TOBRAMYCIN- tobramycin_solution

Tobramycin is an aminoglycoside antibacterial [see Microbiology ( 12. 4 Absorption Tobramycin inhalation solution contains tobramycin, a cationic polar molecule that does not readily cross epithelial membranes. (1) (2) Serum Concentrations The average serum concentration of tobramycin one hour after inhalation of a single 300-mg dose of tobramycin inhalation solution by cystic fibrosis patients was 0. After 20 weeks of therapy on the tobramycin inhalation solution regimen, the average serum tobramycin concentration one hour after dosing was 1. Sputum Concentrations Ten minutes after inhalation of the first 300-mg dose of tobramycin inhalation solution by cystic fibrosis patients, the average concentration of tobramycin was 1237 mcg/g (range 35 to 7417 mcg/g) in sputum. Tobramycin does not accumulate in sputum; after 20 weeks of therapy with the tobramycin inhalation solution regimen, the average concentration of tobramycin at ten minutes after inhalation was 1154 mcg/g (range 39 to 8085 mcg/g) in sputum. Two hours after inhalation, sputum concentrations declined to approximately 14% of tobramycin levels at ten minutes after inhalation. Distribution Following administration of tobramycin inhalation solution, tobramycin remains concentrated primarily in the airways. Binding of tobramycin to serum proteins is negligible. Elimination Metabolism Tobramycin is not metabolized. Excretion The elimination half-life of tobramycin from serum is approximately 2 and 3 hours after intravenous (IV) administration and inhalation, respectively. Systemically absorbed tobramycin is primarily excreted unchanged in the urine principally by glomerular filtration. Unabsorbed tobramycin, following tobramycin inhalation solution administration, is probably eliminated primarily in expectorated sputum. Mechanism of Action Tobramycin is an aminoglycoside antibacterial produced by Streptomyces tenebrarius (1) (3) Tobramycin has in vitro Pseudomonas aeruginosa Resistance Treatment for 6 months with tobramycin inhalation solution in two clinical studies did not affect the susceptibility of the majority of P. aeruginosa P. aeruginosa [see Clinical Studies ( 14 Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.

Tobramycin inhalation solution is indicated for the management of cystic fibrosis in adults and pediatric patients 6 years of age and older with Pseudomonas aeruginosa Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with forced expiratory volume in 1 second (FEV 1 Burkholderia cepacia [see Clinical Studies ( 14 Tobramycin inhalation solution is an aminoglycoside antibacterial indicated for the management of cystic fibrosis in adults and pediatric patients 6 years of age and older with Pseudomonas aeruginosa 1 Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with forced expiratory volume in 1 second (FEV1) 75% predicted, or patients colonized with Burkholderia cepacia.

DOSAGE AND ADMINISTRATION
For oral inhalation only. 1 The recommended dosage for adults and pediatric patients 6 years of age and older is one single-dose ampule (300 mg) twice daily by oral inhalation in alternating periods of 28 days on drug, followed by 28 days off drug. 1 Dosage is not adjusted by weight. 1 Take doses as close to 12 hours apart as possible; but not less than 6 hours apart. 1 Administer each 300 mg dose by inhalation using a hand-held PARI LC PLUS Reusable Nebulizer with a DeVilbiss Pulmo-Aide compressor. 2 Tobramycin inhalation solution is for oral inhalation only [ see Dosage and Administration ( 2. 2 Tobramycin inhalation solution is administered twice daily in alternating periods of 28 days. After 28 days of therapy, patients should stop tobramycin inhalation solution therapy for the next 28 days, and then resume therapy for the next 28 day on/28 day off cycle. The doses should be taken as close to 12 hours apart as possible; they should not be taken less than 6 hours apart. If patients miss a dose, they should take it as soon as possible anytime up to 6 hours prior to their next scheduled dose. If less than 6 hours remain before the next dose, wait until their next scheduled dose. Tobramycin inhalation solution is administered by oral inhalation over an approximately 15-minute period, using a hand-held PARI LC PLUS Reusable Nebulizer with a DeVilbiss Pulmo-Aide compressor. Tobramycin inhalation solution should not be diluted or mixed with dornase alfa or other medications in the nebulizer. Tobramycin inhalation solution is not Prior to administration of tobramycin inhalation solution, read the Patient Information/Instructions for Use for tobramycin inhalation solution for detailed information on how to use tobramycin inhalation solution and follow the manufacturer’s instructions for use and care of the PARI LC PLUS Reusable Nebulizer and DeVilbiss Pulmo-Aide air compressor. Tobramycin inhalation solution is inhaled while the patient is sitting or standing upright and breathing normally through the mouthpiece of the nebulizer. Nose clips may help the patient breathe through the mouth. Instruct patients on multiple therapies to take their medications, prior to inhaling tobramycin inhalation solution or as directed by their physician. Tobramycin inhalation solution should not be used if it is cloudy, if there are particles in the solution, or if it has been stored at room temperature for more than 28 days.
INSTRUCTIONS FOR USE
Tobramycin (toe″ bra mye′ sin) Inhalation Solution for oral inhalation use Read this Instructions for Use before you start using tobramycin inhalation solution and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or treatment. Tobramycin inhalation solution is made for inhalation using a PARI LC PLUStrademark Reusable Nebulizer (manufactured by PARI International) and a DeVilbiss registered registered registered registered You will need the following supplies (See Figure A): 1 Tobramycin inhalation solution plastic ampule (Tobramycin inhalation solution is packaged with 4 ampules in each foil pouch) DeVilbiss registered registered PARI LC PLUStrademark Reusable Nebulizer Tubing to connect the nebulizer and compressor Clean paper or cloth towels Nose clips (optional) (Figure A) It is important that your nebulizer and compressor function properly before starting your tobramycin inhalation solution therapy. Note: Read the manufacturer care and use instructions for important information. Prepare Your Tobramycin Inhalation Solution for Inhalation Therapy Step 1: Step 2: Step 3: See Figure B (Figure B) Step 4: See Figure C Do not (Figure C) Step 5: Unrefrigerated tobramycin inhalation solution, which is normally slightly yellow, may darken with age. This color change does not mean there is any change in the quality of the medicine. Do not Throw it away and get a new one. Step 6: See Figure D Nebulizer Top and Bottom (Nebulizer Cup) Assembly Inspiratory Valve Cap Mouthpiece with Valve Tubing (Figure D) Step 7: See Figure E (Figure E) Step 8: See Figure F (Figure F) Step 9: See Figure G (Figure G) Step 10: See Figure H (Figure H) Step 11: See Figure I (Figure I) Step 12: See Figure J (Figure J) Step 13: See Figure K (Figure K) Step 14: See Figure L (Figure L) Step 15: See Figure M (Figure M) Step 16: See Figure N Make sure to keep the Nebulizer Cup upright. (Figure N) Giving Your Tobramycin Inhalation Solution Inhalation Therapy Step 17: See Figure O (Figure O) Step 18: See Figure P (Figure P) Step 19: See Figure Q Do not (Figure Q) Step 20: If you are interrupted, need to cough or rest during your tobramycin inhalation solution treatment, turn off the compressor to save your medicine. Turn the compressor back on when you are ready to restart your treatment. Follow the nebulizer cleaning and disinfecting instructions after completing your therapy. After Your Tobramycin Inhalation Solution Inhalation Therapy Cleaning Your Nebulizer To reduce the risk of infection, illness or injury from contamination, you must thoroughly clean all parts of the nebulizer as instructed after each treatment. Never use a nebulizer with a clogged nozzle. If the nozzle is clogged, no aerosol mist is made, and your therapy will not be as effective. Replace the nebulizer if clogging occurs. 1) Remove tubing from nebulizer and disassemble nebulizer parts. 2) Wash all parts (except tubing) with warm water and liquid dish soap. 3) Rinse thoroughly with warm water and shake out water. 4) Air dry or hand dry nebulizer parts on a clean, lint-free cloth. Reassemble nebulizer when dry, and store. You can also wash all parts of the nebulizer in a dishwasher (except tubing). 1) Place the nebulizer parts in a dishwasher basket. 2) Place the dishwasher basket on the top rack of the dishwasher. 3) Remove and dry the parts when the cycle is complete. Disinfecting Your Nebulizer Your nebulizer is for your use only. Do not Clean the nebulizer as described above. Every other treatment day, disinfect the nebulizer parts (except tubing) by boiling them in water for a full 10 minutes. Dry parts on a clean, lint-free cloth. Care and Use of Your Pulmo-Aide registered Follow the manufacturer instructions for care and use of your compressor. Filter Change: DeVilbiss registered Compressor Cleaning: With power switch in the "Off" position, unplug power cord from wall outlet. Wipe outside of the compressor cabinet with a clean, damp cloth every few days to keep dust free. Caution: Do not How Should I Store Tobramycin Inhalation Solution? Store tobramycin inhalation solution ampules in a refrigerator between 36°F to 46°F (2°C to 8°C) until needed. You may store the tobramycin inhalation solution ampules in the foil pouches (opened or unopened) at room temperature 77°F (25°C) for up to 28 days. Do not Protect tobramycin inhalation solution ampules from light. Keep tobramycin inhalation solution and all medicines out of the reach of children. This Instructions for Use has been approved by the U. Food and Drug Administration. Additional Information Nebulizer: 1-800-327-8632 Compressor: 1-800-338-1988 Tobramycin Inhalation Solution (Teva Pharmaceuticals): 1-888-838-2872. Manufactured In England By: Norton Healthcare Limited T/A Ivax Pharmaceuticals UK Manufactured For: Teva Pharmaceuticals USA, Inc. G 10/2023 Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J Figure K Figure L Figure M Figure N Figure O Figure P Figure Q.

Tobramycin inhalation solution is contraindicated in patients with a known hypersensitivity to any aminoglycoside. Known hypersensitivity to any aminoglycoside ( 4.

Risk Summary Aminoglycosides can cause fetal harm. Published literature reports that use of streptomycin, an aminoglycoside, can cause total, irreversible, bilateral congenital deafness when administered to a pregnant woman [see Warnings and Precautions ( 5. 5 [see Clinical Pharmacology ( 12. 3 (see Clinical Considerations). (se e Data) The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Data Animal Data No reproductive toxicity studies have been conducted with tobramycin inhalation solution (tobramycin administered by inhalation). However, subcutaneous administration of tobramycin at doses of up to 100 (rat) or 20 (rabbit) mg/kg/day during organogenesis was not associated with adverse developmental outcomes. Doses of tobramycin >=40 mg/kg/day were severely maternally toxic to rabbits and precluded the evaluation of adverse developmental outcomes. Ototoxicity was not evaluated in offspring during non-clinical reproductive toxicity studies with tobramycin. Risk Summary There are no data on the presence of tobramycin inhalation solution in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Limited published data on other formulations of tobramycin in lactating women indicate that tobramycin is present in human milk. However, systemic absorption of tobramycin following inhaled administration is expected to be minimal [see Clinical Pharmacology ( 12. Clinical Considerations Tobramycin may cause intestinal flora alteration. Advise a woman to monitor the breastfed infant for loose or bloody stools and candidiasis (thrush, diaper rash). The safety and efficacy of tobramycin inhalation solution in pediatric patients under 6 years of age has not been established. The use of tobramycin inhalation solution is not indicated in children <6 years of age [see Indications and Usage ( 1 2 Clinical studies of tobramycin inhalation solution did not include patients aged 65 years and over. Tobramycin is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function [ see Warnings and Precautions ( 5.

Concurrent and/or sequential use of tobramycin inhalation solution with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided. 1 Concomitant administration with ethacrynic acid, furosemide, urea, or intravenous mannitol is not recommended due to possible enhancement of aminoglycoside toxicity. 2 Concurrent and/or sequential use of tobramycin inhalation solution with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering aminoglycoside concentrations in serum and tissue. Tobramycin inhalation solution should not be administered concomitantly with ethacrynic acid, furosemide, urea, or intravenous mannitol. The interaction between inhaled mannitol and tobramycin inhalation solution has not been evaluated.

NONCLINICAL TOXICOLOGY
A two-year rat inhalation toxicology study to assess carcinogenic potential of tobramycin inhalation solution has been completed. Rats were exposed to tobramycin inhalation solution for up to 1.5 hours per day for 95 weeks. The clinical formulation of the drug was used for this carcinogenicity study. Serum levels of tobramycin of up to 35 mcg/mL were measured in rats, in contrast to the average 1 mcg/mL levels observed in cystic fibrosis patients in clinical trials. There was no drug-related increase in the incidence of any variety of tumor. Additionally, tobramycin has been evaluated for genotoxicity in a battery of i n vitro in vivo Subcutaneous administration of up to 100 mg/kg of tobramycin did not affect mating behavior or cause impairment of fertility in male or female rats.
CLINICAL STUDIES
Two identically designed, double-blind, randomized, placebo-controlled, parallel group, 24-week clinical studies (Study 1 and Study 2) at a total of 69 cystic fibrosis centers in the United States were conducted in cystic fibrosis patients with P. aeruginosa Burkholderia cepacia All subjects had baseline FEV 1 Table 2: Dosing Regimens in Clinical Studies Cycle 1 Cycle 2 Cycle 3 28 days 28 days 28 days 28 days 28 days 28 days T obramycin Inhalation Solution T obramycin Inhalation Solution 300 mg No drug T obramycin Inhalation Solution 300 mg No drug T obramycin Inhalation Solution 300 mg twice daily No drug Placebo regimen n=262 placebo twice daily No drug placebo twice daily No drug placebo twice daily No drug All patients received either tobramycin inhalation solution or placebo (saline with 1. 25 mg quinine for flavoring) in addition to standard treatment recommended for cystic fibrosis patients, which included oral and parenteral antipseudomonal therapy, beta2-agonists, cromolyn, inhaled steroids, and airway clearance techniques. In addition, approximately 77% of patients were concurrently treated with dornase alfa (PULMOZYME, Genentech). In each study, tobramycin inhalation solution -treated patients experienced significant improvement in pulmonary function. Improvement was demonstrated in the tobramycin inhalation solution group in Study 1 by an average increase in FEV 1 1 Figure 1: Relative Change From Baseline in FEV 1 In each study, tobramycin inhalation solution therapy resulted in a significant reduction in the number of P. aeruginosa Figure 2: Absolute Change From Baseline in Log 10 Patients treated with tobramycin inhalation solution were hospitalized for an average of 5. 1 days compared to 8. 1 days for placebo patients. Patients treated with tobramycin inhalation solution required an average of 9. 6 days of parenteral antipseudomonal, antibacterial treatment compared to 14. During the 6 months of treatment, 40% of tobramycin inhalation solution patients and 53% of placebo patients were treated with parenteral antipseudomonal antibacterials. The relationship between in vitro P. aeruginosa 1 Treatment with tobramycin inhalation solution did not affect the susceptibility of the majority of P. aeruginosa P. aeruginosa Figure 1: Relative Change From Baseline in FEV1% Predicted Figure 2: Absolute Change From Baseline in Log10 CFUs.
PATIENT INFORMATION
Tobramycin Inhalation Solution ( toe″ bra mye′ sin ) for oral inhalation use Wha t is tobramycin inhalation solution ? Tobramycin inhalation solution is a prescription medicine that is used to treat people with cystic fibrosis who have a bacterial infection called Pseudomonas aeruginosa It is not known if tobramycin inhalation solution is safe and effective: in children under 6 years of age in people who have an FEV 1 in people who are colonized with a bacterium called Burkholderia cepacia Do not take tobramycin inhalation solution See the end of this Patient Information for a complete list of ingredients in tobramycin inhalation solution. Befor e you take tobramycin inhalation solution , tell your healthcare provider about all of your medical conditions, including if you: have or have had hearing problems (including noises in your ears such as ringing or hissing), hearing loss, or your mother has had hearing problems after taking an aminoglycoside. have been told you have certain gene variants (a change in the gene) related to hearing abnormalities inherited from your mother. have dizziness have or have had kidney problems have or have had problems with muscle weakness such as myasthenia gravis or Parkinson’s disease have or have had breathing problems such as wheezing, coughing, or chest tightness are pregnant or plan to become pregnant. Tobramycin inhalation solution is in a class of drugs that can harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if tobramycin inhalation solution passes into your breast milk. are receiving aminoglycoside therapy by injection or through a vein (intravenous) while taking tobramycin inhalation solution. Your blood levels of tobramycin will be checked. Tell your healthcare provider about all the medicines you take, How should I take tobramycin inhalation solution ? See the step-by-step Instructions for Use Take tobramycin inhalation solution exactly as your healthcare provider tells you. Do not The usual dose for adults and children over 6 years of age is: 1 single-use ampule of tobramycin inhalation solution inhaled 2 times each day using a hand-held PARI LC PLUS trademark registered registered Each dose of tobramycin inhalation solution should be taken as close to 12 hours apart as possible. You should not take your dose less than 6 hours apart. Tobramycin inhalation solution is taken as a breathing treatment (inhalation) with a hand-held PARI LC PLUS Reusable Nebulizer with a DeVilbiss Pulmo-Aide compressor. D o not Do not mix or dilute tobramycin inhalation solution with dornase alfa or other medicines in your nebulizer system. Each treatment should take about 15 minutes. Tobramycin inhalation solution should be inhaled while you are sitting or standing upright and breathing normally through the mouthpiece of the nebulizer. Nose clips may help you to breathe through your mouth. If you forget to take tobramycin inhalation solution and there are at least 6 hours to your next dose, take your dose as soon as you can. Otherwise, wait for your next dose. Do not double the dose to make up for the missed dose. After using tobramycin inhalation solution for 28 days, you should stop using it and wait 28 days. After you have stopped using tobramycin inhalation solution for 28 days, you should start using tobramycin inhalation solution again for 28 days. Complete the full 28-day course even if you are feeling better. It is important that you keep to the 28-day on, 28-day off cycle. Using tobramycin inhalation solution with certain other medicines can cause serious side effects. If you are using tobramycin inhalation solution, you should discuss with your healthcare provider if you should take: other medicines that may harm your nervous system, kidneys, or hearing “water pills” (diuretics) such as ethacrynic acid, furosemide, or intravenous mannitol urea Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure. What are the possible side effects of tobramycin inhalation solution? Tobramycin inhalation solution may cause serious side effects, including: severe breathing problems (bronchospasm). Tell your healthcare provider right away if you get any of these symptoms of bronchospasm with using tobramycin inhalation solution: shortness of breath with wheezing coughing and chest tightness hearing loss or ringing in the ears (ototoxicity). Tell your healthcare provider right away if you have hearing loss or you hear noises in your ears such as ringing or hissing. Tell your healthcare provider if you develop vertigo, difficulty with balance or dizziness. worsening kidney problems (nephrotoxicity). Tobramycin inhalation solution is in a class of drugs which may cause worsening kidney problems, especially in people with known or suspected kidney problems. Your healthcare provider may do a blood test to check how your kidneys are working while you are using tobramycin inhalation solution. worsening muscle weakness (neuromuscular disorder). Tobramycin inhalation solution is in a class of drugs which can cause muscle weakness to get worse in people who already have problems with muscle weakness (myasthenia gravis or Parkinson’s disease). The most common side effects of tobramycin inhalation solution include: o increased cough o sore throat o increased sputum These are not all of the possible side effects of tobramycin inhalation solution. General information about the safe and effective use of tobramycin inhalation solution What are the ingredients in tobramycin inhalation solution? Active ingredients: Inactive ingredients: Wh a t is Pseudomonas aeruginosa? It is a very common bacterium that infects the lungs of nearly everyone with cystic fibrosis at some time during their lives. Some people do not get this infection until later in their lives, while others get it very young. It is one of the most damaging bacteria for people with cystic fibrosis. If the infection is not properly managed, it will continue to damage your lungs causing further problems to your breathing. Manufactured In England By: Norton Healthcare Limited T/A Ivax Pharmaceuticals UK Manufactured For: Teva Pharmaceuticals USA, Inc. For more information, call 1-888-838-2872. This Patient Information has been approved by the U.S. Food and Drug Administration. Rev. A 10/2023

Teva Pharmaceuticals USA, Inc.

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