Tobramycin (Tobramycin Sulfate) - Indications and Dosage

INDICATIONS AND USAGE

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

Tobramycin 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 pediatric patient 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, 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 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 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.

DOSAGE AND ADMINISTRATION

Tobramycin Injection, USP may be given intramuscularly or intravenously. Recommended dosages are the same for both routes. ADD-Vantage vials are not intravascular administration. 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 1).

Adults with Life-Threatening Infections: Up to 5 mg/kg/day may be administered in 3 or 4 equal doses (see Table 1). 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 1 DOSAGE SCHEDULE GUIDE FOR TOBRAMYCIN INJECTION IN ADULTS WITH NORMAL RENAL FUNCTION (Dosage at 8-Hour Intervals)
For Patient Weighing		Usual Dose for Serious Infections 1 mg/kg q8h		Maximum Dose for Life- Threatening Infections (Reduce as soon as possible) 1.66 mg/kg q8h
kg	lb	(Total, 3 mg/kg/day)		(Total, 5 mg/kg/day)
		mg/dose	mL/dose*	mg/dose	mL/dose*
		q8h		q8h
120	264	120 mg	3 mL	200 mg	5 mL
115	253	115 mg	2.9 mL	191 mg	4.75 mL
110	242	110 mg	2.75 mL	183 mg	4.5 mL
105	231	105 mg	2.6 mL	175 mg	4.4 mL
100	220	100 mg	2.5 mL	166 mg	4.2 mL
95	209	95 mg	2.4 mL	158 mg	4 mL
90	198	90 mg	2.25 mL	150 mg	3.75 mL
85	187	85 mg	2.1 mL	141 mg	3.5 mL
80	176	80 mg	2 mL	133 mg	3.3 mL
75	165	75 mg	1.9 mL	125 mg	3.1 mL
70	154	70 mg	1.75 mL	116 mg	2.9 mL
65	143	65 mg	1.6 mL	108 mg	2.7 mL
60	132	60 mg	1.5 mL	100 mg	2.5 mL
55	121	55 mg	1.4 mL	91 mg	2.25 mL
50	110	50 mg	1.25 mL	83 mg	2.1 mL
45	99	45 mg	1.1 mL	75 mg	1.9 mL
40	88	40 mg	1 mL	66 mg	1.6 mL

* Applicable to all product forms except Tobramycin Injection, 10 mg/mL (Pediatric).

Pediatric Patients (Greater Than 1 Week of Age): 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.

Dosage in Patients with Cystic Fibrosis — In patients with cystic fibrosis, altered pharmacokinetics may result in reduced serum concentration of aminoglycosides. Measurement of tobramycin serum concentration during treatment is especially important as a basis for determining appropriate dose. In patients with severe cystic fibrosis, an initial dosing regimen of 10 mg/kg/day in 4 equally divided doses is recommended. This dosing regimen is suggested only as a guide. The serum levels of tobramycin should be measured directly during treatment due to a wide interpatient variability.

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 cannot 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 1 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 1 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.

Intramuscular Administration — Tobramycin Injection may be administered by withdrawing the appropriate dose directly from a vial. Tobramycin sulfate in 0.9% Sodium Chloride is not intended for intramuscular administration.

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 pediatric patients, 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).

Use of ADD-Vantage Vials — ADD-Vantage Tobramycin Injection vials are not intended for multiple use and should not be used with a syringe in the conventional way. These products are intended for use only with 50 mL or 100 mL ADD-Vantage Flexible Diluent Containers and in those instances in which the physician’s order specified 80 mg doses. Use within 24 hours after activation.

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

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

INSTRUCTIONS FOR USE

To Open Diluent Container:

Peel overwrap from the corner and remove 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.

To Assemble Vial and Flexible Diluent Container:

(Use Aseptic Technique)

1. Remove the protective covers from the top of the vial and the vial port on the diluent container as follows:

   a. To remove the breakaway vial cap, swing the pull ring over the top of the vial and pull down far enough to start the opening (see FIGURE 1.), then pull straight up to remove the cap. (see FIGURE 2.) NOTE: Do not access vial with syringe.

   Fig. 1	Fig. 2

   b. To remove the vial port cover, grasp the tab on the pull ring, pull up to break the three tie strings, then pull back to remove the cover. (see FIGURE 3.)

2. Screw the vial into the vial port until it will go no further. THE VIAL MUST BE SCREWED IN TIGHTLY TO ASSURE A SEAL. This occurs approximately 1/2 turn (180°) after the first audible click. (see FIGURE 4.) The clicking sound does not assure a seal; the vial must be turned as far as it will go. NOTE: Once vial is seated, do not attempt to remove. (see FIGURE 4.)

3. Recheck the vial to assure that it is tight by trying to turn it further in the direction of assembly.

4. Label appropriately.

   Fig. 3	Fig. 4

To Prepare Admixture:

1. Squeeze the bottom of the diluent container gently to inflate the portion of the container surrounding the end of the drug vial.

2. With the other hand, push the drug vial down into the container telescoping the walls of the container. Grasp the inner cap of the vial through the walls of the container. (see FIGURE 5.)

3. Pull the inner cap from the drug vial. (see FIGURE 6.) Verify that the rubber stopper has been pulled out, allowing the drug and diluent to mix.

4. Mix container contents thoroughly and use within the specified time.

   Fig. 5	Fig. 6

Preparation for Administration

(Use Aseptic Technique)

1. Confirm the activation and admixture of vial contents.

2. Check for leaks by squeezing container firmly. If leaks are found, discard unit as sterility may be impaired.

3. Close flow control clamp of administration set.

4. Remove cover from outlet port at bottom of container.

5. Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated. NOTE: See full directions on administration set carton.

6. Lift the free end of the hanger loop on the bottom of the vial, breaking the two tie strings. Bend the loop outward to lock it in the upright position, then suspend container from hanger.

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

8. Open flow control clamp and clear air from set. Close clamp.

9. Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.

10. Regulate rate of administration with flow control clamp.

WARNING: Do not use flexible container in series connections.

HOW SUPPLIED

Tobramycin Injection is supplied in single-dose ADD-Vantage Vials as follows:

List No.	Volume	Vials per Tray	Tobramycin content
3255	8 mL	25	80 mg

Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]

Covered by one or more of the following U.S. patents: 4,614,515 and 4,614,267.