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warnings and cautions
5 WARNINGS AND PRECAUTIONS Bronchospasm: Can occur with inhalation of tobramycin inhalation solution. Treat as medically appropriate, if it occurs ( 5.1 ). Ototoxicity: Tinnitus and hearing loss have been reported in patients receiving tobramycin inhalation solution. If noted, manage as medically appropriate, including potentially discontinuing tobramycin inhalation solution ( 5.2 ). Nephrotoxicity: Has been associated with aminoglycosides as a class. If nephrotoxicity develops, manage the patient as medically appropriate, including potentially discontinuing tobramycin inhalation solution ( 5.3 ). Neuromuscular Disorders: Aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts but mechanical assistance may be necessary ( 5.4 ). Embryo-Fetal Toxicity: Aminoglycosides can cause fetal harm ( 5.5 , 8.1 ) 5.1 Bronchospasm Bronchospasm can occur with inhalation of tobramycin inhalation solution. In clinical studies with tobramycin inhalation solution, changes in FEV1 measured after the inhaled dose were similar in tobramycin inhalation solution and placebo groups. Bronchospasm that occurs during the use of tobramycin inhalation solution should be treated as medically appropriate. 5.2 Ototoxicity Ototoxicity with use of Tobramycin Inhalation Solution Transient tinnitus occurred in eight tobramycin inhalation solution treated patients versus no placebo patients in the clinical studies. Tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants further clinical investigation. In postmarketing experience, patients receiving tobramycin inhalation solution have reported hearing loss. Ototoxicity, manifested as both auditory and vestibular toxicity, has been reported with parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness. Patients with known or suspected auditory or vestibular dysfunction should be closely monitored when taking tobramycin inhalation solution. Monitoring might include obtaining audiometric evaluations and serum tobramycin levels. If ototoxicity is noted, the patient should be managed as medically appropriate, including potentially discontinuing tobramycin inhalation solution [see Adverse Reactions ( 6.2 )] . Risk of Ototoxicity Due to Mitochondrial DNA Variants Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene ( MT-RNR1 ), particularly the m.1555A>G variant. Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. Mitochondrial DNA variants are present in less than 1% of the general US population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies. 5.3 Nephrotoxicity Nephrotoxicity was not seen during clinical studies with tobramycin inhalation solution but has been associated with aminoglycosides as a class. Patients with known or suspected renal dysfunction or taking concomitant nephrotoxic drugs along with tobramycin inhalation solution should have serum concentrations of tobramycin and laboratory measurements of renal function obtained at the discretion of the treating physician. If nephrotoxicity develops, the patient should be managed as medically appropriate, including potentially discontinuing tobramycin inhalation solution. 5.4 Neuromuscular Disorders Aminoglycosides, including tobramycin, may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function. Neuromuscular blockade, respiratory failure, and prolonged respiratory paralysis may occur more commonly in patients with underlying neuromuscular disorders, such as myasthenia gravis or Parkinson's disease. Prolonged respiratory paralysis may also occur in patients receiving neuromuscular blocking agents. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts but mechanical assistance may be necessary. 5.5 Embryo-Fetal Toxicity 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. However, systemic absorption of tobramycin following inhaled administration is expected to be minimal [see Clinical Pharmacology ( 12.3 )]. Patients who use TOBRAMYCIN INHALATION SOLUTION PAK during pregnancy, or become pregnant while taking tobramycin inhalation solution should be apprised of the potential hazard to the fetus [see Use in Specific Populations ( 8.1 )] . 5.6 Concomitant Use of Systemic Aminoglycosides Patients receiving concomitant tobramycin inhalation solution and parenteral aminoglycoside therapy should be monitored as clinically appropriate for toxicities associated with aminoglycosides as a class. Serum tobramycin levels should be monitored.
6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Bronchospasm [ see Warnings and Precautions ( 5.1 )] Ototoxicity [ see Warnings and Precautions ( 5.2 )] The most common adverse reactions (> 5%) in patients treated with tobramycin inhalation solution were increased cough, pharyngitis, increased sputum, dyspnea, hemoptysis, decreased lung function, voice alteration, taste perversion and rash ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact 1-844-548-2247 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Tobramycin inhalation solution was studied in two clinical studies in 258 cystic fibrosis patients ranging in age from 6 to 48 years. Patients received tobramycin inhalation solution 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. Adverse reactions reported in these studies are described below: The most frequent adverse reactions in the tobramycin inhalation arm were cough, pharyngitis, and increased sputum (see Table 1 ). Thirty-three patients (13%) treated with tobramycin inhalation solution complained of voice alteration compared to 17 (7%) placebo patients. Voice alteration was more common in the on-drug periods. Eight patients from the tobramycin inhalation solution group (3%) reported tinnitus compared to no placebo patients. All episodes were transient, resolved without discontinuation of the tobramycin inhalation solution treatment regimen, and were not associated with loss of hearing in audiograms. Table 1 lists the percent of patients with selected adverse reactions that occurred in > 5% of tobramycin inhalation solution patients during the two Phase III studies. Table 1: Percent of Patients with Selected Adverse Reactions Occurring in > 5% of Tobramycin Inhalation Solution Patients 1 Includes reported decreases in pulmonary function tests or decreased lung volume on chest radiograph associated with intercurrent illness or study drug administration. Adverse Reaction Tobramycin Inhalation Solution (n=258) % Placebo (n=262) % Cough Increased 46.1 47.3 Pharyngitis 38.0 39.3 Sputum Increased 37.6 39.7 Dyspnea 33.7 38.5 Hemoptysis 19.4 23.7 Lung Function Decrease 1 16.3 15.3 Voice Alteration 12.8 6.5 Taste Perversion 6.6 6.9 Rash 5.4 6.1 Selected adverse reactions that occurred in less than or equal to 5% of patients treated with tobramycin inhalation solution: Ear and labyrinth disorders Tinnitus Musculoskeletal and connective tissue disorders Myalgia Infections and infestations Laryngitis 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of tobramycin inhalation solution. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Ear and labyrinth disorders Hearing loss: Some of these reports occurred in patients with previous or concomitant treatment with systemic aminoglycosides. Patients with hearing loss frequently reported tinnitus. [see Warnings and Precautions ( 5.2 )] Skin and subcutaneous tissue disorders Hypersensitivity, pruritus, urticaria, rash Nervous system disorders Aphonia, dysgeusia Respiratory, thoracic, and mediastinal disorders Bronchospasm [see Warnings and Precautions ( 5.1 )] , oropharyngeal pain