Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3590
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Flagyl (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.<br/>Treatment of
Anaerobic Infections: The
recommended dosage schedule for adults is: 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 Metronidazole Injection, USP RTU' treatment.
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. 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 levelsand toxicity is recommended. In patients
receiving Metronidazole Injection, USP RTU' 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, USP RTU' 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.<br/>Prophylaxis: For
surgical prophylactic use, to prevent postoperative infection in
contaminated or potentially contaminated colorectal surgery, the recommended dosage schedule for adults is: 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
RTU' be administered, if necessary, at 6-hour intervals to
maintain effective drug levels. Prophylactic use of
Metronidazole Injection, USP RTU' should be limited to the day
of surgery only, following the above guidelines. Caution: Metronidazole Injection, USP
RTU' is to be administered by slow intravenous drip infusion
only, either as a continuous or intermittent infusion.
Additives should not be introduced into Metronidazole
Injection, USP RTU'. 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. Parenteral
drug products should be inspected visually for particulate
matter and discoloration prior to administration, whenever
solution and container permit.
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Metronidazole
Injection, USP RTU', is a parenteral dosage form of the synthetic
antibacterial agent 1-(��-hydroxyethyl)-2-methyl-5-nitroimidazole. Metronidazole
Injection, USP RTU', in 100 mL VIAFLEX Plus single dose plastic
container, is a sterile, nonpyrogenic, iso-osmotic, buffered solution of
500 mg Metronidazole, USP, 790 mg Sodium Chloride, USP, 47.6 mg Dibasic
Sodium Phosphate Dried, USP and 22.9 mg Citric Acid Anhydrous, USP.
Metronidazole Injection, USP RTU' has an osmolarity of 310 mOsmol/L
(calc) and a pH of 5.5 (4.5 to 7.0). Each container contains 14 mEq of
sodium. The plastic
container is fabricated from a specially formulated polyvinyl chloride
plastic. Water can permeate from inside the container into the overwrap
in amounts insufficient to affect the solution significantly. Solutions
in contact with the plastic container can leach out certain of its
chemical components in very small amounts within the expiration period,
e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million.
However, the safety of the plastic has been confirmed in tests in
animals according to USP biological tests for plastic containers as well
as by tissue culture toxicity studies.
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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
(60-80% of the dose), with fecal excretion accounting for 6-15% 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 100-4,000 mg of
metronidazole in normal subjects showed a linear relationship between
dose and peak plasma concentration. In patients treated
with intravenous metronidazole, 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 plasma 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<br/>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: Eubacterium lentum ATCC 43055, Bacteroides fragilis ATCC
25285, and Bacteroides
thetaiotaomicron ATCC 29741. The mode
metronidazole MICs for those three strains are reported to be
0.125, 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 RTU' is contraindicated in patients with a prior history
of hypersensitivity to metronidazole or other nitroimidazole
derivatives.
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Metronidazole
Injection, USP RTU' is supplied in 100 mL single dose plastic
containers, each containing an iso-osmotic, buffered solution of 500 mg
metronidazole as follows: 2B3421 NDC
0338-1055-48 500 mg/100 mL Store at controlled
room temperature, 59��to 86��F (15��to 30��C) and protect from light
during storage. Do not remove unit from overwrap until ready for use.
The overwrap is a moisture barrier. The inner bag maintains the
sterility of the product. After removing overwrap, check for minute
leaks by squeezing inner bag firmly. If leaks are found, discard solution as sterility may be impaired.
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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, USP RTU' to patients receiving
corticosteroids or to patients predisposed to edema. Known or
previously unrecognized candidiasis may present more prominent
symptoms during therapy with Metronidazole Injection, USP RTU'
and requires treatment with a candicidal agent. Prescribing
Metronidazole Injection, USP RTU' 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 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 hemotologic 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
Injection, USP RTU' is prescribed for patients on this type of
anticoagulant therapy. The
simultaneous administration of drugs that induce microsomal
liver enzyme activity, 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 (NAD+���NADH). Interference is due to the similarity
in absorbance peaks of NADH (340nm) and metronidazole (322nm) at
pH 7.<br/>Carcinogenesis and
Mutagenesis and 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:<br/>Teratogenic
Effects:<br/>Nursing Mothers: 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. Metronidazole
is secreted in breast milk in concentrations similar to those
found in plasma.<br/>Pediatric Use: Safety and
effectiveness in pediatric patients have not been
established<br/>Information for
Patients: Patients
should be counseled that antibacterial drugs including
Metronidazole Injection, USP RTU' should only be used to treat
bacterial infections. They do not treat viral infections (e.g.,
the common cold). When Metronidazole Injection, USP RTU' 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 exactlyas
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, USP RTU' or other antibacterial drugs in the
future.
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Use of dosages of
intravenous metronidazole 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 dose of
metronidazole, up to 15 g, have been reported in suicide attempts and
accidental overdoses. Symptoms reported included 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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Flagyl (Injection, Solution)
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Two serious adverse
reactions reported in patients treated with intravenous metronidazole
have been convulsive seizures 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, USP RTU'. 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: Convulsive seizures, peripheral neuropathy, dizziness, vertigo,
incoordination, ataxia, confusion, irritability, depression, weakness
and insomnia. Hypersensitivity:
Urticaria, erythematous rash, 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. Rare cases of
pancreatitis, which abated on withdrawal of the drug, have 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 indication for
Metronidazole Injection, USP RTU'.
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Convulsive Seizures
and Peripheral Neuropathy: Convulsive
seizures 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 RTU' is indicated in the treatment
of serious infections caused by susceptible anaerobic bacteria.
Indicated surgical procedures should be performed in conjunction
with Metronidazole Injection, USP RTU' therapy. In a mixed
aerobic and anaerobic infection, antibiotics appropriate for the
treatment of the aerobic infection should be used in addition to Metronidazole Injection, USP RTU'. Metronidazole Injection, USP RTU' 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 andPeptostreptococcus
species. Skin and Skin Structure
Infections caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species, Peptostreptococcus species andFusobacterium
species. Gynecologic Infections, including
endometritis, endomyometritis, tubo-ovarian abscess and
postsurgical vaginal cuff infection, caused by Bacteroides species including
the B. fragilis group,Clostridium species,Peptostreptococcus
species and Fusobacterium
species. Bacterial Septicemia caused byBacteroides 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.<br/>Prophylaxis: The
prophylactic administration of Metronidazole Injection, USP RTU'
preoperatively, intraoperatively and postoperatively may reduce
the incidence of postoperative infection in patients undergoing
elective colorectal surgery which is classified as contaminated
or potentially contaminated. Prophylactic use of Metronidazole
Injection, USP RTU' 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 (seeDOSAGE AND
ADMINISTRATION). To reduce the development of drug-resistant bacteria and maintain the
effectiveness of Metronidazole Injection, USP RTU' and other
antibacterial drugs, Metronidazole Injection, USP RTU' 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.
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Flagyl
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