Amikacin Sulfate

Name: Amikacin Sulfate

How supplied

Amikacin Sulfate Injection, USP is supplied as a colorless solution which requires no refrigeration. At times the solution may become a very pale yellow; this does not indicate a decrease in potency.

Amikacin Sulfate Injection, USP, 250 mg/mL, is supplied as follows:

NDC 0641-6167-10, 2 mL Single Dose Vial packaged in a carton of 10
NDC 0641-6166-10, 4 mL Vial packaged in a carton of 10

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1- 877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

For Product Inquiry call 1-877-845-0689.

Manufactured by: WEST-WARD A HIKMA COMPANY, Eatontown, NJ 07724 USA. Revised June 2016

Overdose

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.

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

Pathogen Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion Zone Diameters (mm)
S I R S I R
Enteriobacteriaceae* ≤ 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.† ≤ 16 32 ≥ 64 ≥ 17 15-16 ≤ 14
*For Salmonella and Shigella spp., aminoglycosides may appear active in vitro but are not effective clinically; the results should not be reported as susceptible.
†For staphylococci that test susceptible, aminoglycosides are used only in combination with other active agents that test susceptible.

S = susceptible, I = intermediate, R = resistant

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

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Tenth Edition. CLSI document M07- A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard - Twelfth Edition. CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fifth Informational Supplement. CLSI document M100-S25. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.

Actions and Spectrum

  • Usually bactericidal.i

  • Binds to the 30S ribosomal subunit and inhibits protein synthesis in susceptible bacteria.i

  • In vitro spectrum of activity includes many gram-negative aerobic bacteria (including most Enterobacteriaceae and Pseudomonas aeruginosa) and some other organisms (e.g., Mycobacterium); active against only a few gram-positive aerobes and inactive against most anaerobes.1 2 3 4 i h

  • Gram-positive aerobes: active in vitro against penicillinase-producing and nonpenicillinase-producing Staphylococcus aureus and S. epidermidis.1 2 3 4 i May be active against some strains of oxacillin-resistant (methicillin-resistant) staphylococci.1 2 3 4 Streptococcus pyogenes (group A β-hemolytic streptococci), S. pneumoniae, and Enterococcus faecalis usually are resistant.4

  • Gram-negative aerobes: active in vitro and in clinical infections against Acinetobacter, Citrobacter, Enterobacter, Escherichia coli, Haemophilus influenzae, Klebsiella, Proteus, Providencia, Pseudomonas, Salmonella, Shigella, and Serratia.1 2 3 4 i Burkholderia and Stenotrophomonas usually are resistant.4

  • Partial cross-resistance occurs among the aminoglycosides.i Amikacin may be active against some Enterobacteriaceae and Ps. aeruginosa resistant to other aminoglycosides (e.g., gentamicin, tobramycin).1 2 3 i

  • Mycobacterium tuberculosis resistant to streptomycin usually are susceptible to amikacin; M. tuberculosis resistant to kanamycin usually also are resistant to amikacin.218

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Amikacin Sulfate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection

50 mg (of amikacin) per mL*

Amikacin Sulfate Injection

250 mg (of amikacin) per mL*

Amikacin Sulfate Injection

Side effects

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 Blockade

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.

Read the entire FDA prescribing information for Amikacin Sulfate Injection (amikacin sulfate)

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