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Amikacin Sulfate

Amikacin is a semisynthetic aminoglycoside antibiotic.

Administration

Amikacin sulfate is administered by IM injection or IV infusion.

Amikacin Sulfate

For adults, IV infusions are prepared by adding 500 mg of amikacin to 100-200 mL of usual IV infusion fluid such as 0.9% sodium chloride or 5% dextrose injection. Alternatively, ADD-Vantage® vials labeled as containing 500 mg of amikacin should be assembled and the infusion prepared according to the manufacturer’s directions prior to IV infusion. Add-Vantage vials of the drug are not intended for multiple use and should not be used with a syringe in the conventional way. The 12.-g pharmacy bulk package of amikacin is not intended for direct IV infusion; doses of the drug from the bulk package must be further diluted by adding the appropriate dose to 100 or 200 mL of a compatible IV infusion solution prior to administration.

The appropriate dose of amikacin should be infused over 30-60 minutes.

For pediatric patients, the volume of infusion fluid depends on the patient’s needs, but should be sufficient to allow an infusion period of 1-2 hours in infants or 30-60 minutes in older children.

Dosage

Dosage of amikacin sulfate is expressed in terms of amikacin and is identical for either route of administration.

Dosage should be based on an estimate of ideal body weight. The usual dosage of amikacin recommended by the manufacturers for adults, children, and older infants with normal renal function is 15 mg/kg daily given in equally divided doses at 8- or 12-hour intervals.

The manufacturers state that daily dosage should not exceed 15 mg/kg or 1.5 g. The manufacturers state that amikacin should be used with caution in premature and full-term neonates because the renal immaturity of these patients may result in prolongation of serum half-life of the drug. When amikacin is used in neonates, the manufacturers recommend an initial loading dose of 10 mg/kg followed by 7.5 mg/kg every 12 hours.

If amikacin is used for uncomplicated urinary tract infections caused by organisms not susceptible to less toxic anti-infectives, the usual adult dosage is 250 mg twice daily. Alternatively, many clinicians recommend that amikacin dosage be determined using appropriate pharmacokinetic methods for calculating dosage requirements and patient-specific pharmacokinetic parameters (e.g., elimination rate constant, volume of distribution) derived from serum concentration-time data; in determining dosage, the susceptibility of the causative organism, the severity of infection, and the patient’s immune and clinical status also must be considered.

Current evidence suggests that once-daily administration of aminoglycosides is at least as effective as, and may be less toxic than, conventional dosage regimens employing multiple daily doses of the drugs; however, additional controlled studies in children, patients with renal dysfunction, and other appropriate patient groups are needed to fully define the optimal use of once-daily aminoglycoside dosing regimens. Whenever possible, and especially in patients with life-threatening infections, suspected toxicity or nonresponse to treatment, decreased or varying renal function, and/or when increased aminoglycoside clearance (e.g., patients with cystic fibrosis, burns) or prolonged therapy is likely, peak and trough serum concentrations of amikacin should be determined periodically and dosage should be adjusted to maintain desired serum concentrations.

A causal relationship between maintenance of certain peak or trough serum concentrations or other pharmacodynamic endpoints and clinical response or toxicity has not been established to date for aminoglycoside dosing regimens. However, many clinicians have suggested peak and trough serum concentrations of 15-40 and less than 5-10 mcg/mL, respectively, for amikacin.

The manufacturers state that peak serum concentrations (obtained 30-90 minutes after injection) greater than 35 mcg/mL and trough serum concentrations (obtained just before the next dose) greater than 10 mcg/mL should be avoided. In adults, 4-20 mg of amikacin has been administered intrathecally or intraventricularly as a single daily dose in conjunction with IM or IV administration of the drug.

Treatment of Active Tuberculosis

In the treatment of clinical tuberculosis, amikacin is considered a second-line agent for use in multiple-drug regimens for the treatment of active tuberculosis. Therapy for tuberculosis should be continued long enough to prevent relapse.

The minimum duration of treatment currently recommended for patients with culture-positive pulmonary tuberculosis is 6 months (26 weeks), and recommended regimens consist of an initial intensive phase (2 months) and a continuation phase (usually either 4 or 7 months).

The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) state that the usual dosage of amikacin for use in conjunction with other antituberculosis agents for the treatment of active tuberculosis in adults and children 15 years of age or older is 15 mg/kg daily (up to 1 g) given IM or IV as a single daily dose (usually 750-1000 mg daily) 5-7 times weekly for the first 2-4 months or until culture conversion; dosage can then be reduced to 15 mg/kg daily (up to 1 g) given 2 or 3 times weekly, depending on efficacy of the other drugs in the regimen.

However, these experts recommend that adults older than 59 years of age receive a dosage of 10 mg/kg (up to 750 mg) daily.

The dosage of amikacin recommended by the ATS, CDC, and IDSA for the treatment of active tuberculosis in pediatric patients is 15-30 mg/kg daily (up to 1 g) given IM or IV once daily or twice weekly.

Dosage in Renal Impairment

In patients with impaired renal function, doses and/or frequency of administration must be modified in response to serum concentrations of the drug and the degree of renal impairment.

There are various methods to determine dosage and a wide variation in dosage recommendations for these patients. However, even when one of these methods is used, peak and trough serum concentrations of the drug should be monitored, especially in patients with changing renal function.

The manufacturers recommend an initial loading dose of 7.5 mg/kg. For subsequent therapy, the manufacturers state that 7.5-mg/kg doses can be given at intervals (in hours) calculated by multiplying the patient’s steady-state serum creatinine (in mg/dL) by 9. Alternatively, many clinicians recommend the dosing method of Sarubbi and Hull, which is based on corrected creatinine clearance.(See Dosage and Administration: Dosage in Renal Impairment, in the Aminoglycosides General Statement 8:12.02.)

These dosage calculation methods should not be used in patients undergoing hemodialysis or peritoneal dialysis. In adults with renal failure undergoing hemodialysis, some clinicians recommend supplemental doses of 50-75% of the initial loading dose at the end of each dialysis period. However, serum concentrations of the drug should be monitored in dialysis patients and dosage should be adjusted to maintain desired serum concentrations.

Pharmacokinetics

The pharmacokinetics of amikacin are similar to those of the other aminoglycosides. In all studies described in the Pharmacokinetics section, amikacin was administered as the sulfate salt; dosages and concentrations of the drug are expressed in terms of amikacin.

Absorption

Following IM administration of a single dose of amikacin of 7.5 mg/kg in adults with normal renal function, peak plasma amikacin concentrations of 17-25 mcg/mL are attained within 45 minutes to 2 hours; plasma concentrations of the drug average 2.1 mcg/mL at 10 hours. When the same dose is administered by IV infusion over 1 hour, peak plasma concentrations of the drug average 38 mcg/mL immediately following the infusion, 5.5 mcg/mL at 4 hours, and 1.3 mcg/mL at 8 hours. In one study in neonates, peak serum amikacin concentrations of 17-20 mcg/mL were attained 30 minutes after a single IM dose of 7.5 mg/kg. In one adult with meningitis, intrathecal administration of 4 mg of amikacin daily in conjunction with IM administration of 15 mg/kg daily for 2 weeks resulted in CSF concentrations of the drug ranging from 7-40 mcg/mL 12 hours after an intrathecal dose and 1-19 mcg/mL 24 hours after an intrathecal dose.

Distribution

Following administration of usual dosages of amikacin, therapeutic concentrations of the drug are achieved in bone, heart, gallbladder, and lung tissue. Amikacin is also well distributed into bile, sputum, bronchial secretions, and interstitial, pleural, and synovial fluids.

Elimination

The plasma elimination half-life of amikacin is usually 2-3 hours in adults with normal renal function and is reported to range from 30-86 hours in adults with severe renal impairment. The plasma elimination half-life of amikacin is reported to be 4-5 hours in full-term infants 7 days of age or older and 7-8 hours in low birth-weight infants 1-3 days of age. In adults with normal renal function, 94-98% of a single IM or IV dose of amikacin is excreted unchanged by glomerular filtration within 24 hours.

Urine concentrations of amikacin average 563 mcg/mL for 6 hours following a single 250-mg IM dose and 832 mcg/mL following a single 500-mg IM dose in adults with normal renal function.

Complete recovery of the dose in urine requires approximately 10-20 days in patients with normal renal function, and terminal elimination half-lives of greater than 100 hours have been reported in adults with normal renal function following repeated IM or IV administration of the drug.

Chemistry and Stability

Amikacin Sulfate

Chemistry

Amikacin is a semisynthetic aminoglycoside antibiotic derived from kanamycin A. Amikacin occurs as a white, crystalline powder and is sparingly soluble in water. The drug is commercially available as the sulfate salt which is formed in situ during the manufacturing process. Amikacin sulfate injection is a colorless to light straw-colored solution; sulfuric acid is added during the manufacture of the injection to adjust the pH to 3.5-5.

Stability

Amikacin sulfate injection should be stored at a temperature less than 40°C, preferably between 15-30°C; freezing should be avoided. At room temperature, amikacin sulfate injection is stable for at least 2 years following the date of manufacture.

The pharmacy bulk package of amikacin and ADD-Vantage® vials of the drug do not require refrigeration. The manufacturer states that once the bulk package vial closure has been entered with a sterile measured dispensing set, any unused portion should be discarded within 4 hours. Once ADD-Vantage® vials have been connected to an appropriate diluent container and activated for dilution, resultant solutions should be used within 24 hours. C

ommercially available solutions of amikacin sulfate may become a very pale yellow; however, this does not indicate loss of potency.

Amikacin sulfate is stable for 24 hours at room temperature at concentrations of 0.25 and 5 mg/mL in most IV infusion fluids, including 0.9% sodium chloride or 5% dextrose injection.

Amikacin sulfate solutions containing 0.25 and 5 mg/mL in 5% dextrose, 5% dextrose and 0.2 or 0.45% sodium chloride, 0.9% sodium chloride, lactated Ringer’s, Normosol®-M and 5% dextrose, Plasma-Lyte® 56 with 5% dextrose, Normosol®-R and 5% dextrose, or Plasma-Lyte® 148 with 5% dextrose are stable for 24 hours at room temperature after being refrigerated at 4°C for 60 days or frozen for 30 days at -15°C, thawed, and stored at 25°C.

The manufacturers state that amikacin sulfate injection should not be mixed with other drugs. For further information on chemistry and stability, mechanism of action, spectrum, resistance, pharmacokinetics, uses, cautions, drug interactions, and dosage and administration of amikacin, see the Aminoglycosides General Statement 8:12.02.

Preparations

Amikacin Sulfate Parenteral Injection 50 mg (of amikacin) per mL Amikacin Sulfate Pediatric Injection, (with sulfites) Abbott AstraZeneca Bedford Faulding Gensia SoloPak Amikin® Pediatric, (with sodium bisulfite and sodium citrate) Sandoz 250 mg (of amikacin) per mL Amikacin Sulfate Injection, (with sulfites) Abbott AstraZeneca Bedford Elkins- Sinn Faulding Gensia Sanofi SoloPak Amikin®, (with sodium bisulfite and sodium citrate) Sandoz 250 mg (of amikacin) per mL Amikacin Sulfate Injection, (12. g) pharmacy bulk Abbott AstraZeneca package Injection, for IV 62. mg (of amikacin) per mL Amikacin Sulfate ADD-Vantage®, infusion (500 mg) Abbott Amikacin Sulfate in Sodium Chloride Parenteral Injection for IV 5 mg (of amikacin) per mL Amikacin Sulfate in 0.9% infusion (500 mg) in 0.9% Sodium Sodium Chloride Injection, Chloride (LifeCare®) Abbott AHFS DRUG INFORMATION® (2004)

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