Gentamicin Parenteral (Gentamicin)

GARAMYCIN® Parenteral

Schering

Gentamicin Sulfate

Antibiotic

Action And Clinical Pharmacology: Gentamicin is a bactericidal antibiotic which affects bacterial growth by specific inhibition of normal protein synthesis in susceptible bacteria.

It is active against a wide variety of pathogenic gram-negative and gram-positive bacteria: P. aeruginosa, Proteus species (both indole-positive and indole-negative), E. coli, K. pneumoniae, E. aerogenes, S. marcescens and Staphylococcus species (including penicillin- and methicillin-resistant strains).

In addition, gentamicin sulfate is active in vitro against certain species of Streptococcus. Only minimal activity has been found against S. faecalis and S. pneumoniae. Most anaerobes (species of Clostridium, Bacteroides, and Diphtheroids) are resistant.

The bactericidal concentration of gentamicin is usually 1 to 4 times the minimal inhibitory concentration. Gentamicin was over 8 times more active in vitro at pH 7.5 than at pH 5.5, against several urinary pathogens.

If susceptibility tests indicate the causative organism is resistant to gentamicin, institute other or additional antimicrobial therapy.

Combined therapy with gentamicin and a penicillin type of drug has been used in suspected sepsis until bacteriological studies have identified the etiological organism.

Gentamicin serum concentrations via the i.m. route: Adults: In patients with normal renal function, peak serum concentrations, bactericidal for susceptible bacteria, occur between 30 and 90 minutes after injection, the peak serum concentration (g/mL) being 4 times the single dose (mg/kg). The mean serum half-life is approximately 2 hours.

Infants and neonates: Peak serum concentrations of 2.2 to 8.6 g/mL (mean 4.0 g/mL) are observed 0.5 to 1 hour after 2.5 mg/kg of gentamicin sulfate are administered i.m. to infants 7 days of age and under.

The mean serum gentamicin half-life is approximately 5 hours in neonates under 72 hours of age. This may be considerably prolonged in infants weighing less than 1 500 g. In low birth weight infants, prolonged half-life values may extend through the second week of life. In contrast, values of 3 to 3.5 hours are usually observed in full term infants who are 7 days of age and older.

Gentamicin concentrations in serum of infants 2 to 24 months of age following i.m. doses of 2 and 2.5 mg/kg were shown to be in the range of 2.5 to 7.5 g/mL.

Serum concentrations via the i.v. route: Adults: After a 2-hour infusion of a dose of 1 mg/kg to a group of patients, peak gentamicin concentrations were reached at the end of the infusion and averaged 4.5 g/mL (range 0.5 to 8 g/mL).

Slow i.v. injection at recommended doses in patients gave serum levels of 5 to 9 g/mL after 10 minutes.

The mean serum half-life is the same as for the i.m. route of administration.

Infants and neonates: Levels in serum and half-life values after i.v. infusion of gentamicin were similar to those after i.m. administration.

In man, about 25 to 30% of the administered dose of gentamicin is bound by serum protein. Gentamicin is excreted principally in the urine by glomerular filtration. After initial administration to patients with normal renal function, 30 to 100% of the drug is recoverable in the urine in 24 hours. Renal clearance of gentamicin is similar to that of endogenous creatinine.

In patients with impaired renal function, the clearance of gentamicin is decreased; the more severe the impairment, the slower the clearance.

In the newborn, approximately 30% of the administered dose is excreted in 12 hours.

Following parenteral administration gentamicin is detected in tissues and body fluids. Concentrations in bile in general have been low and have suggested minimal biliary excretion. Gentamicin has been found in the cerebrospinal fluid after i.m. injection; however, concentrations have been low and may be inadequate for treatment of certain CNS infections.

Concentrations of gentamicin in CSF of infants with purulent meningitis range from 0.2 to 3.5 g/mL after a dose of 1.5 to 2.5 mg/kg. Peak values are found 4 to 6 hours after the dose, and are dependent on degree of meningeal inflammation and dosage.

Gentamicin has also been found in the sputum, pleural fluid and peritoneal cavity. Gentamicin crosses the peritoneal as well as the placental membranes.

Gentamicin at considerably higher doses than normally recommended, like other aminoglycoside antibiotics, causes neuromuscular blockade in animals. This phenomenon is antagonized by neostigmine or calcium (see Precautions).

Minimal amounts of gentamicin are absorbed following oral administration; therefore, oral administration is not recommended.

Gentamicin has been shown to affect vestibular and renal functions in animals and man. Chronic administration of 5 mg/kg for 50 days in dogs, 10 mg/kg for 40 days in cats and 20 mg/kg for 24 days in rats resulted in mild toxicity in some animals studied. Higher toxic doses resulted in renal and vestibular function damage which appeared to be dose related. In humans the only serious side effect to date has been damage to the eighth cranial nerve, predominantly the vestibular branch. Proteinuria, a rise in BUN or serum creatinine have also occurred (see Adverse Effects). These findings have usually reverted to normal when the drug was discontinued.

Indications And Clinical Uses: The parenteral treatment of serious infections caused by laboratory determined susceptible bacteria, with due regard for relative antibiotic toxicity. Therefore, the drug may be considered for treatment of: (1) bacteremia (2) respiratory tract infections (3) urinary tract infections (4) infected wounds: surgical and traumatic (5) bone and soft tissue infections, including peritonitis and burns complicated by sepsis.

In the majority of cases bacteriologic cultures should be obtained initially, to identify the causative organism and to determine its sensitivity to gentamicin. Garamycin sensitivity discs (2 and 10 g) are available.

In suspected or documented gram-negative septicemia, particularly when shock or hypotension are present, gentamicin injectable may be considered for initial antimicrobial therapy. Gentamicin may also be considered in serious staphylococcal infections when other conventional antimicrobial therapy is inappropriate or when bacterial susceptibility testing and clinical judgment indicate its use. If anaerobic organisms are suspected, additional antimicrobial therapy should be added to the gentamicin regimen.

The decision to continue therapy with gentamicin should be based on results of the sensitivity tests, clinical response of the patient, and consideration of relative antibiotic toxicity.

Clinical studies have shown that organisms previously sensitive to gentamicin have become resistant during therapy. Although this has occurred infrequently, the possibility should nevertheless be considered. There is evidence that cross resistance between gentamicin and aminoglycoside antibiotics may occur since bacteria made resistant to aminoglycoside antibiotics artificially in the laboratory are also resistant to gentamicin; however, gentamicin may be active against clinical isolates of bacteria resistant to other aminoglycosides. Conversely, organisms resistant to gentamicin may be sensitive to other aminoglycoside antibiotics.

Contra-Indications: A history of hypersensitivity or toxic reactions to gentamicin.

Pregnancy: The safety of gentamicin for use during pregnancy has not been established. Aminoglycoside antibiotics cross the placenta and may cause harm when administered to pregnant women. Irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy has been reported. Serious side effects to mother, fetus, or newborn have not been reported following treatment of pregnant women with other aminoglycosides, however, the potential for fetal toxicity exists. It is not known whether gentamicin can cause fetal harm when administered to pregnant women or can affect reproductive capacity. Gentamicin should be used during pregnancy only in life-threatening situations or severe infections, bearing in mind the possible adverse effects on the fetus.

Lactation: Studies in nursing mothers indicate that small amounts of the drug are excreted in breast milk. Because of the potential for serious adverse reactions from aminoglycosides in nursing infants, a decision should be made whether to discontinue nursing, or to discontinue gentamicin therapy, taking into account the importance of the drug to the mother.

Precautions: Ototoxicity: Gentamicin, in common with the antibiotics streptomycin, neomycin and kanamycin, has produced ototoxicity in experimental animals and man. This adverse reaction which may be delayed in onset, is manifested primarily by damage to vestibular function. The reversibility of this adverse reaction is frequently contingent upon early recognition of potential ototoxicity. In all patients developing tinnitus, dizziness or loss of hearing, the attending physician should strongly consider discontinuing this antibiotic except in those cases where gentamicin appears to be the only proven course of therapy.

Complete damage has occurred mainly in patients who were uremic, had renal dysfunction, had prior therapy with ototoxic drugs or received higher doses and longer courses of therapy than those recommended.

In patients who have previously been treated with drugs likely to affect eighth cranial nerve function (e.g., streptomycin, neomycin, kanamycin, etc.), gentamicin should be used with caution and with the understanding that toxic effects may be cumulative with these agents.

Potent diuretics such as ethacrynic acid and furosemide have been associated with eighth cranial nerve dysfunction, and the concomitant use of either of these drugs with gentamicin should be avoided. It is believed that i.v. diuretics may cause fairly rapid rise in gentamicin serum levels and potentiate ototoxicity.

In patients with impaired renal function, the frequency of gentamicin administration should be reduced (see Dosage), and renal function should be monitored along with evaluation of auditory and vestibular function. Serum concentrations of gentamicin should be monitored whenever feasible; prolonged concentrations above 12 g/mL should be avoided.

Nephrotoxicity: Nephrotoxicity manifested by an elevated BUN or serum creatinine level or a decrease in the creatinine clearance has been reported with gentamicin. In most cases, these changes have been reversible when the drug has been discontinued.

The administration of other potentially nephrotoxic agents prior to or in conjunction with gentamicin may increase the risk of nephrotoxicity.

As with other antibiotics, treatment with gentamicin may occasionally result in overgrowth of nonsensitive organisms. If superinfection occurs, appropriate measures should be taken.

Neuromuscular Blocking Action: Neuromuscular blockage and respiratory paralysis have been reported in the cat receiving high doses (40 mg/kg) of gentamicin. The possibility of these phenomena occurring in man should be considered if gentamicin is administered to patients receiving general anesthesia and/or neuromuscular blocking agents such as succinylcholine and tubocurarine.

In patients with myasthenia gravis, use of drugs with potential neuromuscular blocking action may be dangerous.

Neuromuscular blocking action produced by gentamicin in animals may be antagonized by neostigmine or calcium.

Adverse Reactions: In addition to the ototoxicity and nephrotoxicity discussed under Precautions, other adverse reactions reported infrequently and possibly related to gentamicin include increased serum transaminase (AST, ALT), increased reticulocyte count, and increased serum bilirubin, anemia, rash, granulocytopenia, urticaria, thrombocytopenia, headache, vomiting and muscle twitching.

Adverse reactions reported rarely and possibly related to gentamicin are nausea, increased salivation, lethargy and decreased appetite, weight loss, pulmonary fibrosis, purpura, splenomegaly, transient hepatomegaly, itching, numbness, skin tingling, laryngeal edema and spasm, joint pain, drug fever, convulsions, hypotension, hypertension, decreased reticulocyte count, decreased serum calcium, decreased hemoglobin and hematocrit, fifth nerve paresthesia and gastrointestinal hemorrhage. One case of neuromuscular blocking action has been reported in the literature.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: In the event of overdose or toxic reactions, hemodialysis will aid in the removal of gentamicin from the blood. The rate of gentamicin removal is considerably less by peritoneal dialysis than it is by hemodialysis. In the newborn infant, exchange transfusions may also be considered. These procedures are of particular importance for patients with impaired renal function.

Dosage And Administration: Using the recommended doses, considerable variation in the serum concentrations between individual patients has been observed. In order to insure adequate therapeutic concentrations which may be critical, while at the same time avoiding potentially toxic concentrations, it is desirable to measure peak and trough gentamicin serum concentrations. Following i.v. or i.m. administration, 2 or 3 times daily, the peak concentration, measured 30 minutes to 1 hour after administration, is expected to be in the range of 4 to 6 µg/mL. With once daily administration, transient, high peak concentrations can be anticipated. With all regimens, the dosages should be adjusted to avoid prolonged concentrations above 10 to 12 µg/mL. Trough levels above 2 µg/mL, measured just before the next dose, would also be avoided. Determination of the adequacy of a serum level for a particular patient must take into consideration susceptibility of the causative microorganism, severity of infection, and the status of the patient’s host-defense mechanisms.

The usual duration of treatment for all patients is 7 to 10 days. In complicated infections, a longer course of therapy may be necessary. In such cases, monitoring of renal, auditory and vestibular functions is recommended, since toxicity is more likely to occur with treatment extended over 10 days. Dosage should be reduced if clinically indicated.

I.M.: Patients with normal renal function: Urinary tract infections: Gentamicin is highly concentrated in urine and renal tissue. In patients with lower urinary tract infection particularly if chronic or recurrent and without evidence of impairment of renal function, gentamicin may be administered i.m. either in a dose of 160 mg once a day or 80 mg twice daily for 7 to 10 days. For adults weighing less than 60 kg, the single dose should be 3 mg/kg.

Upper urinary tract infections, such as pyelonephritis, and more particularly if there are signs of systemic involvement, should be treated according to one of the dosage schedules for systemic infections.

Since gentamicin activity is increased at pH 7.5, it may be advantageous to alkalinize the urine of patients treated for urinary tract infections.

Systemic Infections: Adults with serious infections and normal renal function: 3 mg/kg/day administered i.m. in 3 equal doses. Therefore, for patients weighing over 60 kg, the usual dosage is 80 mg 3 times daily. For patients weighing 60 kg or less, the usual dosage is 60 mg 3 times a day. In severe infections, the recommended dosage is 3 to 6 mg/kg/day administered in 3 equal doses, every 8 hours. If a dosage greater than 3 mg/kg/day is administered initially, it should be reduced to 3 mg/kg/day when clinically indicated.

Life-Threatening Infections: Administer dosages up to 5 mg/kg/day in 3 or 4 equally divided doses. Reduce to 3 mg/kg/day as soon as clinically indicated.

Children: The precautions for the treatment of infection in children are the same as those for adults.

Infants and Neonates (see Contraindications): In premature and full term neonates, 1 week of age or less, a dosage of 6 mg/kg/day may be administered in 2 equal doses every 12 hours. In infants older than 1 week, gentamicin may be administered in 3 equal doses every 8 hours.

Patients with Impaired Renal Function: Dosage must be adjusted in patients with impaired renal function. Since the creatinine clearance rate and serum creatinine concentration have high correlation with the serum half-life of gentamicin, these laboratory tests may provide the guidance necessary for adjustment of the interval between doses. The serum half-life (in hours) of gentamicin may be estimated by multiplying the serum creatinine (mg/100 mL) by 4. The frequency of administration (in hours) may be approximated by doubling the serum half-life.

In patients with renal failure who are undergoing 14-hour hemodialysis twice weekly, administration of gentamicin 1 mg/kg, at the end of each dialysis period has been suggested.

In those instances when only BUN concentration is available, this value may be utilized initially; however, it should be supplemented with a serum creatinine level or creatinine clearance rate whenever possible.

This dosage schedule is not intended as a rigid recommendation but is provided as a guide to dosage when the measurement of gentamicin serum levels is not feasible. It should be used in conjunction with close clinical and laboratory observations of the patients and modified as deemed necessary by the treating physician.

I.V.: For use in those circumstances when the i.m. route is not feasible, e.g., patients in shock, with hemorrhagic disorders, severe burns, or reduced muscle mass.

The usual dose of gentamicin administered i.v. is 3 mg/kg/day in 3 equally divided doses. For i.v. administration, a single dose (1 mg/kg) is diluted in 100 to 200 mL of sterile normal saline or in a sterile solution of dextrose 5% in water. The solution is infused over a period of 1 to 2 hours and repeated every 8 hours if necessary.

A single dose of gentamicin injectable undiluted may also be given directly into the side arm of an i.v. tubing set, slowly over a period of 2 to 3 minutes and repeated every 8 hours, if necessary.

Compatibility: Garamycin Injection should not be physically premixed with other drugs, but should be administered separately in accordance with the recommended route of administration and dosage schedule.

Availability And Storage: 10 mg/mL: Each mL of aqueous parenteral solution contains: gentamicin (as sulfate USP) 10 mg. pH 3.0 to 4.5. Nonmedicinal ingredients: disodium edetate, methylparaben, propylparaben and sodium bisulfite. Multiple dose vials of 2 and 20 mL. Vials of 2 mL.

40 mg/mL: Each mL of aqueous parenteral solution contains: gentamicin (as sulfate USP) 40 mg. pH 3.0 to 4.5. Nonmedicinal ingredients: disodium edetate, methylparaben, propylparaben and sodium bisulfite. Multiple dose vials of 2 and 20 mL.

Solutions are heat stable and do not require refrigeration. Store at 15 and 30°C.

GARAMYCIN® Parenteral Schering Gentamicin Sulfate Antibiotic

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