Gentamicin (Injection)

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# Black Box Warning

# Overview
Gentamicin (Injection) is an aminoglycoside that is FDA approved for the {{{indicationType}}} of bacterial infection due to klebsiella pneumoniae, bacterial infection due to pseudomonas, bacterial meningitis, bacterial septicemia, bacterial sepsis of newborn, citrobacter infection, eye infection, infection due to enterobacteriaceae, infection due to escherichia coli, infection of bone, infection of skin and/or subcutaneous tissue, infective endocarditis, peritonitis, and other gastrointestinal tract infections, respiratory tract infection, serratia marcescens infection, staphylococcal infectious disease, urinary tract infections. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include neuromuscular blockade, ototoxicity, nephrotoxicity, respiratory tract paralysis.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- The recommended dosage of gentamicin injection for patients with serious infections and normal renal function is 3 mg/kg/day, administered in three equal doses every eight hours (Table 3).
- For patients with life-threatening infections, dosages up to 5 mg/kg/day may be administered in three or four equal doses.  This dosage should be reduced to 3 mg/kg/day as soon as clinically indicated (Table 3).
- It is desirable to measure both peak and trough serum concentrations of gentamicin to determine the adequacy and safety of the dosage.  When such measurements are feasible, they should be carried out periodically during therapy to assure adequate but not excessive drug levels.  For example, the peak concentration (at 30 to 60 minutes after IM injection) is expected to be in the range of 4 to 6 mcg/mL.  When monitoring peak concentrations after IM or IV administration, dosage should be adjusted so that prolonged levels above 12 mcg/mL are avoided.  When monitoring trough concentrations (just prior to the next dose), dosage should be adjusted so that levels above 2 mcg/mL are avoided.  Determination of the adequacy of a serum level for a particular patient must take into consideration the susceptibility of the causative organism, the severity of the infection and the status of the patients host-defense mechanisms.
- In patients with extensive burns, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides.  In such patients treated with gentamicin, measurement of serum concentrations is recommended as a basis for dosage adjustment.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
- Developed by:The Infectious Diseases Society of America
- Class of Recommendation: Class IIa
- Strength of Evidence: Category B
- Dosing Information
- IV gentamicin 1.6 mg/kg every 8 hours.
- Developed by: CDC
- Class of Recommendation: Class IIa
- Strength of Evidence: Category C
- Dosing Information
- Gentamicin loading dose IV or IM (2 mg/kg of body weight) followed by a maintenance dose (1.5 mg/kg) every 8 hours.

### NonGuideline-Supported Use
- IV gentamicin 80 mg twice daily
- Gentamicin was 1.5 mg/kg every 8 hours in adults
- Gentamicin 3 mg/kg every 8 hours
- Gentamicin 2 mg/kg load followed by 1.5 mg/kg
- A once-daily regimen of IV gentamicin 4 mg/kg
- Intramuscular gentamicin 2.5 mg/kg

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
- The recommended dosage of gentamicin injection for patients with serious infections and normal renal function is 3 mg/kg/day, administered in three equal doses every eight hours (Table 3).
- For patients with life-threatening infections, dosages up to 5 mg/kg/day may be administered in three or four equal doses.  This dosage should be reduced to 3 mg/kg/day as soon as clinically indicated (Table 3).
- It is desirable to measure both peak and trough serum concentrations of gentamicin to determine the adequacy and safety of the dosage.  When such measurements are feasible, they should be carried out periodically during therapy to assure adequate but not excessive drug levels.  For example, the peak concentration (at 30 to 60 minutes after IM injection) is expected to be in the range of 4 to 6 mcg/mL.  When monitoring peak concentrations after IM or IV administration, dosage should be adjusted so that prolonged levels above 12 mcg/mL are avoided.  When monitoring trough concentrations (just prior to the next dose), dosage should be adjusted so that levels above 2 mcg/mL are avoided.  Determination of the adequacy of a serum level for a particular patient must take into consideration the susceptibility of the causative organism, the severity of the infection and the status of the patients host-defense mechanisms.
- In patients with extensive burns, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides.  In such patients treated with gentamicin, measurement of serum concentrations is recommended as a basis for dosage adjustment.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Gentamicin (Injection) in pediatric patients.

### NonGuideline-Supported Use
- 2.5 mg/kg every 6 hours for 7 days
- Intramuscular gentamicin 2.5 mg/kg

# Contraindications
- Hypersensitivity to gentamicin is a contraindication 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.

# Warnings
- 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 in non-asthmatic people.
- Aminoglycosides can cause fetal harm when administered to a pregnant woman.  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.  Animal reproduction studies conducted on rats and rabbits did not reveal evidence of impaired fertility or harm to the fetus due to gentamicin sulfate.
- It is not known whether gentamicin sulfate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.  If gentamicin is used during pregnancy or if the patient becomes pregnant while taking gentamicin, she should be apprised of the potential hazard to the fetus.

### Precautions
- Prescribing Gentamicin Injection, USP 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.
- Neurotoxic and nephrotoxic antibiotics may be almost completely absorbed from body surfaces (except urinary bladder) after local irrigation and after topical application during surgical procedures.  The potential toxic effects of antibiotics administered in this fashion (neuromuscular blockage, respiratory paralysis, oto- and nephrotoxicity) should be considered.
- Increased nephrotoxicity has been reported following concomitant administration of aminoglycoside antibiotics and cephalosporins.
- Neuromuscular blockade 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 aminoglycosides are administered by any route to patients receiving anesthetics, or to patients receiving neuromuscular blocking agents, such as succinylcholine, tubocurarine or decamethonium, or in patients receiving massive transfusions of citrate-anticoagulated blood.  If neuromuscular blockade occurs, calcium salts may reverse it.
- Aminoglycosides should be used with caution in patients with neuromuscular disorders, such as myasthenia gravis or parkinsonism, since these drugs may aggravate muscle weakness because of their potential curare-like effects on the neuromuscular junction.  During or following gentamicin therapy, paresthesias, tetany, positive Chvostek and Trousseau signs and mental confusion have been described in patients with hypomagnesemia, hypocalcemia and hypokalemia.  When this has occurred in infants, tetany and muscle weakness has been described.  Both adults and infants required corrective electrolyte therapy.
- 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.
- Cross-allergenicity among aminoglycosides has been demonstrated.
- Patients should be well hydrated during treatment.
- 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.
- Treatment with gentamicin may result in overgrowth of nonsusceptible organisms.  If this occurs, appropriate therapy is indicated.

# Adverse Reactions

## Clinical Trials Experience
- Nephrotoxicity
- Adverse renal effects, as demonstrated by the presence of casts, cells or protein in the urine or by rising BUN, NPN, serum creatinine or oliguria, have been reported.  They occur more frequently in patients with a history of renal impairment (especially if dialysis is required) and in patients treated for longer periods or with larger doses than recommended.
- Neurotoxicity
- Serious adverse effects on both vestibular and auditory branches of the eighth nerve have been reported, primarily in patients with renal impairment (especially if hemodialysis is required) and in patients on high doses and/or prolonged therapy.  Symptoms include dizziness, vertigo, tinnitus, roaring in the ears and also hearing loss, which, as with the other aminoglycosides, may be irreversible.  Hearing loss is usually manifested initially by diminution of high-tone acuity.  Other factors which may increase the risk of toxicity include excessive dosage, dehydration and previous exposure to other ototoxic drugs.
- Peripheral neuropathy or encephalopathy, including numbness, skin tingling, muscle twitching, convulsions and a myasthenia gravis-like syndrome have been reported.
- NOTE: The risk of toxic reactions is low in patients with normal renal function who did not receive gentamicin sulfate at higher doses or for longer periods of time than recommended.
- Other reported adverse reactions possibly related to gentamicin include: respiratory depression, lethargy, confusion, depression, visual disturbances, decreased appetite, weight loss and hypotension and hypertension; rash, itching, urticaria, generalized burning, laryngeal edema, anaphylactoid reactions, fever and headache; nausea, vomiting, increased salivation and stomatitis; purpura, pseudotumor cerebri, acute organic brain syndrome, pulmonary fibrosis, alopecia, joint pain, transient hepatomegaly and splenomegaly.
- Laboratory abnormalities possibly related to gentamicin include: increased levels of serum transaminase (SGOT, SGPT), serum LDH and bilirubin; decreased serum calcium, magnesium, sodium and potassium; anemia, leukopenia, granulocytopenia, transient agranulocytosis, eosinophilia, increased and decreased reticulocyte counts and thrombocytopenia.  While clinical laboratory test abnormalities may be isolated findings, they may also be associated with clinically related signs and symptoms.  For example, tetany and muscle weakness may be associated with hypomagnesemia, hypocalcemia and hypokalemia.
- While the local tolerance of gentamicin sulfate is generally excellent, there has been an occasional report of pain at the injection site. Subcutaneous atrophy or fat necrosis suggesting local irritation has been reported rarely.

## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Gentamicin (Injection) in the drug label.

# Drug Interactions
There is limited information regarding Gentamicin (Injection) Drug Interactions in the drug label.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category D
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gentamicin (Injection) in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Gentamicin (Injection) during labor and delivery.

### Nursing Mothers
There is no FDA guidance on the use of Gentamicin (Injection) with respect to nursing mothers.

### Pediatric Use
There is no FDA guidance on the use of Gentamicin (Injection) with respect to pediatric patients.

### Geriatic Use
There is no FDA guidance on the use of Gentamicin (Injection) with respect to geriatric patients.

### Gender
There is no FDA guidance on the use of Gentamicin (Injection) with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Gentamicin (Injection) with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Gentamicin (Injection) in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Gentamicin (Injection) in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Gentamicin (Injection) in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Gentamicin (Injection) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Intravenous
- Intramuscular

### Monitoring
There is limited information regarding Monitoring of Gentamicin (Injection) in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Gentamicin (Injection) in the drug label.

# Overdosage

## Acute Overdose
- In the event of overdosage or toxic reactions, hemodialysis may aid in the removal of gentamicin from the blood, especially if renal function is, or becomes, compromised.  The rate of removal of gentamicin is considerably lower by peritoneal dialysis than it is by hemodialysis.

## Chronic Overdose
There is limited information regarding Chronic Overdose of Gentamicin (Injection) in the drug label.

# Pharmacology

## Mechanism of Action
- Gentamicin, an aminoglycoside, binds to the prokaryotic ribosome, inhibiting protein synthesis in susceptible bacteria.  It is bactericidal in vitro against Gram-positive and Gram-negative bacteria.

## Structure
- Gentamicin sulfate, a water-soluble antibiotic of the aminoglycoside group, is derived by the growth of Micromonospora purpurea, an actinomycete.
- It has the following structural formula.
- Gentamicin injection is a sterile, nonpyrogenic aqueous solution for parenteral administration.
- Each mL contains: Gentamicin sulfate equivalent to 40 mg gentamicin, methylparaben 1.8 mg and propylparaben 0.2 mg as preservatives, sodium metabisulfite 3.2 mg and edetate disodium 0.1 mg, Water for Injection q.s.  Sodium hydroxide and/or sulfuric acid may have been added for pH adjustment.

## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Gentamicin (Injection) in the drug label.

## Pharmacokinetics
- After intramuscular (IM) administration of gentamicin sulfate, peak serum concentrations usually occur between 30 and 60 minutes and serum levels are measurable for six to eight hours.  When gentamicin is administered by intravenous (IV) infusion over a two-hour period, the serum concentrations are similar to those obtained by IM administration.
- In patients with normal renal function, peak serum concentrations of gentamicin (mcg/mL) are usually up to four times the single IM dose (mg/kg); for example, a 1 mg/kg injection in adults may be expected to result in a peak serum concentration up to 4 mcg/mL; a 1.5 mg/kg dose may produce levels up to 6 mcg/mL.  While some variation is to be expected due to a number of variables such as age, body temperature, surface area and physiologic differences, the individual patient given the same dose tends to have similar levels in repeated determinations.  Gentamicin administered at 1 mg/kg every eight hours for the usual 7 to 10 day treatment period to patients with normal renal function does not accumulate in the serum.
- Gentamicin, like all aminoglycosides, may accumulate in the serum and tissues of patients treated with higher doses and/or for prolonged periods, particularly in the presence of impaired renal function.  In adult patients, treatment with gentamicin dosages of 4 mg/kg/day or higher for 7 to 10 days may result in a slight, progressive rise in both peak and trough concentrations.  In patients with impaired renal function, gentamicin is cleared from the body more slowly than in patients with normal renal function.  The more severe the impairment, the slower the clearance.(Dosage must be adjusted.)
- Since gentamicin is distributed in extra-cellular fluid, peak serum concentrations may be lower than usual in adult patients who have a large volume of this fluid.  Serum concentrations of gentamicin in febrile patients may be lower than those in afebrile patients given the same dose. When body temperature returns to normal, serum concentrations of the drug may rise.  Febrile and anemic states may be associated with a shorter than usual serum half-life. (Dosage adjustment is usually not necessary). In severely burned patients, the half-life may be significantly decreased and resulting serum concentrations may be lower than anticipated from the mg/kg dose.
- Protein binding studies have indicated that the degree of gentamicin binding is low; depending upon the methods used for testing, this may be between 0 and 30%.
- After initial administration to patients with normal renal function, generally 70% or more of the gentamicin dose is recoverable in the urine in 24 hours; concentrations in urine above 100 mcg/mL may be achieved.  Little, if any, metabolic transformation occurs; the drug is excreted principally by glomerular filtration.  After several days of treatment, the amount of gentamicin excreted in the urine approaches the daily dose administered.  As with other aminoglycosides, a small amount of the gentamicin dose may be retained in the tissues, especially in the kidneys.  Minute quantities of aminoglycosides have been detected in the urine weeks after drug administration was discontinued.  Renal clearance of gentamicin is similar to that of endogenous creatinine.
- In patients with marked impairment of renal function, there is a decrease in the concentration of aminoglycosides in urine and in their penetration into defective renal parenchyma.  This decreased drug excretion, together with the potential nephrotoxicity of aminoglycosides, should be considered when treating such patients who have urinary tract infections.
- Probenecid does not affect renal tubular transport of gentamicin.
- The endogenous creatinine clearance rate and the serum creatinine level have a high correlation with the half-life of gentamicin in serum.  Results of these tests may serve as guides for adjusting dosage in patients with renal impairment.
- Following parenteral administration, gentamicin can be detected in serum, lymph, tissues, sputum and in pleural, synovial and peritoneal fluids.
- Concentrations in renal cortex sometimes may be eight times higher than the usual serum levels.  Concentrations in bile, in general, have been low and have suggested minimal biliary excretion.  Gentamicin crosses the peritoneal as well as the placental membranes.  Since aminoglycosides diffuse poorly into the subarachnoid space after parenteral administration, concentrations of gentamicin in cerebrospinal fluid are often low and dependent upon dose, rate of penetration and degree of meningeal inflammation.  There is minimal penetration of gentamicin into ocular tissues following IM or IV administration.
- Drug Resistance
- Bacterial resistance to gentamicin is generally developed slowly.  Bacteria resistant to one aminoglycoside may be resistant to one or more other aminoglycosides.  The following bacteria are usually resistant to the aminoglycosides, including gentamicin: most streptococcal species (including Streptococcus pneumoniae and the Group D streptococci), most enterococcal species (including Enterococcus faecalis, E. faecium, and E. durans), and anaerobic organisms, such as Bacteroides species and Clostridium species.
- Aminoglycosides are known to be not effective against Salmonella and Shigella species in patients.  Therefore, in vitro susceptibility test results should not be reported.
- Interactions with Other Antimicrobials
- In vitro studies show that an aminoglycoside combined with an antibiotic that interferes with cell wall synthesis may act synergistically against some enterococcal strains. The combination of gentamicin and penicillin G has a synergistic bactericidal effect against strains of Enterococcus faecalis, E. faecium and E. durans.  An enhanced killing effect against many of these strains has also been shown in vitro with combinations of gentamicin and ampicillin, carbenicillin, nafcillin or oxacillin.
- The combined effect of gentamicin and carbenicillin is synergistic for many strains of Pseudomonas aeruginosa.  In vitro synergism against other Gram-negative organisms has been shown with combinations of gentamicin and cephalosporins.
- Gentamicin may be active against clinical isolates of bacteria resistant to other aminoglycosides.
- Antibacterial Activity
- Gentamicin has been shown to be active against most of the following bacteria, both in vitro and in clinical infections.
- Gram-Positive Bacteria
Staphylococcus species
- Gram-Negative Bacteria
Citrobacter species
Enterobacter species
Escherichia coli
Klebsiella species
Proteus species
Serratia species
Pseudomonas aeruginosa
- Susceptibility Test Methods
- When available, the clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility tests for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens.  These reports should aid the physician in selecting the most effective antimicrobial.
- Dilution Technique
- Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs).  These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds.  The MICs should be determined using a standardized test method.1, 3 Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of gentamicin powder.  The MIC values should be interpreted according to the criteria provided in Table 1.
- Diffusion Technique
- Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds.  One such standardized procedure requires the use of standardized inoculum concentrations and paper disks impregnated with 10 mcg of gentamicin. 2, 3  The disk diffusion values should be interpreted according to the criteria provided in Table 1.
- aFor Salmonella and Shigella spp., aminoglycosides may appear active in vitro but are not effective clinically; the results should not be reported as susceptible
- bFor staphylococci that test susceptible, aminoglycosides are used only in combination with other active agents that test susceptible
- A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration at the infection site necessary to inhibit growth of the pathogen.  A report of Intermediate indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative clinically feasible drugs, the test should be repeated.  This category implies possible clinical applicability in body sites where the drug is physiologically concentrated.  This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation.  A report of Resistant indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.
- Quality Control
- Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1, 2, 3 Standard gentamicin powder should provide the following range of MIC values provided in Table 2.  For the diffusion technique using the 10-mcg gentamicin disk the criteria provided in Table 2 should be achieved.

## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Gentamicin (Injection) in the drug label.

# Clinical Studies
There is limited information regarding Clinical Studies of Gentamicin (Injection) in the drug label.

# How Supplied
- Gentamicin Injection, USP, containing gentamicin 40 mg/mL is supplied as follows:
- Also available, Gentamicin Injection (Pediatric), 10 mg/mL, supplied in 2 mL (20 mg) vials in packages of 25.
- Store at 20 to 25C (68 to 77F).
- This container closure is not made with natural rubber latex.

## Storage
There is limited information regarding Gentamicin (Injection) Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Patients should be counseled that antibacterial drugs including Gentamicin Injection, USP should only be used to treat bacterial infections.  They do not treat viral infections (e.g., the common cold).  When Gentamicin Injection, USP is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.  Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Gentamicin Injection, USP or other antibacterial drugs in the future.

# Precautions with Alcohol
- Alcohol-Gentamicin (Injection) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
There is limited information regarding Gentamicin (Injection) Brand Names in the drug label.

# Look-Alike Drug Names
There is limited information regarding Gentamicin (Injection) Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price