Amikin (Amikacin)

AMIKIN®

Bristol

Amikacin Sulfate

Antibiotic

Action And Clinical Pharmacology: Amikacin is a semi-synthetic bactericidal aminoglycoside antibiotic affecting bacterial growth by specific inhibition of protein synthesis in susceptible bacteria and is active primarily against gram negative organisms, including Pseudomonas. A 30 g amikacin sensitivity disc should give a zone inhibition of 17 mm or greater to be sensitive, using the Kirby-Bauer method of disc sensitivity for the causative organism.

The pharmacokinetics of amikacin and kanamycin are virtually identical. Amikacin is readily available and rapidly absorbed following i.v. or i.m. administration. The mean serum half-life is 2.2 hours with a mean renal clearance rate of 1.24 mL/kg/minute. No accumulation is associated with dosing at 12 hour intervals in individuals with a normal renal function.

Amikacin is not metabolized. Small amounts (1 to 2% of the dose) are excreted in the bile, while the remainder (98 to 99%) is excreted in the urine via glomerular filtration. The mean human serum protein binding is 11% over a concentration range of 5 to 50 g/mL of serum. The apparent volume of distribution of drug is approximately 0.25 L/kg of body weight. Amikacin pharmacokinetics remain linear over the entire dosage range studied (0.5 g/kg to 9 mg/kg).

Tolerance studies in normal volunteers revealed amikacin to be well tolerated locally following repeated i.m. dosing.

Amikacin has been found in the cerebrospinal fluid, pleural fluid, and peritoneal cavity following parenteral administration.

Spinal fluid concentrations in normal infants are approximately 10 to 20% of the serum concentrations and may reach 50% when the meninges are inflamed. Amikacin crosses the placental barrier and yields 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 And Clinical Uses: The short-term treatment of serious infections due to amikacin susceptible strains of Pseudomonas species, E. coli, Proteus species, Klebsiella-Enterobacter-Serratia species, Providencia species, Salmonella species, Citrobacter species and S. aureus.

Clinical studies have shown Amikin to be effective in bacteremia, septicemia (including neonatal sepsis), osteomyelitis, septic arthritis, respiratory tract, urinary tract, intra-abdominal (including peritonitis) infections and soft tissue abscesses. Appropriate bacteriological studies should be performed in order to identify and determine the susceptibility of the causative organism. Perform relevant surgical procedures when indicated.

Contra-Indications: Allergy to amikacin.

Manufacturers’ Warnings In Clinical States: Patients receiving amikacin should be under close observation and evaluation because of the potential toxicity associated with its use. Ototoxicity mainly at the auditory portion of the 8th nerve, occurs primarily in patients with pre-existing or subsequently developing renal impairment and those receiving higher doses than recommended. This effect has been permanent in a significant proportion of the patients developing varying degrees of hearing loss and assessment of the renal and, where possible, auditory functions should be made before and during treatment in order that appropriate action may be taken to minimize the risk of permanent impairment.

Since the risk of ototoxicity, irreversible deafness and nephrotoxicity is increased when amikacin is used in conjunction with rapidly acting diuretic, nephrotoxic or ototoxic drugs, avoid such therapy whenever possible.

If amikacin is used concurrently with other antibacterial agents to treat mixed or superinfections, it should not be physically mixed. Each agent should be administered separately in accordance with its recommended route of administration and dosage schedule.

Precautions: Perform a pretreatment audiogram in patients with renal and pre-existing 8hnerve impairment and repeat an audiogram during therapy. If tinnitus or subjective hearing loss occurs in patients, the discontinuation of amikacin treatment should be strongly considered.

Because of high amikacin concentrations in the urinary excretory system, patients should be well hydrated to prevent damage to renal tubular cells. Kidney function should be assessed prior to starting therapy and periodically during the course of treatment.

If signs of renal damage appear, such as casts, white or red cells, and albumin, hydration should be increased and a reduction in dosage may be desirable. However, if azotemia or a progressive decrease in urine output occurs, stop treatment. One suggested method for estimating dosage in patients with known or suspected diminished renal function is to multiply the serum creatinine concentration (mg/100 mL) by 9 and to use the resulting figure as the interval (in hours) between doses; e.g.: if the creatinine concentration is 2.0 mg/100 mL, the recommended dose (7.5 mg/kg) should be administered every 18 hours. Such calculations cannot be used safely in the elderly where dosage should be based on creatinine clearance. If the creatinine clearance is available, determine the maintenance dose in elderly patients as follows: the maintenance dose to be administered every 12 hours equals the calculated loading dose multiplied by the ratio of the observed creatinine clearance to the normal creatinine clearance. Since renal function may alter appreciably during therapy, the serum creatinine should be checked frequently. Changes in the concentration necessitate changes in the dosage frequency.

Animal studies have demonstrated that amikacin is capable of producing neuromuscular blockade. Although proof that this adverse effect can be produced in man does not exist, exercise caution when anesthetic or muscle relaxant drugs are to be administered to patients receiving amikacin.

Pregnancy: Although studies in pregnant animals have not revealed any teratogenic effects, amikacin is not recommended during pregnancy unless the benefit outweighs the risk.

Cross allergenicity among aminoglycosides has been demonstrated. If superinfection occurs with the use of amikacin, institute appropriate therapy.

Adverse Reactions: Nephrotoxicity: renal failure, abnormal urinalysis, including albuminuria, presence of red and white cells and granular casts; azotemia, hemoglobinuria, oliguria, elevated BUN or serum creatinine levels or a decrease in creatinine clearance. In most cases, these changes are reversible when amikacin is discontinued.

Ototoxicity: tinnitus, vertigo, dizziness, nystagmus, fullness in the ear, staggering, and partial (reversible to irreversible) deafness have been reported, usually associated with higher than recommended dosage. Rapid development of hearing loss may occur in patients with poor kidney function treated concurrently with amikacin and one of the rapidly acting diuretic agents given i.v. These have included ethacrynic acid, furosemide and mannitol.

Miscellaneous: skin rash, drug fever, nausea, headache, paresthesia. With i.m. administration, mild to severe pain at injection sites, as well as localized burning and erythema. Induration and sterile ulcers have been noted on rare occasions. The following adverse effects have been observed although it is felt they are not drug related: hematological changes including decrease in hematocrit and hemoglobin, thrombocytopenia, granulo-cytopenia/lymphocytosis, anemia and increase in eosinophils; hepatic changes, including increased serum bilirubin, serum transaminases [AST, ALT], hepatic enzymes, and alkaline phosphatase; pruritus, upper gastrointestinal bleeding, vomiting, diarrhea, fatigue, weakness, loss of appetite, weight loss, diplopia, sterile abscess, multifocal premature nodal and ventricular contractions, vasoconstriction, hypotension, seizures, Parkinson-like tremor, Bell’s palsy, phlebitis and thrombophlebitis.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: In the event of overdosage or toxic reactions, peritoneal dialysis or hemodialysis should be considered. These procedures are of particular importance in patients with impaired renal function.

Dosage And Administration: A maximum total adult dose of 15 g during a course of treatment by all routes of administration should not be exceeded. Treatment should not exceed 1.5 g/day and should not be administered for longer than 10 days. In the unusual circumstance, where treatment beyond 10 days or a dose larger than 1.5 g daily or 15 g total is considered, the use of amikacin should be reevaluated. If amikacin administration is prolonged, monitor renal and auditory functions daily.

In patients with impaired renal function, the interval between doses should be prolonged. The dosage interval may be calculated by the following formula: Serum creatinine (mg/100 mL)´9=dosage interval (in hours). This formula should not be used to calculate dosage for elderly patients.

If there is evidence of progressive renal dysfunction during therapy, consider discontinuation of amikacin.

Infants and neonates: In order to insure adequate therapeutic concentrations, which may be critical, while at the same time avoiding potentially toxic concentrations, serum concentrations should be monitored.

The usual dosage in adults, children and neonates is 15 mg/kg/day administered as 7.5 mg/kg every 12 hours i.m., or i.v. over a 30 to 60 minute period.

The solution for i.v. use is prepared by adding the contents of a 500 mg/2 mL vial to 250 mL of sterile diluent. Use solutions for i.v. administration within 12 hours after preparation.

Stability/Compatibility: Amikin is supplied as a colorless solution which requires no refrigeration. It is stable at room temperature for 18 months. At times the solution becomes pale yellow; this does not indicate a loss of potency. Discard dark colored solutions.

Amikin in concentrations of 0.25 or 5 mg/mL has been found to be compatible for 12 hours at 25°C in the following i.v. solutions: normal saline, 0.25% sodium chloride in water, sterile water for injection USP, 5% dextrose USP, 2.5% dextrose and 0.9% sodium chloride, 5% dextrose and 0.33% sodium chloride, 5% dextrose in Ringer’s Injection, 10% invert sugar in 0.9% sodium chloride, lactated Ringer’s injection USP, Ringer’s injection USP, Ionosol D-CM (Abbott).

If Amikin solution is used concurrently with other antibacterial agents, it should not be physically mixed. Each agent should be administered separately in accordance with its recommended route of administration and dosage schedule.

Availability And Storage: Each mL of aqueous solution contains: amikacin sulfate 250 mg, sodium bisulfite 0.66%, and sodium citrate 2.5% with pH adjusted to 4.5 with sulfuric acid. Nonmedicinal ingredients: sodium bisulfite 0.66% w/v (preservative), sodium citrate 2.5% w/v (buffer), sulfuric acid 7.7% w/v, water for injection. Sodium:

AMIKIN® Bristol Amikacin Sulfate Antibiotic

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