Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3325
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AMIKACIN Sulfate (Injection, Solution)
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The patient's pretreatment body weight should be obtained
for calculation of correct dosage. Amikacin Sulfate Injection, USP may be
given intramuscularly or intravenously. The status of
renal function should be estimated by measurement of the serum creatinine
concentration or calculation of the endogenous creatinine clearance rate.
The blood urea nitrogen (BUN) is much less reliable for this purpose. Reassessment
of renal function should be made periodically during therapy. Whenever
possible, amikacin concentrations in serum should be measured to assure adequate
but not excessive levels. It is desirable to measure both peak and trough
serum concentrations intermittently during therapy. Peak concentrations (30-90
minutes after injection) above 35 micrograms per mL and trough concentrations
(just prior to the next dose) above 10 micrograms per mL should be avoided.
Dosage should be adjusted as indicated. Intramuscular
Administration for Patients with Normal Renal Function-The recommended
dosage for adults, children and older infants (see���WARNINGS���box) with normal renal function is 15 mg/kg/day divided into 2 or 3 equal
doses administered at equally-divided intervals, i.e., 7.5 mg/kg q.12h
or 5 mg/kg q.8h. Treatment of patients in the heavier weight classes should
not exceed 1.5 gram/day. When amikacin is indicated
in newborns (see���WARNINGS���box), it is recommended that a
loading dose of 10 mg/kg be administered initially to be followed with 7.5
mg/kg every 12 hours. The usual duration of treatment
is 7 to 10 days. It is desirable to limit the duration of treatment to short
term whenever feasible. The total daily dose by all routes of administration
should not exceed 15 mg/kg/day. In difficult and complicated infections where
treatment beyond 10 days is considered, the use of amikacin should be re-evaluated.
If continued, amikacin serum levels and renal, auditory, and vestibular functions
should be monitored. At the recommended dosage level, uncomplicated infections
due to amikacin-sensitive organisms should respond in 24 to 48 hours. If definite
clinical response does not occur within 3 to 5 days, therapy should be stopped
and the antibiotic susceptibility pattern of the invading organism should
be rechecked. Failure of the infection to respond may be due to resistance
of the organism or to the presence of septic foci requiring surgical drainage. When
amikacin is indicated in uncomplicated urinary tract infections, a dose of
250 mg twice daily may be used. Intramuscular Administration
for Patients with Impaired Renal Function-Whenever possible, serum
amikacin concentrations should be monitored by appropriate assay procedures.
Doses may be adjusted in patients with impaired renal function either by administering
normal doses at prolonged intervals or by administering reduced doses at a
fixed interval. Both methods are based on the patient's
creatinine clearance or serum creatinine values since these have been found
to correlate with aminoglycoside half-lives in patients with diminished renal
function. These dosage schedules must be used in conjunction with careful
clinical and laboratory observations of the patient and should be modified
as necessary. Neither method should be used when dialysis is being performed. Normal Dosage at Prolonged Intervals-If the creatinine clearance rate is not available
and the patient's condition is stable, a dosage interval in hours for
the normal dose can be calculated by multiplying the patient's serum
creatinine by 9, e.g., if the serum creatinine concentration is 2 mg/100
mL, the recommended single dose (7.5 mg/kg) should be administered every 18
hours. Reduced Dosage
at Fixed Time Intervals-When
renal function is impaired and it is desirable to administer amikacin at a
fixed time interval, dosage must be reduced. In these patients serum amikacin
concentrations should be measured to assure accurate administration of amikacin
and to avoid concentrations above 35 mcg/mL. If serum assay determinations
are not available and the patient's condition is stable, serum creatinine
and creatinine clearance values are the most readily available indicators
of the degree of renal impairment to use as a guide for dosage. First,
initiate therapy by administering a normal dose, 7.5 mg/kg, as a loading dose.
This loading dose is the same as the normally recommended dose which would
be calculated for a patient with a normal renal function as described above. To
determine the size of maintenance doses administered every 12 hours, the loading
dose should be reduced in proportion to the reduction in the patient's
creatinine clearance rate: An alternate rough guide for determining reduced dosage
at 12 hour intervals (for patients whose steady state serum creatinine values
are known) is to divide the normally recommended dose by the patient's
serum creatinine. The above dosage schedules are not
intended to be rigid recommendations but are provided as guides to dosage
when the measurement of amikacin serum levels is not feasible. Intravenous Administration-The individual dose,
the total daily dose, and the total cumulative dose of amikacin sulfate are
identical to the dose recommended for intramuscular administration. The solution
for intravenous use is prepared by adding the contents of a 500 mg vial to
100-200 mL of sterile diluent such as 0.9% Sodium Chloride Injection,USP
or 5% Dextrose Injection, USP or any of the compatible solutions listed below. The
solution is administered to adults over a 30 to 60 minute period. The total
daily dose should not exceed 15 mg/kg/day and may be divided into either 2
or 3 equally-divided doses at equally-divided intervals. In
pediatric patients the amount of fluid used will depend on the amount ordered
for the patient. It should be a sufficient amount to infuse the amikacin over
a 30 to 60 minute period. Infants should receive a 1 to 2 hour infusion. Stability in I.V. Fluids-Amikacin sulfate is stable
for 24 hours at room temperature at concentrations of 0.25 and 5.0 mg/mL in
the following solutions: 5% Dextrose Injection, USP 5% Dextrose and 0.2% Sodium Chloride Injection, USP 5% Dextrose and 0.45% Sodium Chloride Injection, USP 0.9% Sodium Chloride Injection, USP Lactated Ringer's
Injection, USP Normosol-M in 5%
Dextrose Injection Normosol-R in
5% Dextrose Injection Parenteral drug products should
be inspected visually for particulate matter and discoloration prior to administration
whenever the solution and container permit. Aminoglycosides
administered by any of the above routes should not be physically premixed
with other drugs but should be administered separately. Because
of the potential toxicity of aminoglycosides,���fixed dosage���recommendations
which are not based upon body weight are not advised. Rather, it is essential
to calculate the dosage to fit the needs of each patient. To
prevent needle-stick injuries, needles should not be recapped, purposely bent,
or broken by hand.
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Amikacin sulfate is a semi-synthetic aminoglycoside antibiotic
derived from kanamycin. It is CHNO���2HSOD-Streptamine, 0-3-amino-3-deoxy-��-D-glucopyranosyl(1���6)-0-[6-amino-6-deoxy-��-D-glucopyranosyl(1���4)]-N-(4-amino-2-hydroxy-1-oxobutyl)-2-deoxy-,
(S)-, sulfate (1:2) (salt). Molecular
weight is 781.75. The dosage form is supplied as a sterile,
colorless to light straw colored solution, for I.M. or I.V. use. The 100 mg
per 2 mL vial contains, in addition to amikacin sulfate, 0.12% sodium metabisulfite
and 0.57% sodium citrate, dihydrate. Nitrogen gassed. Contains sulfuric acid
for pH adjustment. pH 4.5(3.5 to 5.5). The 500 mg per 2 mL vial and syringe,
and the 1 gram per 4 mL vial contain 0.6% sodium metabisulfite and 2.9% sodium
citrate, dihydrate. Contains sulfuric acid for pH adjustment. pH 4.5 (3.5
to 5.5). Amikacin Sulfate Injection, USP is oxygen sensitive.
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Intramuscular Administration-Amikacin
is rapidly absorbed after intramuscular administration. In normal adult volunteers,
average peak serum concentrations of about 12, 16, and 21 mcg/mL are obtained
1 hour after intramuscular administration of 250-mg (3.7 mg/kg), 375-mg (5
mg/kg), 500-mg (7.5 mg/kg), single doses, respectively. At 10 hours, serum
levels are about 0.3 mcg/mL, 1.2 mcg/mL, and 2.1 mcg/mL, respectively. Tolerance
studies in normal volunteers reveal that amikacin is well tolerated locally
following repeated intramuscular dosing, and when given at maximally recommended
doses, no ototoxicity or nephrotoxicity has been reported. There is no evidence
of drug accumulation with repeated dosing for 10 days when administered according
to recommended doses. With normal renal function, about
91.9% of an intramuscular dose is excreted unchanged in the urine in the first
8 hours, and 98.2% within 24 hours. Mean urine concentrations for 6 hours
are 563 mcg/mL following a 250-mg dose, 697 mcg/mL following a 375-mg
dose, and 832 mcg/mL following a 500-mg dose. Preliminary
intramuscular studies in newborns of different weights (less than 1.5 kg,
1.5 to 2.0 kg, over 2.0 kg) at a dose of 7.5 mg/kg revealed that, like
other aminoglycosides, serum half-life values were correlated inversely with
post-natal age and renal clearances of amikacin. The volume of distribution
indicates that amikacin, like other aminoglycosides, remains primarily in
the extracellular fluid space of neonates. Repeated dosing every 12 hours
in all the above groups did not demonstrate accumulation after 5 days. Intravenous Administration-Single doses of 500
mg (7.5 mg/kg) administered to normal adults as an infusion over a period
of 30 minutes produced a mean peak serum concentration of 38 mcg/mL at the
end of the infusion, and levels of 24 mcg/mL, 18 mcg/mL, and 0.75 mcg/mL at
30 minutes, 1 hour, and 10 hours post-infusion, respectively. Eighty-four
percent of the administered dose was excreted in the urine in 9 hours and
about 94% within 24 hours. Repeat infusions of 7.5 mg/kg
every 12 hours in normal adults were well tolerated and caused no drug accumulation.<br/>General: -Pharmacokinetic studies in normal adult subjects reveal
the mean serum half-life to be slightly over 2 hours with a mean total apparent
volume of distribution of 24 liters (28% of the body weight). By the ultrafiltration
technique, reports of serum protein binding range from 0 to 11%. The mean
serum clearance rate is about 100mL/min and the renal clearance rate is 94 mL/min
in subjects with normal renal function. Amikacin is
excreted primarily by glomerular filtration. Patients with impaired renal
function or diminished glomerular filtration pressure excrete the drug much
more slowly (effectively prolonging the serum half-life). Therefore, renal
function should be monitored carefully and dosage adjusted accordingly (see
suggested dosage schedule under DOSAGE AND ADMINISTRATION). Following
administration at the recommended dose, therapeutic levels are found in bone,
heart, gallbladder, and lung tissue in addition to significant concentrations
in urine, bile, sputum, bronchial secretions, interstitial, pleural, and synovial
fluids. Spinal fluid levels in normal infants are approximately
10 to 20% of the serum concentrations and may reach 50% when the meninges
are inflamed. Amikacin has been demonstrated to cross the placental barrier
and yield significant concentrations in amniotic fluid. The peak fetal serum
concentration is about 16% of the peak maternal serum concentration and maternal
and fetal serum half-life values are about 2 and 3.7 hours, respectively.
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A history of hypersensitivity to amikacin is a contraindication
for its use. A history of hypersensitivity or serious toxic reactions to aminoglycosides
may contraindicate the use of any other aminoglycoside because of the known
cross-sensitivities of patients to drugs in this class.
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Amikacin Sulfate Injection, USP is supplied as a colorless
solution which requires no refrigeration. At times the solution may become
a light straw yellow; this does not indicate a decrease in potency. Store at 20-25��C (68-77��F) [See USP Controlled
Room Temperature] *Bauer, A.W., Kirby, W.M.M., Sherris,
J.C., and Turck, M.: Antibiotic Testing by a Standardized Single Disc Method. Am.J.Clin.Pathol., 45:493, 1966; Standardized
Disc Susceptibility Test, FEDERAL REGISTER, 37:20527-29, 1972. HOSPIRA, INC., LAKE FOREST,
IL 60045 USA
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WARNINGS Patients
treated with parenteral aminoglycosides should be under close clinical observation
because of the potential ototoxicity and nephrotoxicity associated with their
use. Safety for treatment periods which are longer than 14 days has not been
established. Neurotoxicity, manifested as vestibular
and permanent bilateral auditory ototoxicity, can occur in patients with preexisting
renal damage and in patients with normal renal function treated at higher
doses and/or for periods longer than those recommended. The risk of aminoglycoside-induced
ototoxicity is greater in patients with renal damage. High frequency deafness
usually occurs first and can be detected only by audiometric testing. Vertigo
may occur and may be evidence of vestibular injury. Other manifestations of
neurotoxicity may include numbness, skin tingling, muscle twitching and convulsions.
The risk of hearing loss due to aminoglycosides increases with the degree
of exposure to either high peak or high trough serum concentrations. Patients
developing cochlear damage may not have symptoms during therapy to warn them
of developing eighth-nerve toxicity, and total or partial irreversible bilateral
deafness may occur after the drug has been discontinued. Aminoglycoside-induced
ototoxicity is usually irreversible. Aminoglycosides
are potentially nephrotoxic. The risk of nephrotoxicity is greater in patients
with impaired renal function and in those who receive high doses or prolonged
therapy. Neuromuscular blockade and respiratory paralysis
have been reported following parenteral injection, topical instillation (as
in orthopedic and abdominal irrigation or in local treatment of empyema),
and following oral use of aminoglycosides. The possibility of these phenomena
should be considered if aminoglycosides are administered by any route, especially
in patients receiving anesthetics, neuromuscular blocking agents such as tubocurarine,
succinylcholine, decamethonium, or in patients receiving massive transfusions
of citrate-anticoagulated blood. If blockage occurs, calcium salts may reverse
these phenomena, but mechanical respiratory assistance may be necessary. Renal
and eighth-nerve function should be closely monitored especially in patients
with known or suspected renal impairment at the onset of therapy and also
in those whose renal function is initially normal but who develop signs of
renal dysfunction during therapy. Serum concentrations of amikacin should
be monitoredwhen feasible to assure adequate levels and to avoid potentially
toxic levels and prolonged peak concentrations above 35 micrograms per mL.
Urine should be examined for decreased specific gravity, increased excretion
of proteins, and the presence of cells or casts. Blood urea nitrogen, serum
creatinine, or creatinine clearance should be measured periodically. Serial
audiograms should be obtained where feasible in patients old enough to be
tested, particularly high risk patients. Evidence of ototoxicity (dizziness,
vertigo, tinnitus, roaring in the ears, and hearing loss) or nephrotoxicity
requires discontinuation of the drug or dosage adjustment. Concurrent
and/or sequential systemic, oral, or topical use of other neurotoxic or nephrotoxic
products, particularly bacitracin, cisplatin, amphotericin B, cephaloridine,
paromomycin, viomycin, polymyxin B, colistin, vancomycin, or other aminoglycosides
should be avoided. Other factors that may increase risk of toxicity are advanced
age and dehydration. The concurrent use of amikacin
with potent diuretics (ethacrynic acid, or furosemide) should be avoided since
diuretics by themselves may cause ototoxicity. In addition, when administered,
intravenously, diuretics may enhance aminoglycoside toxicity by altering antibiotic
concentrations in serum and tissue.
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Aminoglycosides are quickly and almost totally absorbed when
they are applied topically, except to the urinary bladder, in association
with surgical procedures. Irreversible deafness, renal failure, and death
due to neuromuscular blockade have been reported following irrigation of both
small and large surgical fields with an aminoglycoside preparation. Amikacin
Sulfate Injection, USP is potentially nephrotoxic, ototoxic and neurotoxic.
The concurrent or serial use of other ototoxic or nephrotoxic agents should
be avoided either systemically or topically because of the potential for additive
effects. Increased nephrotoxicity has been reported following concomitant
parenteral administration of aminoglycoside antibiotics and cephalosporins.
Concomitant cephalosporins may spuriously elevate creatinine determinations. Since
amikacin is present in high concentrations in the renal excretory system,
patients should be well-hydrated to minimize chemical irritation of the renal
tubules. Kidney function should be assessed by the usual methods prior to
starting therapy and daily during the course of treatment. If
signs of renal irritation appear (casts, white or red cells, or albumin),
hydration should be increased. A reduction in dosage (see DOSAGE AND ADMINISTRATION)
may be desirable if other evidence of renal dysfunction occurs such as decreased
creatinine clearance; decreased urine specific gravity; increased BUN, creatinine,
or oliguria. If azotemia increases or if a progressive decrease in urinary
output occurs, treatment should be stopped. Note: When patients are well-hydrated and kidney function
is normal the risk of nephrotoxic reactions with amikacin is low if the dosage
recommendations (see DOSAGE AND ADMINISTRATION) are not exceeded. Elderly
patients may have reduced renal function which may not be evident in routinescreening tests such as BUN or serum creatinine. A creatinine
clearance determination may be more useful. Monitoring of renal function during
treatment with aminoglycosides is particularly important. Aminoglycosides
should be used with caution in patients with muscular disorders such as myasthenia
gravis or parkinsonism since these drugs may aggravate muscle weakness because
of their potential curare-like effect on the neuromuscular junction. In vitro mixing of aminoglycosides with beta-lactam
antibiotics (penicillin or cephalosporins) may result in a significant mutual
inactivation. A reduction in serum half-life or serum level may occur when
an aminoglycoside or penicillin-type drug is administered by separate routes.
Inactivation of the aminoglycoside is clinically significant only in patients
with severely impaired renal function. Inactivation may continue in specimens
of body fluids collected for assay, resulting in inaccurate aminoglycoside
readings. Such specimens should be properly handled (assayed promptly, frozen,
or treated with beta-lactamase). Cross-allergenicity
among aminoglycosides has been demonstrated. As with
other antibiotics, the use of amikacin may result in overgrowth of nonsusceptible
organisms. If this occurs, appropriate therapy should be instituted. Aminoglycosides
should not be given concurrently with potent diuretics (see���WARNINGS���box).<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: -Long term studies in animals to evaluate carcinogenic potential
have not been performed, and mutagenicity has not been studied. Amikacin sulfate
administered subcutaneously to rats at doses up to 4 times the human daily
dose did not impair male or female fertility.<br/>Pregnancy: -Category D (See���WARNINGS���section).<br/>Nursing Mother: s-It is not known whether amikacin is excreted in human milk.
Because many drugs are excreted in human milk and because of the potential
for serious adverse reactions in nursing infants from amikacin, 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: -Aminoglycosides should be used with caution in premature
and neonatal infants because of the renal immaturity of these patients and
the resulting prolongation of serum half-life of these drugs.<br/>General: Prescribing amikacin 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/>Information for Patients: Patients should be counseled that antibacterial drugs including
amikacin should only be used to treat bacterial infections. They do not treat
viral infections (e.g., the common cold). When an antibacterial drug product
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 amikacin or other antibacterial drugs in the
future.
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In the event of overdosage or toxic reaction, peritoneal
dialysis or hemodialysis will aid in the removal of amikacin from the blood.
In the newborn infant, exchange transfusion may also be considered.
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Amikacin Sulfate
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AMIKACIN Sulfate (Injection, Solution)
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All aminoglycosides have the potential to induce auditory,
vestibular, and renal toxicity and neuromuscular blockade (see���WARNINGS���box). They occur more frequently in patients with present or past history
of renal impairment, of treatment with other ototoxic or nephrotoxic drugs,
and in patients treated for longer periods and/or with higher doses than recommended. Neurotoxicity-Ototoxicity-Toxic effects on the
eighth cranial nerve can result in hearing loss, loss of balance, or both.
Amikacin primarily affects auditory function. Cochlear damage, includes high
frequency deafness and usually occurs before clinical hearing loss can be
detected. Neurotoxicity-Neuromuscular
Blockage-Acute muscular paralysis and apnea can occur following
treatment with aminoglycoside drugs. Nephrotoxicity-Elevation of serum creatinine, albuminuria, presence of red and
white cells, casts, azotemia, and oliguria have been reported. Renal function
changes are usually reversible when the drug is discontinued. As would be
expected with any aminoglycoside, reports of toxic nephropathy and acute renal
failure have been received during postmarketing surveillance. Other-In addition to those described above, other
adverse reactions which have been reported on rare occasions are skin rash,
drug fever, headache, paresthesia, tremor, nausea and vomiting, eosinophilia,
arthralgia, anemia, hypotension, and hypomagnesemia. Macular infarction sometimes
leading to permanent loss of vision has been reported following intravitreous
administration (injection into the eye) of amikacin.
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Amikacin Sulfate Injection, USP is indicated in the short-term
treatment of serious infections due to susceptible strains of Gram-negative
bacteria, including Pseudomonas species, Escherichia coli, species of indole-positive
and indole-negative Proteus, Providencia species, Klebsiella-Enterobacter-Serratiaspecies, and Acinetobacter
(Mima-Herellea) species. Clinical studies
have shown Amikacin Sulfate Injection, USP to be effective in bacterial septicemia
(including neonatal sepsis); in serious infections of the respiratory tract,
bones and joints, central nervous system (including meningitis) and skin and
soft tissue; intra-abdominal infections (including peritonitis); and in burns
and postoperative infections (including post-vascular surgery). Clinical studies
have shown amikacin also to be effective in serious complicated and recurrent
urinary tract infections due to these organisms. Aminoglycosides, including
Amikacin Sulfate Injection, USP, are not indicated in uncomplicated initial
episodes of urinary tract infections unless the causative organisms are not
susceptible to antibiotics having less potential toxicity. Bacteriologic
studies should be performed to identify causative organisms and their susceptibilities
to amikacin. Amikacin may be considered as initial therapy in suspected Gram-negative
infections and therapy may be instituted before obtaining the results of susceptibility
testing. Clinical trials demonstrated that amikacin was effective in infections
caused by gentamicin and/or tobramycin-resistant strains of Gram-negative
organisms, particularly Proteus rettgeri, Providencia
stuartii, Serratia marcescens, and Pseudomonas
aeruginosa. The decision to continue therapy with the drug should
be based on results of the susceptibility tests, the severityof the infection,
the response of the patient and the important additional considerations contained
in the���WARNINGS���box above. Amikacin
has also been shown to be effective in staphylococcal infections and may be
considered as initial therapy under certain conditions in the treatment of
known or suspected staphylococcal disease such as, severe infections where
the causative organism may be either a Gram-negative bacterium or a staphylococcus,
infections due to susceptiblestrains of staphylococci in patients allergic
to other antibiotics, and in mixed staphylococcal/Gram-negative infections. In
certain severe infections such as neonatal sepsis, concomitant therapy with
a penicillin-type drug may be indicated because of the possibility of infections
due to Gram-positive organisms such as streptococci or pneumococci. To
reduce the development of drug-resistant bacteria and maintain the effectiveness
of amikacin and other antibacterial drugs, amikacin 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 the empiric selection of therapy.
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AMIKACIN Sulfate
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