Gentamicin Sulfate Injection, USP

GENTAMICIN SULFATE INJECTION USP

Novopharm

Antibiotic

Action And Clinical Pharmacology: Gentamicin exerts its bactericidal effect by specific inhibition of normal protein synthesis in susceptible bacteria. It binds primarily to the 30S subunit of bacterial ribosomes.

Gentamicin is poorly absorbed following oral administration and must be given parenterally for systemic use. When administered i.m., peak serum concentrations are attained in 0.5 to 1 hour. Peak serum concentrations following i.v. administration occur at the end of the infusion and vary with the rate of infusion. The serum elimination half-life is about 2 hours in patients with normal renal function.

Gentamicin is excreted by the kidney in unchanged form, mostly by glomerular filtration. After initial administration of gentamicin, 30 to 100% of the dose is recoverable in the urine in 24 hours in patients with normal renal function. Approximately 30% is excreted in 12 hours in the newborn.

Gentamicin Serum Levels via the I.M. Route in Adults: Peak bactericidal serum concentrations for susceptible bacteria in patients with normal renal function occur between 30 and 90 minutes after injection. The peak serum level (g/mL) was found to be 4 times the single dose (mg/kg), and the mean serum half-life is approximately 2 hours.

Gentamicin Serum Levels via the I.M. Route in Infants and Neonates: Gentamicin administered i.m. to infants 7 days of age and under resulted in peak serum concentrations of 2.2 to 8.6 g/mL (mean 4.0 g/mL) one-half to 1 hour after a dose of 2.5 mg/kg.

The mean serum gentamicin half-life in neonates under 72 hours of age is approximately 5 hours. The half-life may be considerably prolonged in infants weighing less than 1 500 g. Prolonged half-life values may extend through the second week of life in low birth weight infants.

In contrast, full-term infants 7 days of age and older have half-lives of about 3 to 3.5 hours. I.M. doses of 2 and 2.5 mg/kg administered to infants 2 to 24 months of age resulted in gentamicin serum concentrations in the range of 2.5 to 7.5 g/mL.

Gentamicin Serum Levels via the I.V. Route in Adults: Peak gentamicin concentrations were reached at the end of a 2-hour infusion of a dose of 1 mg/kg to a group of patients and averaged 4.5 g/mL (range 0.5 to 8 g/mL).

Serum levels of 5 to 9 g/mL were obtained following slow i.v. injection after 10 minutes at recommended doses.

The mean serum half-life is approximately 2 hours which is the same as for the i.m. route of administration.

Gentamicin Serum Levels via the I.V. Route in Infants and Neonates: Half-life values and serum gentamicin levels after i.v. infusion were similar to those after i.m. administration.

Gentamicin Excretion: Following a dose of gentamicin in man, about 25 to 30% is bound by serum protein, and it is released as the drug is excreted.

Gentamicin is excreted principally in the urine in an unchanged form by glomerular filtration thus resulting in high urinary concentration of the antibiotic. After initial administration of gentamicin, 30 to 100% of the dose is recoverable in the urine in 24 hours in patients with normal renal function. Renal clearance of gentamicin is similar to the renal clearance of endogenous creatinine. The clearance of gentamicin is decreased in patients with impaired renal function; the more severe the impairment, the slower the clearance.

Approximately 30% of the administered dose is excreted in 12 hours in the newborn.

Gentamicin Penetration (Distribution): Gentamicin is detected in tissues and body fluids following parenteral administration. In general, gentamicin concentration in the bile has been low suggesting minimal biliary excretion. Following i.m. injection, gentamicin has been found in the cerebrospinal fluid in low concentrations which may be inadequate for treatments of certain CNS infections.

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

Gentamicin has also been found in the peritoneal cavity, sputum and pleural fluid. Gentamicin crosses placental as well as peritoneal membranes. Oral administration is not recommended since minimal amounts of gentamicin are absorbed orally.

Indications And Clinical Uses: In the treatment of serious infections caused by susceptible strains of the following microorganisms: P. aeruginosa, Proteus species (indole negative and indole positive), E. coli, K. pneumoniae, E. aerogenes, S. marcescens, Staphylococcus species (including penicillin and methicillin-resistant strains).

Gentamicin may be considered for the treatment of the following: (1) bacteremia (2) respiratory tract infections (3) urinary tract infections (4) infected wounds: surgical and traumatic (5) soft tissue infections, including peritonitis and burns complicated by sepsis (6) bone infections.

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

Susceptibility: In the majority of cases, appropriate cultures and susceptibility studies should be obtained initially to identify the causative organism and to determine its sensitivity to gentamicin.

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

Additional or other antimicrobial therapy should be instituted if susceptibility tests indicate that the causative organism is resistant to gentamicin. In suspected sepsis, combined therapy with gentamicin and a penicillin type of drug has been used until bacteriological studies have identified the etiological organism.

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

Contra-Indications: Individuals with a history of hypersensitivity or toxic reactions to its use. A history of hypersensitivity or serious toxic reactions to other aminoglycosides may contraindicate use of gentamicin because of the known cross-sensitivity of patients to drugs in this class. Aminoglycosides, including gentamicin, are not indicated in uncomplicated initial episodes of urinary tract infections unless the causative organisms are susceptible to these antibiotics and are not susceptible to antibiotics having less potential for toxicity.

Manufacturers’ Warnings In Clinical States: Patients treated with aminoglycosides should be under close clinical observation because of the potential toxicity associated with their use.

Neurotoxicity: Neurotoxicity manifested by ototoxicity, both vestibular and auditory can occur in patients treated with gentamicin, primarily in those with preexisting renal damage and in patients with normal renal function treated with higher doses and/or for longer periods than recommended. Aminoglycoside-induced ototoxicity is usually irreversible.

The onset of ototoxicity may be delayed and is primarily manifested by damage to vestibular function. Physicians should strongly consider discontinuing gentamicin in patients developing tinnitus, dizziness or hearing loss, except in cases where gentamicin appears to be the only proven course of therapy.

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

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

Nephrotoxicity: As with other aminoglycosides, gentamicin is potentially nephrotoxic. Nephrotoxicity may be manifested by elevated serum creatinine or blood urea nitrogen levels or by a decrease in the creatinine clearance. These changes have been reversible in most cases when the drug has been discontinued. The risk of nephrotoxicity is greater in patients with impaired renal function and in those who receive high dosage or prolonged therapy.

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

Note: Gentamicin injection contains sodium bisulfite, 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 in nonasthmatic people.

Precautions: The frequency of administration of gentamicin should be reduced in patients with impaired renal function (see Dosage). In addition, renal function should be monitored and auditory and vestibular function evaluated in patients with impaired renal function.

Whenever feasible, serum concentrations of gentamicin should be monitored and prolonged concentrations above 12 µg/mL should be avoided.

Superinfection: Overgrowth of nonsensitive organisms may occasionally result with gentamicin treatment.

Neuromuscular Blocking Action: The administration of high doses (40 mg/kg) of gentamicin in the cat has resulted in neuromuscular blocking and respiratory paralysis. These phenomena may occur in man with the concomitant administration of gentamicin with general anesthetics and/or neuromuscular blocking agents such as succinylcholine and tubocurarine, or massive transfusions of citrate anticoagulated blood. Neuromuscular blocking action produced by gentamicin may be antagonized by neostigmine or calcium salts.

The use of drugs with potential neuromuscular blocking action may be dangerous in patients with myasthenia gravis.

Drug Interactions: The concomitant use of potent diuretics such as ethacrynic acid and furosemide with gentamicin has been associated with eighth cranial nerve dysfunction and should therefore be avoided. In addition, when administered i.v., diuretics may enhance aminoglycoside toxicity by altering the antibiotic concentration in serum and tissue. It is believed that i.v. diuretics may potentiate ototoxicity and cause a fairly rapid rise in gentamicin serum levels.

Concurrent and/or sequential systemic or topical use of other potentially neurotoxic and/or nephrotoxic drugs, such as cisplatin, cephaloridine, kanamycin, amikacin, neomycin, polymyxin B, colistin, paromomycin, streptomycin, tobramycin, vancomycin and viomycin should be avoided.

Although the in vitro mixing of gentamicin and carbenicillin results in a rapid and significant inactivation of gentamicin, this interaction has not been demonstrated in patients with normal renal function who received both drugs by different routes of administration. A reduction in gentamicin serum half-life has been reported in patients with severe renal impairment receiving carbenicillin concomitantly with gentamicin.

Cross-allergenicity among aminoglycosides has been demonstrated.

Geriatrics: Elderly patients may have reduced renal function which may not be evident in the results of routine screening tests, such as BUN or serum creatinine. A creatinine clearance determination may be more useful. Monitoring of renal function during treatment with gentamicin, as with other aminoglycosides, is particularly important in such patients. A Fanconi-like syndrome, with aminoaciduria and metabolic acidosis, has been reported in some adults and infants being given gentamicin injections.

Pregnancy: Gentamicin injection is not recommended during pregnancy except in life-threatening situations, even though studies in expectant animals have not revealed teratogenic effects. Aminoglycoside antibiotics cross the placenta, and there have been several reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Serious side effects to mother, fetus, or newborn have not been reported in the treatment of pregnant women with other aminoglycosides.

Newborns: Except for life-threatening infections, gentamicin injection should be used with caution in premature and neonatal infants because of their renal immaturity and the resultant prolongation of serum half-life of the drug. No adverse reactions have been revealed in these cases although follow-up has been limited.

Adverse Reactions: Adverse reactions reported infrequently and possibly related to gentamicin, in addition to the ototoxicity and nephrotoxicity discussed under Precautions, include the following grouped by system: Hypersensitivity: rash, urticaria, itching, drug fever, anaphylactoid reactions.

Gastrointestinal: vomiting, nausea, decreased appetite, weight loss, gastrointestinal hemorrhage, stomatitis.

Blood: increased and decreased reticulocyte counts, anemia, granulocytopenia, thrombocytopenia, leukopenia, eosinophilia, transient agranulocytosis, hypotension, hypertension, decreased hemoglobin and hematocrit, increased serum LDH, purpura, splenomegaly, decreased serum calcium, magnesium, sodium and potassium.

Hepatic: increased serum transaminase (AST, ALT), increased serum bilirubin, transient hepatomegaly.

Local Reactions: pain at the injection site, s.c. atrophy or fat necrosis, joint pain.

CNS: headache, muscle twitching, convulsions, fifth nerve paresthesia, confusion, depression, pseudotumor cerebri, acute organic brain syndrome, numbness, skin tingling.

Respiratory: respiratory depression, neuromuscular blockade, pulmonary fibrosis.

Miscellaneous: increased salivation, lethargy, laryngeal edema and spasm, visual disturbances, generalized burning, alopecia.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Peritoneal dialysis or hemodialysis will aid in the removal of gentamicin from the blood in the event of overdosage or toxic reactions. These procedures are particularly important in patients with impaired renal function. The rate of removal of gentamicin is considerably less by peritoneal dialysis than it is by hemodialysis.

Dosage And Administration: I.M. injection is the usual route of administration for gentamicin injection. Administration via the i.v. route is generally reserved for special indications (see I.V. Administration). Treatment usually lasts from 7 to 10 days. A longer course of therapy may be necessary, however, in difficult and complicated infections. Monitoring of vestibular, auditory and renal functions is advisable in such cases.

The patient’s pretreatment body weight should be obtained for calculation of correct dosage. The dosage of aminoglycosides in obese patients should be based on an estimate of the lean body mass.

Serum concentrations of aminoglycosides should be monitored when feasible to assure adequate levels and to avoid potentially toxic levels. When monitoring gentamicin peak concentrations, dosage should be adjusted so that prolonged levels above 12 µg/mL are avoided. When monitoring gentamicin trough concentrations, dosage should be adjusted so that levels above 2 µg/mL are avoided. Excessive peak and/or trough serum concentrations of aminoglycosides may increase the risk of renal and eighth cranial nerve toxicity.

I.M. Administration: Patients with Normal Renal Function: Urinary Tract Infections: Gentamicin is highly concentrated in renal tissue and urine. Gentamicin may be administered i.m. either in a dose of 160 mg once a day or 80 mg b.i.d. for 7 to 10 days in patients with lower urinary tract infections particularly if chronic or recurrent and without evidence of impairment of renal function. The single daily dose should be 3 mg/kg of body weight for adults weighing less than 60 kg.

Dosage schedules for systemic infections should be followed for patients with upper urinary tract infections, such as pyelonephritis, and more particularly, if there are signs of systemic involvement.

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

Systemic Infections: Adults: For adult patients with serious infection and normal renal function: 3 mg/kg/day administered i.m. in 3 equal doses (every 8 hours). Therefore, the usual dosage is 80 mg 3 times daily for patients weighing over 60 kg. The usual dosage is 60 mg 3 times daily for patients weighing 60 kg or less.

Life-Threatening Infections: Dosages up to 5 mg/kg/day should be administered in 3 or 4 equally divided doses in patients with life-threatening infections. As soon as clinically indicated, this dosage should be reduced to 3 mg/kg/day.

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

The recommended dosage for children 1 to 12 years of age is 3 to 6 mg/kg/day in 3 equal doses every 8 hours for severe infections. If a dosage greater than 3 mg/kg/day is initially administered, it should be reduced to 3 mg/kg/day when clinically indicated.

Infants and Neonates (see Precautions): A dosage of 6 mg/kg/day in 2 equal doses every 12 hours may be administered to premature and full-term neonates, 1 week of age or less. Gentamicin may be administered at 6 mg/kg/day in 3 equal doses every 8 hours in infants older than 1 week to approximately 1 year of age.

Considerable variation in the serum levels between individual patients has been observed with these recommended doses. Serum levels should be monitored in order to insure adequate therapeutic levels which may be critical, while at the same time avoiding potentially toxic concentrations. Following i.m. administration, a serum level in excess of 10 to 12 µg/mL should be considered potentially toxic.

Patients with Impaired Renal Function: Dosage adjustments must be made in patients with impaired renal function to assure therapeutically adequate, but not excessive, blood levels. Serum concentrations of gentamicin must be monitored in these patients.

One method of dosage adjustment is to increase the interval between administration of the usual dosage.

Since the serum half-life of gentamicin is highly correlated with the creatinine clearance rate and serum creatinine concentration, these laboratory tests may provide the guidance necessary for adjustment of the interval between doses of gentamicin injection. To estimate the serum half-life of gentamicin (in hours), multiply the serum creatinine (µmol/L) by 0.045. The frequency of administration (in hours) may be approximated by doubling the serum half-life.

A second method of dosage adjustment is to administer the antibiotic at the usual interval but in reduced dose

When only serum creatinine levels are available, the following formula (based on sex, weight, and the age of the patient) may be used to convert this value into estimated creatinine clearance. The serum creatinine should represent a steady-state of renal function.

Males: Creatinine Clearance (mL/s) = Weight (kg)´(140-age) 49´serum creatinine (mol/L)

Females: = 0.85´above value. In patients with renal failure who are undergoing 14-hour hemodialysis twice weekly, administration of gentamicin injection in a dose of 1 mg/kg at the end of each dialysis period has been suggested.

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

I.V. Injection: 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 i.v. administration of gentamicin injection is recommended.

The recommended dosage for i.v. administration is identical to that recommended for i.m. use.

Administration: For i.v. administration, a single dose of gentamicin injection 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 injection 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.

I.V. Administration: The appropriate dose of gentamicin injection may be added to either of the solutions for i.v. infusion listed below: Normal Saline, Dextrose 5% in water.

The diluted infusion mixture should be prepared immediately before use and any unused portion must be discarded. Store at room temperature (15 to 30°C).

Incompatibility: Gentamicin injection should be administered separately in accordance with the recommended route of administration and dosage schedule and should not be physically premixed with other drugs.

Availability And Storage: Each mL of sterile, aqueous solution contains: gentamicin (as sulfate) 10 mg or gentamicin (as sulfate) 40 mg. Nonmedicinal ingredients: edetate disodium 0.1 mg, sodium metabisulfite 0.8 mg and water for injection. Sodium hydroxide and/or sulfuric acid may be added to adjust pH to a range of 3.0 to 5.5. Vials of 2 mL. Store at room temperature (15 to 30°C).

GENTAMICIN SULFATE INJECTION USP Novopharm Antibiotic

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