Amikacin Sulfate

AMIKACIN SULFATE- amikacin sulfate injection, solution
Heritage Pharmaceuticals Inc. d/b/a Avet Pharmaceuticals Inc.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of the 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 bacteria.

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 monitored when 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.

DESCRIPTION

Amikacin sulfate is semi-synthetic aminoglycoside antibiotic derived from kanamycin. It is C22 H43 N5 O13 •2H2 SO4O -3-amino-3-deoxy-α-D-glucopyranosyl-(1→4)-O -[6-amino-6-deoxy-α-D-glucopyranosyl-(1→6)]-N3 -(4-amino-L-2-hydroxybutyryl)-2-deoxy-L-streptamine sulfate (1:2)

structure
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M.W. 585.61

The dosage form is supplied as a sterile, colorless to light straw colored solution for intramuscular or intravenous use. The 500 mg per 2 mL vial and 1 gram per 4 mL vial contains per each mL: 250 mg Amikacin (as the Amikacin sulfate USP), 0.66% sodium metabisulfite as an antioxidant, 2.5% sodium citrate dihydrate as a buffering agent with pH adjusted to 4.5 with sulfuric acid.

CLINICAL PHARMACOLOGY

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 kg, over 2 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.

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 100 mL/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.

Microbiology

Mechanism of Action

Amikacin, an aminoglycoside, binds to the prokaryotic ribosome, inhibiting protein synthesis in susceptible bacteria. It is bactericidal in vitro against Gram-positive and Gram-negative bacteria.

Mechanism of Resistance

Aminoglycosides are known to be ineffective against Salmonella and Shigella species in patients. Therefore, in vitro susceptibility test results should not be reported.

Amikacin resists degradation by certain aminoglycoside inactivating enzymes known to affect gentamicin, tobramycin, and kanamycin.

Aminoglycosides in general have a low order of activity against Gram-positive organisms other than Staphylococcal isolates.

Interaction with Other Antimicrobials

In vitro studies have shown that amikacin sulfate combined with a beta-lactam antibiotic acts synergistically against many clinically significant Gram-negative organisms.

Antimicrobial Activity

Amikacin has been shown to be active against the following bacteria, both in vitro and in clinical infections [see Indications and Usage]

Gram-positive Bacteria

Staphylococcus species

Gram-negative Bacteria

Pseudomonas species

Escherichia coli

Proteus species (indole-positive and indole-negative)

Klebsiella species

Enterobacter species

Serratia species

Acinetobacter species

Amikacin has demonstrated in vitro activity against the following bacteria. The safety and effectiveness of amikacin in treating clinical infections due to these bacteria have not been established in adequate and well-controlled trials.

Citrobacter freundii

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility tests for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method.1, 3 Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of amikacin powder. The MIC values should be interpreted according to the criteria provided in Table 1.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure requires the use of standardized inoculum concentrations and paper disks impregnated with 30 mcg of amikacin.2, 3 The disk diffusion values should be interpreted according to the criteria provided in Table 1.

Table 1: Susceptibility Test Interpretive Criteria for Amikacin

S = susceptible, I = intermediate, R = resistant

a For Salmonella and Shigella spp., aminoglycosides may appear active in vitro but are not effective clinically; the results should not be reported as susceptible

b For staphylococci that test susceptible, aminoglycosides are used only in combination with other active agents that test susceptible

Pathogen Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion Zone Diameters (mm)
S I R S I R
Enterobacteriaceaea ≤ 16 32 ≥ 64 ≥ 17 15-16 ≤ 14
Pseudomonas aeruginosa ≤ 16 32 ≥ 64 ≥ 17 15-16 ≤ 14
Acinetobacter spp. ≤ 16 32 ≥ 64 ≥ 17 15-16 ≤ 14
other Non-Enterobacteriaceae ≤ 16 32 ≥ 64
Staphylococcus spp.b ≤ 16 32 ≥ 64 ≥ 17 15-16 ≤ 14

A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration at the infection site necessary to inhibit growth of the pathogen. A report of “Intermediate” indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1, 2, 3 Standard amikacin powder should provide the following range of MIC values provided in Table 2. For the diffusion technique using the 30-mcg amikacin disk the criteria provided in Table 2 should be achieved.

Table 2: Acceptable Quality Control Ranges for Amikacin
Quality Control Organism Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion Zone Diameters (mm)
Escherichia coli ATCC 25922 0.5-4 19 – 26
Pseudomonas aeruginosa ATCC 27853 1-4 18-26
Staphylococcus aureus ATCC 25923 Not Applicable 20-26
Staphylococcus aureus ATCC 29213 1-4 Not Applicable
Enterococcus faecalis ATCC 29212 64-256 Not Applicable
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