Hepatic
Impairment
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Patients with hepatic impairment
metabolize metronidazole slowly, with resultant accumulation of metronidazole and
increase the plasma concentrations. Reduce the dose of Metronidazole
Injection, USP by 50% in patients with severe hepatic impairment (Child-Pugh
C). For patients with mild to moderate hepatic impairment, no dosage adjustment
is needed but these patients should be monitored for metronidazole associated
adverse events.
Patients with severe hepatic
encephalopathy metabolize metronidazole slowly, with resultant accumulation of
metronidazole. This may cause exacerbation of CNS adverse effects. Reduce the
dose of Metronidazole Injection, USP as necessary.
Renal
Impairment
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For patients with mild to moderate
renal impairment dose adjustment is not considered necessary as elimination
half-life is not significantly altered. In patients with severe renal
impairment or end stage of renal disease, metronidazole and metronidazole
metabolites may accumulate significantly because of reduced urinary excretion
in those patients. Monitoring for metronidazole associated adverse
events is recommended when metronidazole is administered in patients with
severe renal impairment or end stage of renal disease who are not undergoing hemodialysis.
Hemodialysis removes significant amounts
of metronidazole and its metabolites from systemic circulation. Therefore,
supplementation of metronidazole following a hemodialysis session may be
necessary.
Patients receiving peritoneal dialysis should
be monitored for signs of toxicity due to the potential accumulation of
metronidazole metabolites.
Use in Patients with Blood Dyscrasias
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Metronidazole is a nitroimidazole, and
should be used with care in patients with evidence of or history of blood
dyscrasia. Agranulocytosis, leukopenia and
neutropenia have been associated with metronidazole administration.
Monitor complete blood count in these patients.
Monitoring for Leukopenia
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Monitoring of complete blood count (CBC)
is
recommended before, during …
Sodium Retention
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Metronidazole Injection, USP contains 790
mg
of sodium per 100 mL. Care should be taken when administering
Metronidazole Injection, USP to patients receiving a controlled sodium diet
or corticosteroids or to patients predisposed to edema.
Drug Interactions Disulfiram
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Psychotic reactions and confusion
have been reported in alcoholic patients who are using metronidazole and
disulfiram concurrently. Do not administer Metronidazole Injection,
USP to patients who have taken disulfiram within the last two weeks.
Alcoholic Beverages
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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, USP.
Warfarin and other Oral Anticoagulants
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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, USP 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
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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
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and/or revisions underlined:
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, USP should not be administered concomitantly
with busulfan unless the benefit outweighs the risk …
Drugs that Inhibit CYP450 Enzymes
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and/or revisions underlined:
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
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he 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
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and/or revisions underlined:
Concomitant use of Metronidazole
Injection, USP 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
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Metronidazole Injection, USP decreases the
clearance of 5-fluorouracil and may therefore cause 5-fluorouracil toxicity.
Vecuronium
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and/or revisions underlined:
Metronidazole Injection, USP may
potentiate the effects of vecuronium.
Drug/Laboratory Test Interactions
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and/or revisions underlined:
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.
Pregnancy
Teratogenic Effects
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… Metronidazole crosses the placental
barrier and its effects on the human fetal organogenesis are not known.
Reproduction studies have been performed in rats, rabbits and mice at doses
similar to the maximum recommended daily dose based on body surface area
comparisons. There was no evidence of harm to the fetus due to metronidazole.
Healthcare provider should carefully
consider the potential risks and benefits for each specific patient before
prescribing Metronidazole Injection, USP.
Geriatric Use
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and/or revisions underlined:
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.
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and/or revisions underlined:
Central and Peripheral Nervous System
Effects
Severe neurological disturbances,
including encephalopathy, cerebellar symptoms, convulsive seizures, peripheral
neuropathy, optic neuropathy, and aseptic meningitis, have been reported in
patients treated with metronidazole.
Encephalopathy associated with
metronidazole may manifest as confusion or decreased level of consciousness,
and is associated with widespread lesions on magnetic resonance imaging (MRI)
of the brain. Cerebellar toxicity
associated with metronidazole may manifest as ataxia, dizziness, dysarthria,
nystagmus and saccadic pursuit and is accompanied by T2 flair lesions within
the dentate nuclei seen on MRI. Cerebellar toxicity may concurrently occur with
encephalopathy,
peripheral neuropathy or seizures. CNS symptoms and CNS lesions
are generally reversible within days to weeks upon discontinuation of
Metronidazole Injection, USP. Peripheral neuropathy, usually
symmetric and mainly of sensory type is characterized by numbness or
paresthesia of an extremity. Symptoms
may be prolonged after drug discontinuation. Aseptic meningitis may
occur within hours of dose administration and generally resolve after
metronidazole therapy is discontinued.
Advise patients to report neurologic
symptoms that occur during metronidazole administration. Discontinue
metronidazole treatment if any abnormal neurologic symptoms occur
such as ataxia, dizziness, confusion or any other CNS adverse reaction.
Risk of Hepatotoxicity and Death in
Patients with Cockayne Syndrome
Cases of severe hepatotoxicity/acute
hepatic failure, including cases with a fatal outcome with very rapid onset
after treatment initiation in patients with Cockayne syndrome have been
reported with products containing metronidazole for systemic use. In this
population, metronidazole should therefore be used after careful benefit-risk assessment
and only if no alternative treatment is available. Obtain liver function tests
prior to the start of therapy, within the first 2-3 days after
initiation of therapy, frequently during therapy and after end of treatment.
Discontinue metronidazole if elevation of liver function occurs, and monitor
liver function tests until the baseline values are reached.
Advise patients with Cockayne syndrome to
stop taking metronidazole immediately if they experience any symptoms of
potential liver injury, such as abdominal pain, nausea, change in stool color
or jaundice, and to contact their healthcare provider.
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The following reactions have been reported
during treatment with metronidazole formulations:
INFECTIONS AND INFESTATIONS: Vaginal
candidiasis
BLOOD AND LYMPHATIC SYSTEM DISORDERS:
Agranulocytosis, Leukopenia, Neutropenia, Thrombocytopenia, Eosinophilia
IMMUNE SYSTEM DISORDERS: Anaphylactic
reaction, Hypersensitivity
METABOLISM AND NUTRITION DISORDERS:
Decreased appetite
PSYCHIATRIC DISORDERS: Confusional state,
Depression, Insomnia, Decreased libido
NERVOUS SYSTEM DISORDERS: Encephalopathy,
Seizure, Neuropathy peripheral, Ataxia, Dizziness, Hypoesthesia, Paresthesia,
Dysgeusia, Headache, Nystagmus, Aseptic meningitis, Somnolence, Dysarthria,
Numbness, Syncope
EYE DISORDERS: Optic neuropathy, Saccadic
eye movement
EAR AND LABYRINTH DISORDERS: Vertigo
CARDIAC DISORDERS: Tachycardia,
Palpitation
RESPIRATORY, THORACIC AND MEDIASTINAL
DISORDERS: Dyspnea
GASTROINTESTINAL DISORDERS: Pancreatitis,
Abdominal pain, Diarrhea, Nausea, Vomiting, Asthenia, Proctitis
HEPATOBILIARY DISORDERS:
Hepatotoxicity/Liver Failure in patients with Cockayne syndrome (See WARNINGS),
Jaundice
SKIN AND SUBCUTANEOUS DISORDERS: Toxic
epidermal necrolysis, Swelling face, Pruritus, Urticaria, Hyperhidrosis,
Erythema, Rash; Stevens-Johnson syndrome, Drug Reaction with
Eosinophilia and Systemic Symptoms(DRESS)
MUSCULOSKELETAL AND CONNECTIVE TISSUE
DISORDERS: Muscle spasms, Arthralgia, Myalgia
RENAL AND URINARY DISORDERS: Chromaturia,
Dysuria
REPRODUCTIVE: Dyspareunia
GENERAL DISORDERS AND ADMINISTRATION SITE
CONDITIONS: Injection site reaction, Malaise, Face edema, Edema peripheral,
Chest pain, Chills
INVESTIGATIONS: Hepatic enzyme increased
Patients with Crohn's disease are known to
have an increased incidence of gastrointestinal and certain extraintestinal cancers
…
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