OMNIKACIN Injection (Amikacin sulfate)

Table of Content

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 that are longer than 14 days has not been established.

Neurotoxicity, manifested as vestibular and permanent bilateral auditory ototoxicity, can occur in patients with pre-existing 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 aminoglycoside 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.

Aminoglycoside 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, or 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 (BUN), 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 the antibiotic concentrations in serum and tissue.

Composition

OMNIKACIN 500 Injection
Each 2 ml contains:
Amikacin Sulfate, IP, equivalent to Amikacin..... 500 mg
Methylparaben, IP... 0.04% w/v
Propylparaben, IP.... 0.01%
Water for injection, IP... q.s.

OMNIKACIN 250 Injection
Each 2 ml contains:
Amikacin Sulfate, IP, equivalent to Amikacin..... 250 mg
Methylparaben, IP... 0.08% w/v
Propylparaben, IP.... 0.02%
Water for injection, IP... q.s.

OMNIKACIN 100 Injection
Each 2 ml contains:
Amikacin Sulfate, IP, equivalent to Amikacin..... 100 mg
Methylparaben, IP... 0.08% w/v
Propylparaben, IP.... 0.02%
Water for injection, IP... q.s.

Dosage Form/s

Injection for both intramuscular and intravenous use

Pharmacology

Pharmacodynamics

Amikacin is a semi-synthetic aminoglycoside antibiotic derived from Kanamycin A. It is active against a broad spectrum of Gram-negative organisms, including Pseudomonas, Escherichia coli and some Gram-positive organisms, e.g. Staphylococcus aureus.

Aminoglycoside antibiotics are bactericidal in action. Although the exact mechanism of action has not been fully elucidated, the drugs appear to inhibit protein synthesis in susceptible bacteria by irreversibly binding to 30S ribosomal subunits.

Microbiology

Gram-negative
Amikacin is active in vitro against Pseudomonas species, Escherichia coli, Proteus species (indole-positive and indole-negative), Providencia species, Klebsiella-Enterobacter-Serratia species, Acinetobacter (formerly Mima-Herellea) species, and Citrobacter freundii.

When strains of the above organisms are found to be resistant to other aminoglycosides, including gentamicin, tobramycin and kanamycin, many are susceptible to amikacin in vitro.

Gram-positive
Amikacin is active in vitro against penicillinase and non-penicillinase-producing Staphylococcus species, including methicillin-resistant strains. However, aminoglycosides, in general, have a low order of activity against other Gram-positive organisms, viz. Streptococcus pyogenes, enterococci, and Streptococcus pneumoniae (formerly Diplococcus pneumoniae).

Amikacin resists degradation by most aminoglycoside inactivating enzymes known to affect gentamicin, tobramycin and kanamycin. In vitro studies have shown that amikacin sulfate combined with a beta-lactam antibiotic acts synergistically against many clinically significant Gram-negative organisms.

Pharmacokinetics

Intramuscular Administration
Amikacin is rapidly absorbed after intramuscular administration. In normal adult volunteers, average peak serum concentrations of about 12, 16, and 21 mg/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 μg/mL, 1.2 μg/mL, and 2.1 μg/mL, respectively.
Tolerance studies in normal volunteers reveal that amikacin sulfate 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 g/mL following a 250 mg dose, 697 g/mL following a 375 mg dose, and 832 g/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. Of the administered dose, 84% 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 ultra-filtration 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

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, and 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.

Indications

Amikacin sulfate injection 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-Serratia species, and Acinetobacter (Mima-Herellea) species.

Clinical studies have shown amikacin sulfate injection 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 post-operative 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, 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 severity of the infection, the response of the patient and the important additional considerations are mentioned in the WARNING 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 susceptible strains 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 sulfate injection and other antibacterial drugs, amikacin sulfate injection 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.

Dosage and Administration

The patient's pre-treatment body weight should be obtained for calculation of correct dosage.

Amikacin sulfate injection 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 BUN test 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 to 90 minutes after injection) above 35 μg per mL and trough concentrations (just prior to the next dose) above 10 μg 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 with normal renal function is 15 mg/kg/day divided into two or three equal doses administered at equally divided intervals, i.e., 7.5 mg/kg q12h or 5 mg/kg q8h. Treatment of patients in the heavier weight classes should not exceed 1.5 g/day.

When amikacin is indicated in newborns, 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 the 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.

DOSAGE GUIDELINES
ADULTS AND CHILDREN WITH NORMAL RENAL FUNCTION
Patient Weight
Dosage
 
7.5 mg/kg
5 mg/kg
lbs
kg
q12h
q8h
99
45
337.5 mg
225 mg
110
50
375 mg
250 mg
121
55
412.5 mg
275 mg
132
60
450 mg
300 mg
143
65
487.5 mg
325 mg
154
70
525 mg
350 mg
165
75
562.5 mg
375 mg
176
80
600 mg
400 mg
187
85
637.5 mg
425 mg
198
90
675 mg
450 mg
209
95
712.5 mg
475 mg
220
100
750 mg
500 mg

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 of 7.5 mg/kg, as a loading dose. This loading dose is the same as the normally recommended dose that would be calculated for a patient with 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:

Maintenance
Dose Every 12
Hours
 
=
observed ClCr in mL/min
normal ClCr in mL/min
 
×
calculated loading
dose in mg
(ClCr: creatinine clearance rate)

Intravenous Administration

p>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.

p>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 or 200 mL of sterile diluent such as 0.9% Sodium Chloride Injection or 5% Dextrose Injection, or any other compatible solution.

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 two or three equally divided doses at equally-divided intervals.

In pediatric patients, the amount of fluid used will depend on the amount of amikacin sulfate ordered for the patient. It should be a sufficient amount to infuse the amikacin dose over a 30- to 60-minute period. Infants should receive a 1- to 2-hour infusion.

Amikacin should not be physically premixed with other drugs but should be administered separately according to the recommended dosage and route.

Stability in Intravenous Fluids
Amikacin sulfate is stable for 24 hours at room temperature at concentrations of 0.25 and 5 mg/mL in the following solutions:

  • 5% Dextrose Injection, USP
  • 5% Dextrose, USP, and 0.2% Sodium Chloride Injection, USP
  • 5% Dextrose, USP, and 0.45% Sodium Chloride Injection, USP
  • 0.9% Sodium Chloride Injection, USP
  • Lactated Ringer's Injection, USP
  • Normosol M in 5% Dextrose Injection, USP (or Plasma-Lyte 56 injection in 5% Dextrose, USP, in water)
  • Normosol R in 5% Dextrose Injection, USP (or Plasma-Lyte 148 injection in 5% Dextrose, USP, in water)

In the above solutions with amikacin sulfate concentrations of 0.25 and 5 mg/mL, solutions aged for 60 days at 4°C and then stored at 25°C had utility times of 24 hours.

At the same concentrations, solutions frozen and aged for 30 days at -15°C, thawed, and stored at 25°C had utility times of 24 hours.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

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.

Contraindications

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.

Aminoglycosides may impair neuromuscular transmission, and should not be given to patients with myasthenia gravis.

Warnings and Precautions

Warnings

Please refer the WARNINGS box given earlier.

Aminoglycosides can cause fetal harm when administered to a pregnant woman. Aminoglycosides cross the placenta and there have been several reports of total irreversible, bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Although serious side effects to the fetus or newborns have not been reported in the treatment of pregnant women with other aminoglycosides, the potential for harm exists. Reproduction studies of amikacin have been performed in rats and mice and revealed no evidence of impaired fertility or harm to the fetus due to amikacin. There are no well-controlled studies in pregnant women, but investigational experience does not include any positive evidence of adverse effects to the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

This product contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes, in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than non-asthmatic people.

Clostridium difficile-associated diarrhea (CDAD) has been reported with the use of nearly all antibacterial agents, including amikacin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, leading to the overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require a colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Precautions

General
Prescribing amikacin sulfate injection 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.

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 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 aminoglycosides, 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 (please refer to DOSAGE AND ADMINISTRATION) may be desirable if other evidence of renal dysfunction occurs such as decreased ClCr; 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 (please see DOSAGE AND ADMINISTRATION) are not exceeded.

Elderly patients may have reduced renal function, which may not be evident in routine screening tests such as BUN or serum creatinine. A ClCr 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 non-susceptible organisms. If this occurs, appropriate therapy should be instituted.
Aminoglycosides should not be given concurrently with potent diuretics (please refer to the WARNINGS box).

Interaction with Other Medicinal Products and Other Forms of Interaction

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 cephalosporin use may spuriously elevate creatinine serum level determinations.

The concurrent use of amikacin sulfate injection 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.

In vitro admixture of aminoglycosides with beta-lactam antibiotics (penicillins or cephalosporins) may result in significant mutual inactivation. A reduction in serum activity may also occur when an aminoglycoside or penicillin-type drug is administered in vivo 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).

There is an increased risk of hypocalcemia when aminoglycosides are administered with bisphosphonates.

There is an increased risk of nephrotoxicity and possibly of ototoxicity when aminoglycoside are administered with platinum compounds.

Concomitantly administered thiamine (vitamin B1) may be destroyed by the reactive sodium bisulfite component of the amikacin sulfate formulation.

The intraperitoneal use of amikacin is not recommended in patients under the influence of anesthetics or muscle-relaxing drugs (including ether, halothane, d-tubocurarine, succinylcholine, and decamethonium) as neuromuscular blockade and consequent respiratory depression may occur.

Concurrent use with other potentially nephrotoxic or ototoxic drug substances should be avoided, particularly bacitracin, cisplatin, amphotericin B, cephaloridine, paromomycin, viomycin, polymyxin B, colistin, vancomycin, or other aminoglycosides.

Where the above is not possible, monitor carefully.

Indomethacin may increase the plasma concentration of amikacin in neonates.

Pregnancy

Pregnancy Category D (please refer to the WARNINGS section)

There are limited data on the use of aminoglycosides in pregnancy. Amnioglycosides can cause fetal harm. Aminoglycosides cross the placenta and there have been reports of total, irreversible, bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Although adverse effects on the fetus or newborns have not been reported in pregnant women treated with other aminoglycosides, the potential for harm exists. In reproduction toxicity studies in mice and rats no effects on fertility or fetal toxicity were reported. If amikacin is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. The safety of amikacin in pregnancy has not yet been established.

Lactation

It is not known whether amikacin is excreted in human milk. A decision should be made whether to discontinue breastfeeding or to discontinue therapy.

Amikacin should be administered to pregnant women and neonatal infants only when clearly needed and under medical supervision.

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.

Geriatric Use

Elderly patients may have reduced renal function which may not be evident in routine screening tests such as BUN or serum creatinine. A ClCr determination may be more useful. Monitoring of renal function during treatment with aminoglycosides is particularly important (please refer to DOSAGE AND ADMINISTRATION).

Effects on the Ability to Drive and Use Machine

No studies on the effects on the ability to drive and use machines have been performed. Due to the occurrence of some adverse reactions, the ability to drive and use machines may be impaired.

Undesirable Effects

All aminoglycosides have the potential to induce auditory, vestibular and renal toxicity and neuromuscular blockade (please refer to the WARNINGS box). They occur more frequently in patients presently having or with a 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 that 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 eyes) of amikacin.

Overdosage

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.

Incompatibility

Amikacin is incompatible with some penicillins and cephalosporins, amphotericin chlorothiazide sodium, erythromycin gluceptate, heparin, nitrofurantoin sodium, phenytoin sodium, thiopentone sodium and warfarin sodium and, depending on the composition and strength of the vehicle, tetracyclines, vitamins of the B group with vitamin C, and potassium chloride.

At times, amikacin may be indicated as concurrent therapy with other antibacterial agents in mixed or super-infections. In such instances, amikacin should not be physically mixed with other antibacterial agents in syringes, infusion bottles or any other equipment. Each agent should be administered separately.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit.

Shelf-life

See on the pack.

Storage and Handling Instructions

Store in a cool and dark place.
Do not freeze.
Do not use if solution is not clear.

Packaging Information

OMNIKACIN 500 Injection: Vial pack 10/5/2 ml
OMNIKACIN 250 Injection: Vial pack 10/5/2 ml
OMNIKACIN 100 Injection: Vial pack 10/5/2 ml