Data from FDA - Curated by EPG Health - Last updated 20 December 2016

Indication(s)

INDICATIONS AND USAGE Tobramycin sulfate is indicated for the treatment of serious bacterial infections caused by susceptible strains of the designated microorganisms in the diseases listed below: Septicemia in the neonate, child, and adult caused by P aeruginosa, E coli, and Klebsiella sp Lower respiratory tract infections caused by P aeruginosa, Klebsiella sp, Enterobacter sp, Serratia sp, E coli, and S aureus (penicillinase and non-penicillinase-producing strains) Serious central-nervous-system infections (meningitis) caused by susceptible organisms Intra-abdominal infections, including peritonitis, caused by E coli, Klebsiella sp, and Enterobacter sp Skin, bone, and skin-structure infections caused by P aeruginosa, Proteus sp, E coli, Klebsiella sp, Enterobacter sp

and S aureus Complicated and recurrent urinary tract infections caused by P aeruginosa, Proteus sp (indole-positive and indole-negative), E coli, Klebsiella sp, Enterobacter sp, Serratia sp, S aureus, Providencia sp, and Citrobacter sp Aminoglycosides, including tobramycin sulfate, are not indicated in uncomplicated initial episodes of urinary tract infections unless the causative organisms are not susceptible to antibiotics having less potential toxicity.

Tobramycin sulfate may be considered in serious staphylococcal infections when penicillin or other potentially less toxic drugs are contraindicated and when bacterial susceptibility testing and clinical judgment indicate its use.

Bacterial cultures should be obtained prior to and during treatment to isolate and identify etiologic organisms and to test their susceptibility to tobramycin.

If susceptibility tests show that the causative organisms are resistant to tobramycin, other appropriate therapy should be instituted.

In patients in whom a serious life-threatening gram-negative infection is suspected, including those in whom concurrent therapy with a penicillin or cephalosporin and an aminoglycoside may be indicated, treatment with tobramycin sulfate may be initiated before the results of susceptibility studies are obtained.

The decision to continue therapy with tobramycin should be based on the results of susceptibility studies, the severity of the infection, and the important additional concepts discussed in the WARNINGS box above.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of tobramycin and other antibacterial drugs, tobramycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

When culture and susceptibility information are available, they should be considered in selecting or modifying antimicrobial therapy.

In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

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Advisory information

contraindications
CONTRAINDICATIONS A hypersensitivity to any aminoglycoside is a contraindication to the use of tobramycin. A history of hypersensitivity or serious toxic reactions to aminoglycosides may also contraindicate the use of any other aminoglycoside because of the known cross-sensitivity of patients to drugs in this class.
Special warnings and precautions

PRECAUTIONS Serum and urine specimens for examination should be collected during therapy, as recommended in the WARNINGS box.

Serum calcium, magnesium, and sodium should be monitored.

Peak and trough serum levels should be measured periodically during therapy.

Prolonged concentrations above 12 ?g/mL should be avoided.

Rising trough levels (above 2?g/mL) may indicate tissue accumulation.

Such accumulation, advanced age, and cumulative dosage may contribute to ototoxicity and nephrotoxicity.

It is particularly important to monitor serum levels closely in patients with known renal impairment.

A useful guideline would be to perform serum level assays after 2 or 3 doses, so that the dosage could be adjusted if necessary, and also at 3- to 4-day intervals during therapy.

In the event of changing renal function, more frequent serum levels should be obtained and the dosage or dosage interval adjusted according to the guidelines provided in the DOSAGE AND ADMINISTRATION section.

In order to measure the peak level, a serum sample should be drawn about 30 minutes following intravenous infusion or 1 hour after an intramuscular injection.

Trough levels are measured by obtaining serum samples at 8 hours or just prior to the next dose of tobramycin.

These suggested time intervals are intended only as guidelines and may vary according to institutional practices.

It is important, however, that there be consistency within the individual patient program unless computerized pharmacokinetic dosing programs are available in the institution.

These serum-level assays may be especially useful for monitoring the treatment of severely ill patients with changing renal function or of those infected with less sensitive organisms or those receiving maximum dosage.

Neuromuscular blockade and respiratory paralysis have been reported in cats receiving very high doses of tobramycin (40 mg/kg).

The possibility of prolonged or secondary apnea should be considered if tobramycin is administered to anesthetized patients who are also receiving neuromuscular blocking agents, such as succinylcholine, tubocurarine, or decamethonium, or to patients receiving massive transfusions of citrated blood.

If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts.

Cross-allergenicity among aminoglycosides has been demonstrated.

In patients with extensive burns or cystic fibrosis, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides.

In such patients treated with tobramycin, measurement of serum concentration is especially important as a basis for determination of appropriate dosage.

Elderly patients may have reduced renal function that 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 aminoglycosides is particularly important in such patients.

An increased incidence of nephrotoxicity has been reported following concomitant administration of aminoglycoside antibiotics and cephalosporins.

Aminoglycosides should be used with caution in patients with muscular disorders, such as myasthenia gravis or parkinsonism, since these drugs may aggravate muscle weakness because of their potential curare-like effect on neuromuscular function.

Aminoglycosides may be absorbed in significant quantities from body surfaces after local irrigation or application and may cause neurotoxicity and nephrotoxicity.

Aminoglycosides have not been approved for intraocular and/or subconjunctival use.

Physicians are advised that macular necrosis has been reported following administration of aminoglycosides, including tobramycin, by these routes.

See WARNINGS box regarding concurrent use of potent diuretics and concurrent and sequential use of other neurotoxic or nephrotoxic drugs.

The inactivation of tobramycin and other aminoglycosides by?

-lactam-type antibiotics (penicillins or cephalosporins) has been demonstrated in_vitro and in patients with severe renal impairment.

Such inactivation has not been found in patients with normal renal function who have been given the drugs by separate routes of administration.

Therapy with tobramycin may result in overgrowth of nonsusceptible organisms.

If overgrowth of nonsusceptible organisms occurs, appropriate therapy should be initiated.

General Prescribing tobramycin 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.

Information for Patients Patients should be counseled that antibacterial drugs including tobramycin should only be used to treat bacterial infections.

They do not treat viral infections (e.g. the common cold).

When an antibacterial drug product 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 tobramycin or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics, which usually ends when the antibiotic is discontinued.

Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic.

If this occurs, patients should contact their physician as soon as possible.

Pregnancy Category D: 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.

If tobramycin is used during pregnancy or if the patient becomes pregnant while taking tobramycin, she should be apprised of the potential hazard to the fetus.

Usage in Children: See INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION.

Adverse reactions

ADVERSE REACTIONS Neurotoxicity: Adverse effects on both the vestibular and auditory branches of the eighth nerve have been noted, especially in patients receiving high doses or prolonged therapy, in those given previous courses of therapy with an ototoxin, and in cases of dehydration.

Symptoms include dizziness, vertigo, tinnitus, roaring in the ears, and hearing loss.

Hearing loss is usually irreversible and is manifested initially by diminution of high-tone acuity.

Tobramycin and gentamicin sulfates closely parallel each other in regard to ototoxic potential.

Nephrotoxicity: Renal function changes, as shown by rising BUN, NPN, and serum creatinine and by oliguria, cylindruria, and increased proteinuria, have been reported, especially in patients with a history of renal impairment who are treated for longer periods or with higher doses than those recommended.

Adverse renal effects can occur in patients with initially normal renal function.

Clinical studies and studies in experimental animals have been conducted to compare the nephrotoxic potential of tobramycin and gentamicin.

In some of the clinical studies and in the animal studies, tobramycin caused nephrotoxicity significantly less frequently than gentamicin.

In some other clinical studies, no significant difference in the incidence of nephrotoxicity between tobramycin and gentamicin was found.

Other reported adverse reactions possibly related to tobramycin sulfate include anemia, granulocytopenia, and thrombocytopenia; and fever, rash, exfoliative dermatitis, itching, urticaria, nausea, vomiting, diarrhea, headache, lethargy, pain at the injection site, mental confusion, and disorientation.

Laboratory abnormalities possibly related to tobramycin sulfate include increased serum transaminases (SGOT, SGPT); increased serum LDH and bilirubin; decreased serum calcium, magnesium, sodium, and potassium; and leukopenia, leukocytosis, and eosinophilia.

To report SUSPECTED

ADVERSE EVENTS, contact FDA at 1-800-FDA-1088 or www.fda.gov.

Usage information

Dosing and administration

DOSAGE AND ADMINISTRATION Tobramycin sulfate injection may be given intramuscularly or intravenously.

Recommended dosages are the same for both routes.

Tobramycin in 0.9 % Sodium Chloride Injection is administered by intravenous infusion only.

The patient 's pretreatment body weight should be obtained for calculation of correct dosage.

It is desirable to measure both peak and trough serum concentrations (see WARNINGS box and PRECAUTIONS).

Administration for Patients with Normal Renal Function Adults with Serious Infections: 3 mg/kg/day in 3 equal doses every 8 hours (see Table 3).

Adults with Life-Threatening Infections: Up to 5 mg/kg/day may be administered in 3 or 4 equal doses (see Table 3).

The dosage should be reduced to 3 mg/kg/day as soon as clinically indicated.

To prevent increased toxicity due to excessive blood levels, dosage should not exceed 5 mg/kg/day unless serum levels are monitored (see WARNINGS box and PRECAUTIONS).

Table 3.

Dosage

Schedule Guide for Adults with

Normal Renal Function (Dosage at 8-Hour Intervals) For Patient Weighing Usual Dose for Serious Infections Maximum Dose for Life - Threatening Infections (Reduce as soon as possible) 1 mg/kg q8h 1.66 mg/kg q8h (Total, 3 mg/kg/day) (Total, 5 mg/kg/day) kg lb mg/dose mg/dose 120 264 120 mg 200 mg 115 253 115 mg 191 mg 110 242 110 mg 183 mg 105 231 105 mg 175 mg 100 220 100 mg 166 mg 95 209 95 mg 158 mg 90 198 90 mg 150 mg 85 187 85 mg 141 mg 80 176 80 mg 133 mg 75 165 75 mg 125 mg 70 154 70 mg 116 mg 65 143 65 mg 108 mg 60 132 60 mg 100 mg 55 121 55 mg 91 mg 50 110 50 mg 83 mg 45 99 45 mg 75 mg 40 88 40 mg 66 mg NOTE: For information concerning the use of tobramycin in infants and children, see Pediatric tobramycin product information.

Children: 6 to 7.5 mg/kg/day in 3 or 4 equally divided doses (2 to 2.5 mg/kg every 8 hours or 1.5 to 1.89 mg/kg every 6 hours).

Premature or Full-Term Neonates 1 Week of Age or Less: Up to 4 mg/kg/day may be administered in 2 equal doses every 12 hours.

It is desirable to limit treatment to a short term.

The usual duration of treatment is 7 to 10 days.

A longer course of therapy may be necessary in difficult and complicated infections.

In such cases, monitoring of renal, auditory, and vestibular functions is advised, because neurotoxicity is more likely to occur when treatment is extended longer than 10 days.

Administration for Patients With Impaired Renal Function Whenever possible, serum tobramycin concentrations should be monitored during therapy.

Following a loading dose of 1 mg/kg, subsequent dosage in these patients must be adjusted, either with reduced doses administered at 8-hour intervals or with normal doses given at prolonged intervals.

Both of these methods are suggested as guides to be used when serum levels of tobramycin can not be measured directly.

They are based on either the creatinine clearance or the serum creatinine of the patient, because these values correlate with the half-life of tobramycin.

The dosage schedules derived from either method should be used in conjunction with careful clinical and laboratory observations of the patient and should be modified as necessary.

Neither method should be used when dialysis is being performed.

Reduced dosage at 8-hour intervals When the creatinine clearance rate is 70 mL or less per minute or when the serum creatinine value is known, the amount of the reduced dose can be determined by multiplying the normal dose from Table 3 by the percent of normal dose from the accompanying nomogram.

An alternate rough guide for determining reduced dosage at 8-hour intervals (for patients whose steady-state serum creatinine values are known) is to divide the normally recommended dose by the patient 's serum creatinine.

Normal dosage at prolonged intervals: If the creatinine clearance rate is not available and the patient 's condition is stable, a dosage frequency in hours for the dosage given in Table 3 can be determined by multiplying the patient 's serum creatinine by 6.

Dosage in Obese Patients The appropriate dose may be calculated by using the patient 's estimated lean body weight plus 40 % of the excess as the basic weight on which to figure mg/ kg.

Intravenous Administration For intravenous administration, the usual volume of diluent (0.9 % Sodium Chloride Injection or 5 % Dextrose Injection) is 50 to 100 mL for adult doses.

For children, the volume of diluent should be proportionately less than for adults.

The diluted solution usually should be infused over a period of 20 to 60 minutes.

Infusion periods of less than 20 minutes are not recommended because peak serum levels may exceed 12 mcg/mL (see WARNINGS box).

Tobramycin in 0.9 % Sodium Chloride Injection should not be physically premixed with other drugs but should be administered separately according to the recommended dose and route.

The above schedules are not intended as rigid recommendations but are provided as guides to dosage when the measurement of tobramycin sulfate serum levels is not feasible.

A variety of methods are available to measure tobramycin concentrations in body fluids; these include microbiology, enzymatic and radioimmunoassay techniques.

Tobramycin in 0.9 % Sodium Chloride Injection is a ready-to-use isotonic solution.

NO DILUTION OR BUFFERING IS REQUIRED.

If the prescribed dose is exactly 60 or 80 mg, use the appropriate container.

If the prescribed dose is higher or lower than that of the supplied containers, adjustments can be made in either container.

If the dose is higher than the contents of the 80 mg container, the additional amount should be removed from a container of tobramycin and added to the 80 mg container.

If the prescribed dose is less, decrements can be made by removing and discarding the appropriate amount from either unit.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

See CONTRAINDICATIONS.

INSTRUCTIONS FOR

USE To Open Tear outer wrap at notch and remove solution container.

Some opacity of the plastic due to moisture absorption during the sterilization process may be observed.

This is normal and does not affect the solution quality or safety.

The opacity will diminish gradually.

Preparation for Administration (Use aseptic technique) Close flow control clamp of administration set.

Remove cover from outlet port at bottom of container.

Insert piercing pin of administration set into port with a twisting motion until the set is firmly seated.

NOTE: See full directions on administration set carton.

Suspend container from hanger.

Squeeze and release drip chamber to establish proper fluid level in chamber.

Open flow control clamp and clear air from set.

Close clamp.

Attach set to venipuncture device.

If device is not indwelling, prime and make venipuncture.

Regulate rate of administration with flow control clamp.

WARNING:

Do not use flexible container in series connections.

Reduced Doasage

Nomogram

More information

Category Value
Authorisation number ANDA063081
Orphan designation No
Product NDC 0409-3470,0409-3469
Date Last Revised 11-11-2013
Type HUMAN PRESCRIPTION DRUG
RXCUI 242825
Marketing authorisation holder Hospira, Inc.
Warnings

WARNINGS Patients treated with Tobramycin Injection and other aminoglycosides should be under close clinical observation, because these drugs have an inherent potential for causing ototoxicity and nephrotoxicity.

Neurotoxicity, manifested as both auditory and vestibular ototoxicity, can occur.

The auditory changes are irreversible, are usually bilateral, and may be partial or total.

Eighth-nerve impairment and nephrotoxicity may develop, primarily in patients having pre-existing renal damage and in those with normal renal function to whom aminoglycosides are administered for longer periods or in higher doses than those recommended.

Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching, and convulsions.

The risk of aminoglycoside-induced hearing loss increases with the degree of exposure to either high peak or high trough serum concentrations.

Patients who develop cochlear damage may not have symptoms during therapy to warn them of eighth-nerve toxicity, and partial or total irreversible bilateral deafness may continue to develop after the drug has been discontinued.

Rarely, nephrotoxicity may not become apparent until the first few days after cessation of therapy.

Aminoglycoside-induced nephrotoxicity usually is reversible.

Renal and eighth-nerve function should be closely monitored in patients with known or suspected renal impairment and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy.

Peak and trough serum concentrations of aminoglycosides should be monitored periodically during therapy to assure adequate levels and to avoid potentially toxic levels.

Prolonged serum concentrations above 12 ?g/mL should be avoided.

Rising trough levels (above 2?g/mL) may indicate tissue accumulation.

Such accumulation, excessive peak concentrations, advanced age, and cumulative dose may contribute to ototoxicity and nephrotoxicity (see PRECAUTIONS).

Urine should be examined for decreased specific gravity and increased excretion of protein, cells, and casts.

Blood urea nitrogen, serum creatinine, and creatinine clearance should be measured periodically.

When feasible, it is recommended that serial audiograms be obtained in patients old enough to be tested, particularly high-risk patients.

Evidence of impairment of renal, vestibular, or auditory function requires discontinuation of the drug or dosage adjustment.

Tobramycin should be used with caution in premature and neonatal infants because of their renal immaturity and the resulting prolongation of serum half-life of the drug.

Concurrent and sequential use of other neurotoxic and/or nephrotoxic antibiotics, particularly other aminoglycosides (e.g., amikacin, streptomycin, neomycin, kanamycin, gentamicin, and paromomycin), cephaloridine, viomycin, polymyxin B, colistin, cisplatin, and vancomycin, should be avoided.

Other factors that may increase patient risk are advanced age and dehydration.

Aminoglycosides should not be given concurrently with potent diuretics, such as ethacrynic acid and furosemide.

Some diuretics themselves cause ototoxicity, and intravenously administered diuretics enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.

Aminoglycosides can cause fetal harm when administered to a pregnant woman (see PRECAUTIONS).