TOBI™ PathoGenesis Tobramycin (as sulfate) Respiratory Antibiotic   Action and Clinical Pharmacology TOBI is a formulation of tobramycin designed specifically for administration by inhalation. When tobramycin solution for inhalation is inhaled, tobramycin can be detected at high concentration in the sputum of cystic fibrosis patients.: The drug substance, tobramycin, is an aminoglycoside antibiotic derived from S. tenebrarius. Tobramycin, a cationic polar molecule that does not readily cross epithelial membranes, is chemically and pharmacologically related to the aminoglycoside class of antibiotics. The primary mode of action is bactericidal resulting from disruption of protein synthesis in susceptible bacteria. Pharmacokinetics: Concentrations of tobramycin in the sputum vary widely. This variation may be explained by individual differences in nebulizer performance and airway pathology. Following administration of tobramycin solution for inhalation, the drug remains concentrated primarily in sputum in the airways. Sputum Concentrations: Ten minutes after inhalation of the first 300 mg dose of tobramycin solution for inhalation by cystic fibrosis patients, the mean (median) concentration of tobramycin in the sputum was 1 237 µg/g (959 µg/g) with the range from 35 to 7 417 µg/g. Tobramycin does not accumulate in sputum; after 20 weeks of therapy with the tobramycin solution for inhalation regimen, the mean (median) concentration of tobramycin at 10 minutes after inhalation was 1 154 µg/g (818 µg/g), ranging from below quantifiable limits to 8 085 µg/g. High intra- and inter-subject variability of tobramycin concentrations in the sputum was observed. Two hours after inhalation, sputum tobramycin concentrations declined to approximately 14% of sputum tobramycin concentrations at 10 minutes after inhalation. Serum Concentrations: The mean (median) serum concentration of tobramycin 1 hour after inhalation of a single 300 mg dose of tobramycin solution for inhalation by cystic fibrosis patients was 0.95 µg/mL (0.91 µg/mL), ranging from below quantifiable limits to 3.62 µg/mL. After 20 weeks of therapy on the tobramycin solution for inhalation regimen, the mean (median) serum tobramycin concentration 1 hour after dosing was 1.05 µg/mL (0.94 µg/mL), ranging from below quantifiable limits to 3.41 µg/mL. Elimination: The elimination half-life of tobramycin from serum is approximately 2 hours after i.v. administration. Assuming tobramycin absorbed following inhalation behaves similarly to tobramycin following i.v. administration, systemically absorbed tobramycin is eliminated principally by glomerular filtration. Unabsorbed tobramycin, following tobramycin solution for inhalation administration, may be eliminated in expectorated sputum or via the gastrointestinal tract. 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 US were conducted in cystic fibrosis patients with P. aeruginosa. Subjects who were less than 6 years of age, had a baseline creatinine of >2 mg/dL, or had B. cepacia isolated from sputum were excluded. All subjects had baseline FEV 1% predicted between 25 and 75%. In these clinical studies, 258 patients received tobramycin solution for inhalation therapy on an outpatient basis (see Table I) using a hand-held Pari LC Plus reusable nebulizer with a DeVilbiss Pulmo-Aide compressor. CPS:TABLE_C46400$$$1_t1 Table I--TOBI Dosing Regimens in Clinical Studies Cycle 3 Cycle 1 Cycle 2 Cycle 3 28 Days 28 Days 28 Days 28 Days 28 Days 28 Days TOBI regimen n=258 TOBI 300 mg b.i.d. no drug TOBI 300 mg b.i.d. no drug TOBI 300 mg b.i.d. no drug Placebo regimen n=262 placebo b.i.d. no drug placebo b.i.d. no drug placebo b.i.d. no drug All patients received either tobramycin solution for inhalation 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, b 2-agonists, cromolyn, inhaled steroids, and airway clearance techniques. In addition, approximately 77% of patients were concurrently treated with dornase alfa (Pulmozyme). In each study, tobramycin solution for inhalation-treated patients experienced significant improvement in pulmonary function. Improvement was demonstrated in the tobramycin solution for inhalation group in Study 1 by an average increase in FEV 1 % predicted of about 11% relative to baseline (Week 0) during 24 weeks compared to no average change in placebo patients. In Study 2, tobramycin solution for inhalation-treated patients had an average increase of about 7% compared to an average decrease of about 1% in placebo patients. Figure I shows the average relative change in FEV 1 % predicted over 24 weeks for both studies. Figure I--TOBI Mean Relative Change From Baseline in FEV 1 % Predicted al> In each study, tobramycin solution for inhalation therapy resulted in a significant reduction of approximately 1 log in the number of P. aeruginosa colony forming units (CFUs) in sputum during the on-drug periods. Sputum bacterial density returned to baseline during the off-drug periods. Reductions in sputum bacterial density were smaller in each successive cycle (see Figure II). Figure II--TOBI Mean Absolute Change From Baseline in Log 10 CFUs al> Patients treated with tobramycin solution for inhalation were hospitalized for an average 5.1 days compared to 8.1 days for placebo patients. Patients treated with tobramycin solution for inhalation required an average of 9.7 days of parenteral antipseudomonal antibiotic treatment compared to 14.1 days for placebo patients. During the 6 months of treatment, 40% of tobramycin solution for inhalation patients and 53% of placebo patients were treated with parenteral antipseudomonal antibiotics. Treatment with tobramycin solution for inhalation for 3 cycles was associated with a decline in the in vitro susceptibility of P. aeruginosa isolates to tobramycin compared to placebo. The percentage of patients with P. aeruginosa isolates with tobramycin MICs ³16 µg/mL was 13% at the beginning, and 23% at the end of 6 months of the tobramycin solution for inhalation regimen, compared to 10 and 8% in the placebo group. The relationship between in vitro susceptibility test results and clinical outcome with tobramycin solution for inhalation therapy is not clear. However, 4 tobramycin solution for inhalation patients who began the clinical study with P. aeruginosa isolates having MIC values ³128 µg/mL did not experience an improvement in FEV 1 or a decrease in sputum bacterial density. Over 3 cycles of therapy with tobramycin solution for inhalation, the prevalence of S. aureus in sputum tended to decline while that of Aspergillis sp. and C. albicans increased. Indications And Clinical Uses : For the management of cystic fibrosis patients with chronic pulmonary P. aeruginosa infections. Demonstration of safety and efficacy of tobramycin solution for inhalation is limited to clinical trial data obtained over 3 cycles (6 months) of therapy for efficacy and up to 6 cycles (12 months) of therapy for safety. Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with FEV 1 < 25% or >75% predicted, or patients colonized with B. cepacia. Culture and sensitivity testing performed periodically will provide information on changing microbial flora and the possible emergence of bacterial resistance (see Pharmacology, Clinical Studies). Contra-Indications: In patients with a known hypersensitivity to any aminoglycoside.WarningWarnings: Warnings in Clinical States: Caution should be exercised when prescribing tobramycin solution for inhalation to patients with known or suspected renal, auditory, vestibular, or neuromuscular dysfunction. Patients receiving concomitant parenteral aminoglycoside therapy should be monitored as clinically appropriate. Pregnancy: Aminoglycosides can cause fetal harm when administered to a pregnant woman. Aminoglycosides cross the placenta, and streptomycin has been associated with several reports of total, irreversible, bilateral congenital deafness in pediatric patients exposed in utero. Patients who use tobramycin solution for inhalation during pregnancy, or become pregnant while taking tobramycin solution for inhalation should be apprised of the potential hazard to the fetus. Ototoxicity: Ototoxicity, manifested as both auditory and vestibular toxicity, has been reported with aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness. Tinnitus is a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants caution. In clinical studies, transient tinnitus occurred in 8 tobramycin solution for inhalation-treated patients vs no placebo patients. In postmarketing experience, severe hearing loss has been reported in some patients who received tobramycin solution for inhalation therapy in association with either previous or concomitant parenteral aminoglycoside use (see Precautions and Adverse Effects). Nephrotoxicity: Nephrotoxicity was not seen during 4 to 6 cycles of tobramycin solution for inhalation therapy in clinical studies but has been associated with aminoglycosides as a class. If nephrotoxicity occurs in a patient receiving tobramycin solution for inhalation, tobramycin therapy should be discontinued until serum concentrations fall below 2 µg/mL. Muscular Disorders: Tobramycin solution for inhalation should be used cautiously in patients with muscular disorders, such as myasthenia gravis or Parkinson's disease, since aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function. Bronchospasm: Bronchospasm can occur with inhalation of tobramycin solution for inhalation. In clinical studies of 3 cycles of tobramycin for inhalation therapy, acute changes in FEV 1% predicted, measured 30 minutes after the inhaled dose, documented decreases of ³20% FEV 1% predicted in 12 tobramycin solution for inhalation patients (4.7%) and 2 placebo patients (0.8%). Bronchospasm should be treated as medically appropriate. Precautions: Laboratory Tests: Audiograms: Physicians should consider an audiogram for patients with known or suspected auditory dysfunction, or who are at increased risk for auditory dysfunction. Tinnitus may be a sentinel symptom of ototoxicity and therefore the onset of this symptom warrants caution. Clinical studies of 4 to 6 cycles duration of tobramycin solution for inhalation therapy did not identify hearing loss using audiometric tests which used as criteria a bilateral, high frequency decrease of ³15 dB at 2 consecutive frequencies, evaluating frequencies up to 8 000 Hz. However, tinnitus was documented in a small number of tobramycin solution for inhalation patients, and there have been occasional reports of severe hearing loss in postmarketing experience where patients received tobramycin solution for inhalation in association with previous or concomitant parenteral aminoclycoside use (see Warnings and Adverse Effects). Serum Concentrations: In patients with normal renal function treated with tobramycin solution for inhalation, serum tobramycin concentrations are approximately 1 µg/mL 1 hour after dose administration and do not require routine monitoring. Serum concentrations of tobramycin in patients with renal dysfunction or patients treated with concomitant parenteral tobramycin should be monitored at the discretion of the treating physician. Renal Function: The clinical studies of tobramycin solution for inhalation did not reveal any imbalance in the percentage of patients in the tobramycin solution for inhalation and placebo groups who experienced at least a 50% rise in serum creatinine from baseline through 3 cycles of therapy (see Adverse Effects). Laboratory tests of urine and renal function should be conducted at the discretion of the treating physician. Drug Interactions : In clinical studies of tobramycin solution for inhalation, patients taking tobramycin solution for inhalation concomitantly with dornase alfa (Pulmozyme), b-agonists, inhaled corticosteroids, other antipseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole. In postmarketing experience, some patients receiving tobramycin solution for inhalation with previous or concomitant parenteral aminoglycosides have reported severe hearing loss. Concurrent and/or sequential use of tobramycin solution for inhalation with other drugs with neurotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. Tobramycin solution for inhalation should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. Pregnancy: No reproduction toxicology studies have been conducted with tobramycin solution for inhalation. However, s.c. administration of tobramycin at doses of 100 or 20 mg/kg/day during organogenesis was not teratogenic in rats or rabbits, respectively. Doses of tobramycin ³40 mg/kg/day were severely maternally toxic to rabbits and precluded the evaluation of teratogenicity. Aminoglycosides can cause fetal harm (e.g., congenital deafness) when administered to a pregnant woman. Ototoxicity was not evaluated in offspring during nonclinical reproduction toxicity studies with tobramycin. If tobramycin solution for inhalation is used during pregnancy, or if the patient becomes pregnant while taking tobramycin solution for inhalation, the patient should be apprised of the potential hazard to the fetus. Lactation: It is not known if tobramycin solution for inhalation will reach sufficient concentrations after administration by inhalation to be excreted in human breast milk. Because of the potential for ototoxicity and nephrotoxicity in infants, a decision should be made whether to terminate nursing or discontinue tobramycin solution for inhalation. Children: The safety and efficacy of tobramycin solution for inhalation have not been studied in pediatric patients under 6 years of age. Adverse Reactions: :Tobramycin solution for inhalation was generally well tolerated during 2 clinical studies in 258 cystic fibrosis patients ranging in age from 6 to 48 years. Patients received tobramycin solution for inhalation in alternating periods of 28 days on and 28 days off drug in addition to their standard cystic fibrosis therapy for a total of 24 weeks. Voice alteration and tinnitus were the only adverse experiences reported by significantly more tobramycin solution for inhalation-treated patients. Thirty-three patients (13%) treated with tobramycin solution for inhalation complained of voice alteration compared to 17 (7%) placebo patients. Voice alteration was more common in the on-drug periods. Episodes were transient and resolved during the off-drug period. Eight patients from the tobramycin solution for inhalation group (3%) reported tinnitus compared to no placebo patients. All episodes were transient, resolved without discontinuation of the tobramycin solution for inhalation treatment regimen, and were not associated with loss of hearing in scheduled audiograms. (The audiogram schedule did not necessarily coincide with the tinnitus episode.) Tinnitus is one of the sentinel symptoms of cochlear toxicity, and patients with this symptom should be carefully monitored for high frequency hearing loss (see Warnings and Precautions). The numbers of patients reporting vestibular adverse experiences such as dizziness were similar in the tobramycin solution for inhalation and placebo groups. Nine (3%) patients in the tobramycin solution for inhalation group and nine (3%) patients in the placebo group had increases in serum creatinine of at least 50% over baseline. In all 9 patients in the tobramycin solution for inhalation group, creatinine decreased at the next visit. Table II lists the percent of patients with treatment-emergent adverse experiences (spontaneously reported and solicited) that occurred in >5% of tobramycin solution for inhalation patients during the two Phase III studies, where patients received up to 3 cycles of therapy (see Pharmacology, Clinical Studies). CPS:TABLE_C46400$$$1_t2 Table II--TOBI Percent of Patients With Treatment Emergent Adverse Experiences Occurring in >5% of TOBI Patients During Phase III Studies (Up to 6 Months of Therapy) Adverse Event TOBI (n=258) % Placebo (n=262) % Body as a Whole Asthenia 35.7 39.3 Fevera 32.9 43.5 Headache 26.7 32.1 Chest Pain 26.0 29.8 Abdominal Pain 12.8 23.7 Pain 8.1 12.6 Back Pain 7.0 8.0 Malaise 6.2 5.3 Digestive Anorexia 18.6 27.9 Vomiting 14.0 22.1 Nausea 11.2 16.0 Diarrhea 6.2 10.3 Metabolic and Nutritional Disorders Weight Loss 10.1 15.3 Nervous System Dizziness 5.8 7.6 Respiratory Cough Increased 46.1 47.3 Pharyngitis 38.0 39.3 Sputum Increased 37.6 39.7 Rhinitis 34.5 33.6 Dyspnea 33.7 38.5 Lung Disorder 31.4 31.3 Sputum Discoloration 21.3 19.8 Hemoptysis 19.4 23.7 Lung Function Decreasedb 16.3 15.3 Asthma 15.9 20.2 Voice Alteration 12.8 6.5 Sinusitis 8.1 9.2 Epistaxis 7.0 6.5 Lower Respiratory Tract Infection 5.8 8.0 Hyperventilation 5.4 9.9 Special Senses Ear Pain 7.4 8.8 Taste Perversion 6.6 6.9 Skin and Appendages Rash 5.4 6.1 a Includes subjective complaints of fever. b Includes reported decreases in pulmonary function tests or decreased lung volume on chest radiograph associated with intercurrent illness or study drug administration. In a follow-on study of tobramycin solution for inhalation, the following adverse experiences were observed at a higher frequency in patients who received 4 to 6 cycles (over 6 to 12 months) of tobramycin solution for inhalation therapy than that seen in patients who received £3 cycles (up to 6 months) (see Table III). The role of chronic progression of disease on the increasing frequency of adverse experiences should be considered in the interpretation of these data. CPS:TABLE_C46400$$$1_t3 Table III--TOBI Treatment Emergent Adverse Experiences* Occurring at Higher Frequency During 6 to 12 Months of TOBI Therapy Adverse Event 4-6 Cycles (n=192) % £3 Cycles (n=204) % Body as a Whole Asthenia 44.3 38.2 Chest Pain 36.5 35.3 Back Pain 10.4 5.9 Lymphadenopathy 8.3 6.9 Chills 6.8 5.9 Sweating 5.7 4.9 Digestive Anorexia 29.2 27.5 Diarrhea 16.7 12.7 Oral Monoliasis 6.3 2.5 Dyspepsia 5.2 4.9 Musculoskeletal Myalgia 5.7 5.4 Respiratory Cough Increased 49.5 48.0 Pharyngitis 47.9 43.6 Sputum Increased 43.8 38.2 Dyspnea 41.7 33.8 Rhinitis 37.5 33.3 Hemoptysis 31.3 27.0 Lung Function Decreased 28.6 23.0 Asthma 28.1 23.5 Sputum Discoloration 24.5 19.1 Upper Respiratory Infection 13.5 9.8 Voic Alteration 12.0 6.4 Hyperventilation 8.9 5.4 Laryngitis 5.2 3.4 Special Senses Otitis Media 5.2 2.0 *Includes Adverse Experiences that were observed in >5% of patients in the 4 to 6 Cycles group and at a higher frequency than in the £3 Cycles group. (The £3 Cycles group received placebo during Phase III studies). In open label follow-on clinical trials and postmarketing surveillance, the following additional adverse events have been reported infrequently in patients receiving tobramycin solution for inhalation concurrently with other medications: Allergic reactions, fungal infection, hearing loss, hypoxia, mouth ulcerations and photosensitivity reaction. Symptoms And Treatment Of Overdose : OverdoseSigns and symptoms of acute toxicity from overdosage of i.v. tobramycin might include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, and neuromuscular blockade. Administration by inhalation results in low systemic bioavailability of tobramycin. Tobramycin is not significantly absorbed following oral administration. Tobramycin serum concentrations may be helpful in monitoring overdose.: In all cases of suspected overdosage, physicians should contact the Regional Poison Control Centre for information about effective treatment. In the case of any overdosage, the possibility of drug interactions with alterations in drug disposition should be considered. Dosage And Administration: The recommended dosage for both adults and pediatric patients 6 years of age and older is 1 single-use ampul (300 mg) administered twice a day (b.i.d.) for 28 days. The doses should be taken as close to 12 hours apart as possible; they should not be taken less than 6 hours apart. Tobramycin solution for inhalation is administered b.i.d. in alternating periods of 28 days. After 28 days of therapy, patients should stop tobramycin solution for inhalation therapy for the next 28 days, and then resume therapy for the next 28 day on / 28 day off cycle. Dosage is not adjusted by weight. All patients should be administered 300 mg b.i.d. Administration: Tobramycin solution for inhalation is supplied as a single-use ampul and is administered by inhalation. Tobramycin solution for inhalation is not for s.c., i.v. or intrathecal administration. Tobramycin solution for inhalation is administered using a hand-held Pari LC Plus reusable nebulizer with a DeVilbiss Pulmo-Aide compressor over a 15-minute period on average. Tobramycin solution for inhalation 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. Tobramycin solution for inhalation should not be diluted or mixed with dornase alfa (Pulmozyme) in the nebulizer. During clinical studies, patients on multiple therapies were instructed to take them first, followed by tobramycin solution for inhalation. Dosage And Administration: TOBI is a tobramycin solution for inhalation. Each ampul of sterile, clear, slightly yellow, nonpyrogenic, aqueous solution, with a pH (6.0) and salinity specifically adjusted for administration by a compressed air driven reusable nebulizer, contains: tobramycin solution 300 mg (as sulfate). Nonmedicinal ingredients: nitrogen, sodium chloride, sodium hydroxide, sterile water for injection and sulfuric acid. Preservative-free. Low-density polyethylene plastic ampuls of 5 mL. Boxes of 56 (14 flexible, laminated foil over-pouches, each containing 4 ampuls). Store under refrigeration at 2 to 8°C. Upon removal from the refrigerator, or if refrigeration is unavailable, the pouches (opened or unopened) may be stored at room temperature (up to 25°C). Do not use beyond the expiration date stamped on the ampul when stored under refrigeration (2 to 8°C) or beyond 28 days when stored at room temperature (25°C). Ampuls should not be exposed to intense light. The solution in the ampul is slightly yellow, but may darken with age if not stored in the refrigerator; however, the color change does not indicate any change in the quality of the product as long as it is stored within the recommended storage conditions.