mL single dose flexible containers, each containing 500 mg
(5 mg/mL) of metronidazole (List 7811). Metronidazole
Injection, USP should be stored at 20 to 25��C (68 to 77��F)
[See USP Controlled Room Temperature] and protected from light during
storage. Revised: June, 2008
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WARNING Metronidazole has been shown to be carcinogenic
in mice and rats (see PRECAUTIONS). Its use, therefore, should be reserved for the conditions described
in the INDICATIONS AND USAGE section below.
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General:: Patients with severe hepatic disease metabolize
metronidazole slowly, with resultant accumulation of metronidazole
and its metabolites in the plasma. Accordingly, for such patients,
doses below those usually recommended should be administered cautiously. Administration of solutions containing sodium
ions may result in sodium retention. Care should be taken when administering
metronidazole injection to patients receiving corticosteroids or to
patients predisposed to edema. Known
or previously unrecognized candidiasis may present more prominent
symptoms during therapy with metronidazole and requires treatment
with a candicidal agent. Prescribing
metronidazole 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.<br/>Laboratory Tests:: Metronidazole is a nitroimidazole, and metronidazole
should be used with care in patients with evidence of or history of
blood dyscrasia. A mild leukopenia has been observed during its administration;
however, no persistent hematologic abnormalities attributable to metronidazole
have been observed in clinical studies. Total and differential leukocyte
counts are recommended before and after therapy.<br/>Drug Interactions:: Metronidazole has been reported to potentiate
the anticoagulant effect of warfarin and other oral 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. The simultaneous administration of drugs that induce microsomal liver
enzymes, such as phenytoin or phenobarbital, may accelerate the elimination
of metronidazole, resulting in reduced plasma levels; impaired clearance
of phenytoin has also been reported. The simultaneous administration of drugs that decrease microsomal
liver enzyme activity, such as cimetidine, may prolong the half-life
and decrease plasma clearance of metronidazole. Alcoholic beverages should not be consumed during metronidazole therapy
because abdominal cramps, nausea, vomiting, headaches and flushing
may occur. Psychotic reactions have
been reported in alcoholic patients who are using metronidazole and
disulfiram concurrently. Metronidazole should not be given to patients
who have taken disulfiram within the last two weeks.<br/>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 hexokinase glucose.
Values of zero may be observed. All of the assays in which interference
has been reported involve enzymatic coupling of the assay to oxidation-reduction
of nicotine adenine dinucleotide (NADNADH). Interference
is due to the similarity in absorbance peaks of NADH (340 nm) and
metronidazole (322 nm) at pH 7.<br/>Carcinogenesis, Mutagenesis,
Impairment of Fertility:: Tumorigenicity
in Rodents: Metronidazole
has shown evidence of carcinogenic activity in studies involving chronic,
oral administration in mice and rats, but similar studies in the hamster
gave negative results. Also, metronidazole has shown mutagenic activity
in a number of in vitro assay
systems, but studies in mammals (in vivo) failed to demonstrate a potential for genetic damage.<br/>Pregnancy:: Teratogenic effects���Pregnancy Category B. Metronidazole
crosses the placental barrier and enters the fetal circulation rapidly.
Reproduction studies have been performed in rats at doses up to five
times the human dose and have revealed no evidence of impaired fertility
or harm to the fetus due to metronidazole. Metronidazole administered
intraperitoneallyto pregnant mice at approximately the human dose
caused fetotoxicity; administered orally to pregnant mice, no fetotoxicity
was observed. There are, however, no adequate and well-controlled
studies in pregnant women. Because animal reproduction studies are
not always predictive of human response, and because metronidazole
is a carcinogen in rodents, this drug should be used during pregnancy
only if clearly needed (see CONTRAINDICATIONS).<br/>Nursing Mothers:: Metronidazole is secreted in breast milk
in concentrations similar to those found in plasma. 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.<br/>Pediatric Use:: The safety and effectiveness in children
have not been established.<br/>Information for Patients:: Patients should be counseled that antibacterial
drugs, including metronidazole, should only be used to treat bacterial
infections. They do not treat viral infections (e.g., the common cold).
When metronidazole 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 or other antibacterial drugs in the
future.
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The use of dosages of metronidazole hydrochloride
higher than those recommended has been reported. These include the
use of 27 mg/kg three times a day for 20 days, and the use of 75 mg/kg
as a single loading dose followed by 7.5 mg/kg maintenance doses.
No adverse reactions were reported in either of the two cases. Single oral doses of metronidazole, up to 15 g, have been
reported in suicide attempts and accidental overdoses. Symptoms reported
include nausea, vomiting, and ataxia. Oral metronidazole
has been studied as a radiation sensitizer in the treatment of malignant
tumors. Neurotoxic effects, including seizures and peripheral neuropathy,
have been reported after 5 to 7 days of doses of 6 to 10.4 g every
other day. Treatment: There is no specific antidote for overdose:
Therefore, management of the patient should consist of symptomatic
and supportive therapy.
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Metronidazole
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Metronidazole (Injection, Solution)
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The most serious adverse reactions reported in patients
treated with metronidazole injection have been convulsive seizures,
encephalopathy, aseptic meningitis, optic and peripheral neuropathy,
the latter characterized mainly by numbness or paresthesia of an extremity.
Since persistent peripheral neuropathy has been reported in some patients
receiving prolonged oral administration of metronidazole, patients
should be observed carefully if neurologic symptoms occur and a prompt
evaluation made of the benefit/risk ratio of the continuation of therapy. The following reactions have also been reported during
treatment with metronidazole injection: Gastrointestinal:
Nausea, vomiting, abdominal discomfort, diarrhea, and an unpleasant
metallic taste. Hematopoietic: Reversible neutropenia
(leukopenia). Dermatologic: Erythematous rash
and pruritus. Central Nervous System: Headache,
dizziness, syncope, ataxia and confusion. Local
Reactions: Thrombophlebitis after intravenous infusion. This reaction
can be minimized or avoided by avoiding prolonged use of indwelling
intravenous catheters. Other: Fever. Instances
of a darkened urine have also been reported, and this manifestation
has been the subject of a special investigation. Although the pigment
which is probably responsible for this phenomenon has not been positively
identified, it is almost certainly a metabolite of metronidazole and
seems to have no clinical significance. The
following adverse reactions have been reported during treatment with
oral metronidazole: Gastrointestinal: Nausea,
sometimes accompanied by headache, anorexia, and occasionally vomiting;
diarrhea, epigastric distress, abdominal cramping, and constipation. Mouth: A sharp, unpleasant metallic taste is not unusual.
Furry tongue, glossitis, and stomatitis have occurred; these may be
associated with a sudden overgrowth of Candida which may occur during effective therapy. Hematopoietic: Reversible neutropenia (leukopenia); rarely,
reversible thrombocytopenia. Cardiovascular:
Flattening of the T-wave may be seen in electrocardiographic tracings. Central Nervous System: Encephalopathy, aseptic meningitis,
convulsive seizures, optic neuropathy, peripheral neuropathy, dizziness,
vertigo, incoordination, ataxia, confusion, dysarthria, irritability,
depression, weakness, and insomnia. Hypersensitivity:
Urticaria, erythematous rash, Stevens-Johnson Syndrome, flushing,
nasal congestion, dryness of the mouth (or vagina or vulva), and fever. Renal: Dysuria, cystitis, polyuria, incontinence, a sense
of pelvic pressure, and darkened urine. Other:
Proliferation of Candida in
the vagina, dyspareunia, decrease of libido, proctitis, and fleeting
joint pains sometimes resembling���serum sickness.���If
patients receiving metronidazole drink alcoholic beverages, they may
experience abdominal distress, nausea, vomiting, flushing, or headache.
A modification of the taste of alcoholic beverages has also been reported. Crohn's disease patients are known to have an increased
incidence of gastrointestinal and certain extraintestinal cancers.
There have been some reports in the medical literature of breast and
colon cancer in Crohn's disease patients who have been treated
with metronidazole at high doses for extended periods of time. A cause
and effect relationship has not been established. Crohn's disease
is not an approved indicationfor metronidazole injection.
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Central and Peripheral
Nervous System Effects: Convulsive
seizures, encephalopathy, aseptic meningitis, optic and peripheral
neuropathy, the latter characterized mainly by numbness or paresthesia
of an extremity, have been reported in patients treated with metronidazole.
The appearance of abnormal neurologic signs demands the prompt evaluation
of the benefit/risk ratio of the continuation of therapy.
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Treatment of Anaerobic
Infections Metronidazole Injection,
USP is indicated in the treatment of serious infections caused by
susceptible anaerobic bacteria. Indicated surgical procedures should
be performed in conjunction with metronidazole therapy. In a mixed
aerobic and anaerobic infection, antibiotics appropriate for the treatment
of the aerobic infection should be used in addition to metronidazole. Metronidazole is effective in Bacteroides fragilis infections resistant to clindamycin,
chloramphenicol and penicillin. 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. Skin and Skin Structure
Infections caused by Bacteroides species including B. fragilis group, Clostridium species, Peptococcus species, Peptostreptococcus species and Fusobacterium species. Gynecologic Infections, including
endometritis, endomyometritis, tubo-ovarian abscess, and post-surgical
vaginal cuff infection, caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species and Peptostreptococcus species. Bacterial Septicemia caused by Bacteroides species
including the B. fragilis group
and Clostridium species. Bone and Joint Infections, as adjunctive therapy, caused by Bacteroides species including the B. fragilis group. Central
Nervous System (CNS) Infections , including meningitis and
brain abscess, caused by Bacteroides species including the B. fragilis group. Lower
Respiratory Tract Infections, including pneumonia, empyema,
and lung abscess, caused by Bacteroides species including the B. fragilis group. Endocarditis caused by Bacteroides species
including the B. fragilis group. Prophylaxis: The
prophylactic administration of Metronidazole Injection, USP preoperatively,
intraoperatively, and postoperatively may reduce the incidence of
postoperative infection in patients undergoing selective colorectal
surgery which is classified as contaminated or potentially contaminated. Prophylactic use of Metronidazole Injection, USP 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 and other
antibacterial drugs, metronidazole 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
antimicrobial therapy. In the absence of such data, local epidemiology
and susceptibility patterns may contribute to theempiric selection
of therapy.
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Metronidazole
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