ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling:oBronchospasm [see Warnings and Precautions (5.1) ]oOtotoxicity [see Warnings and Precautions (5.2) ]oNephrotoxicity [see Warnings and Precautions (5.3) ]oNeuromuscular Disorders [see Warnings and Precautions (5.4) ]oEmbryo-fetal Toxicity [see Warnings and Precautions (5.5) ]oConcomitant Use of Systemic Aminoglycosides [see Warnings and Precautions (5.6) ]. oBronchospasm [see Warnings and Precautions (5.1) ]. oOtotoxicity [see Warnings and Precautions (5.2) ]. oNephrotoxicity [see Warnings and Precautions (5.3) ]. oNeuromuscular Disorders [see Warnings and Precautions (5.4) ]. oEmbryo-fetal Toxicity [see Warnings and Precautions (5.5) ]. oConcomitant Use of Systemic Aminoglycosides [see Warnings and Precautions (5.6) ]. Most common adverse reactions (incidence 5%) are increased cough, pharyngitis, increased sputum, dyspnea, hemoptysis, decreased lung function, voice alteration, taste perversion and rash. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.TOBI was studied in two Phase clinical studies involving 258 cystic fibrosis patients ranging in age from to 48 years. Patients received TOBI in alternating periods of 28 days on and 28 days off drug in addition to their standard cystic fibrosis therapy for total of 24 weeks.Table lists the percent of patients with selected adverse reactions that occurred in 5% of TOBI patients during the two Phase studies.Table 1: Percent of Patients With Selected Adverse Reactions Occurring in 5% of TOBI PatientsAdverse ReactionTobramycin Inhalation Solution (n 258)%Placebo (n 262) Cough Increased46.147.3Pharyngitis 38.039.3Sputum Increased37.639.7Dyspnea33.738.5Hemoptysis19.423.7Lung Function DecreasedIncludes reported decreases in pulmonary function tests or decreased lung volume on chest radiograph associated with intercurrent illness or study drug administration. 16.315.3Voice Alteration12.86.5Taste Perversion6.66.9Rash5.46.1Selected adverse reactions that occurred in less than or equal to 5% of patients treated with TOBI:Ear and Labyrinth Disorders: Tinnitus Musculoskeletal and ConnectiveTtissue Disorders: MyalgiaInfections and Infestations: Laryngitis Voice Alteration and TinnitusVoice alteration and tinnitus were the only adverse reactions reported by significantly more TOBI-treated patients. Thirty-three patients (13%) treated with TOBI complained of voice alteration compared to 17 (7%) placebo patients. Voice alteration was more common in the on-drug periods.Eight patients from the TOBI group (3%) reported tinnitus compared to no placebo patients. All episodes were transient, resolved without discontinuation of the TOBI treatment regimen, and were not associated with loss of hearing in audiograms. Tinnitus is one of the sentinel symptoms of cochlear toxicity, and patients with this symptom should be carefully monitored for high frequency hearing loss. The numbers of patients reporting vestibular adverse experiences such as dizziness were similar in the TOBI and placebo groups.Changes in Serum CreatinineNine (3%) patients in the TOBI group and nine (3%) patients in the placebo group had increases in serum creatinine of at least 50% over baseline. In all nine patients in the TOBI group, creatinine decreased at the next visit.. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TOBI. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Ear and Labyrinth DisordersHearing 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 DisordersHypersensitivity, pruritus, urticaria, rashNervous System DisordersAphonia, dysgeusiaRespiratory, Thoracic, and Mediastinal DisordersBronchospasm [see Warnings and Precautions (5.1)] oropharyngeal painMetabolism and Nutrition DisordersDecreased appetite.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. two-year rat inhalation toxicology study to assess carcinogenic potential of TOBI has been completed. Rats were exposed to TOBI 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 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 battery of in vitro and in vivo tests. The Ames bacterial reversion test, conducted with tester strains, failed to show significant increase in revertants with or without metabolic activation in all strains. Tobramycin was negative in the mouse lymphoma forward mutation assay, did not induce chromosomal aberrations in Chinese hamster ovary cells, and was negative in the mouse micronucleus test.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 PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action. Tobramycin is an aminoglycoside antibacterial [see Microbiology (12.4)].. 12.3 Pharmacokinetics. AbsorptionTOBI contains tobramycin, cationic polar molecule that does not readily cross epithelial membranes. (1)The bioavailability of TOBI may vary because of individual differences in nebulizer performance and airway pathology. (2)Following administration of TOBI, tobramycin remains concentrated primarily in the airways.Serum ConcentrationsThe average serum concentration of tobramycin one hour after inhalation of single 300-mg dose of TOBI by cystic fibrosis patients was 0.95 mcg/mL. After 20 weeks of therapy on the TOBI regimen, the average serum tobramycin concentration one hour after dosing was 1.05 mcg/mL.Sputum ConcentrationsTen minutes after inhalation of the first 300-mg dose of TOBI 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 TOBI 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.DistributionFollowing administration of TOBI, tobramycin remains concentrated primarily in the airways. Binding of tobramycin to serum proteins is negligible.EliminationMetabolismTobramycin is not metabolized.ExcretionThe elimination half-life of tobramycin from serum is approximately and 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 TOBI administration, is probably eliminated primarily in expectorated sputum.. 12.4 Microbiology. Mechanism of ActionTobramycin is an aminoglycoside antibacterial produced by Streptomyces tenebrarius. (1)It acts primarily by disrupting protein synthesis, leading to altered cell membrane permeability, progressive disruption of the cell envelope, and eventual cell death.(3) Tobramycin has in vitro activity against gram-negative bacteria including Pseudomonas aeruginosa. It is bactericidal in vitro at concentrations equal to or slightly greater than the minimum inhibitory concentration (MIC).ResistanceTreatment for months with TOBI in two clinical studies did not affect the susceptibility of the majority of P. aeruginosa isolates tested; however, increased minimum inhibitory concentrations (MICs) were noted in some patients. The clinical significance of this information has not been clearly established in the treatment of P. aeruginosa in cystic fibrosis patients [see Clinical Studies (14) ].Susceptibility Test MethodsInterpretive criteria for inhaled antibacterial products are not defined. The in vitro antimicrobial susceptibility test methods used for parenteral tobramycin therapy can be used to monitor the susceptibility of P. aeruginosa isolated from cystic fibrosis patients. If decreased susceptibility is noted, the results should be reported to the clinician.Susceptibility breakpoints established for parenteral administration of tobramycin do not apply to aerosolized administration of TOBI. The relationship between in vitro susceptibility test results and clinical outcome with TOBI therapy is not clear.A single sputum sample from cystic fibrosis patient may contain multiple morphotypes of Pseudomonas aeruginosa and each morphotype may have different level of in vitro susceptibility to tobramycin.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES Two identically designed, double-blind, randomized, placebo-controlled, parallel group, 24-week clinical studies (Study and Study 2) at total of 69 cystic fibrosis centers in the United States were conducted in cystic fibrosis patients with P. aeruginosa. Subjects who were less than years of age, had baseline creatinine of 2 mg/dL, or had Burkholderia cepacia isolated from sputum were excluded. All subjects had baseline FEV1% predicted between 25% and 75%. In these clinical studies, 258 patients received TOBI therapy on an outpatient basis (see Table 2) using hand-held PARI LC PLUS Reusable Nebulizer with DeVilbiss Pulmo-Aide compressor.Table 2: Dosing Regimens in Clinical StudiesCycle 1Cycle 2Cycle 328 days28 days28 days28 days28 days28 daysTOBIregimenn 258TOBI300 mgtwice dailyNo drugTOBI300 mgtwice dailyNo drugTOBI300 mgtwice dailyNo drugPlaceboregimenn 262placebotwice dailyNo drugplacebotwice dailyNo drugplacebotwice dailyNo drugAll patients received either TOBI 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, 2-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, TOBI-treated patients experienced significant improvement in pulmonary function. Improvement was demonstrated in the TOBI group in Study by an average increase in FEV1% predicted of about 11% relative to baseline (Week 0) during 24 weeks compared to no average change in placebo patients. In Study 2, TOBI-treated patients had an average increase of about 7% compared to an average decrease of about 1% in placebo patients. Figure shows the average relative change in FEV1% predicted over 24 weeks for both studies.In each study, TOBI therapy resulted in significant reduction 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 2).Patients treated with TOBI were hospitalized for an average of 5.1 days compared to 8.1 days for placebo patients. Patients treated with TOBI required an average of 9.6 days of parenteral antipseudomonal, antibacterial treatment compared to 14.1 days for placebo patients. During the months of treatment, 40% of TOBI patients and 53% of placebo patients were treated with parenteral antipseudomonal antibacterials.The relationship between in vitro susceptibility test results and clinical outcome with TOBI therapy is not clear. However, four TOBI patients who began the clinical trial with P. aeruginosa isolates having MIC values >= 128 mcg/mL did not experience an improvement in FEV1 or decrease in sputum bacterial density.Treatment with TOBI did not affect the susceptibility of the majority of P. aeruginosa isolates during the 6-month studies. However, some P. aeruginosa isolates did exhibit increased tobramycin MICs. The percentage of patients with P. aeruginosa isolates with tobramycin MICs >= 16 mcg/mL was 13% at the beginning, and 23% at the end of months of the TOBI regimen.. Figure 1: Relative Change From Baseline in FEV 1% Predicted. Figure 2: Absolute Change From Baseline in Log 10 CFUs.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS TOBI is contraindicated in patients with known hypersensitivity to any aminoglycoside.. Known hypersensitivity to any aminoglycoside (4).

DESCRIPTION SECTION.

11 DESCRIPTION. TOBI(R) is tobramycin solution for inhalation. It is sterile, clear, slightly yellow, non-pyrogenic, aqueous solution with the pH and salinity adjusted specifically for administration by compressed air driven reusable nebulizer. The chemical formula for tobramycin is C18H37N5O9 and the molecular weight is 467.52 g/mol. Tobramycin is O-3-amino-3-deoxy--D-glucopyranosyl-(1->4)-O-[2,6-diamino-2,3,6- trideoxy--D-ribo-hexopyranosyl-(1->6)]-2-deoxy-L-streptamine. The structural formula for tobramycin is:Each single-dose mL ampoule contains 300 mg tobramycin and 11.25 mg sodium chloride in sterile water for injection. Sulfuric acid and sodium hydroxide are added to adjust the pH to 6.0. Nitrogen is used for sparging. All ingredients meet USP requirements. The formulation contains no preservatives.. The structural formula for tobramycin is sterile, clear, slightly yellow, non-pyrogenic, aqueous solution with the pH and salinity adjusted specifically for administration by compressed air driven reusable nebulizer. The chemical formula for tobramycin is C18H37N5O9 and the molecular weight is 467.52 g/mol. Tobramycin is O-3-amino-3-deoxy--D glucopyranosyl-(1->4)-O-[2,6-diamino-2,3,6- trideoxy--D-ribo-hexopyranosyl-(1->6)]-2-deoxy-L-streptamine.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oFor oral inhalation only. (2.1) oThe recommended dosage for adults and pediatric patients years of age and older is one single-dose ampoule (300 mg) twice daily by oral inhalation in alternating periods of 28 days on drug, followed by 28 days off drug. (2.1)oDosage is not adjusted by weight. (2.1)oTake doses as close to 12 hours apart as possible; but not less than hours apart. (2.1)oAdminister each 300 mg dose by inhalation using hand-held PARI LC PLUS Reusable Nebulizer with DeVilbiss Pulmo-Aide compressor. (2.2). oFor oral inhalation only. (2.1) oThe recommended dosage for adults and pediatric patients years of age and older is one single-dose ampoule (300 mg) twice daily by oral inhalation in alternating periods of 28 days on drug, followed by 28 days off drug. (2.1). oDosage is not adjusted by weight. (2.1). oTake doses as close to 12 hours apart as possible; but not less than hours apart. (2.1). oAdminister each 300 mg dose by inhalation using hand-held PARI LC PLUS Reusable Nebulizer with DeVilbiss Pulmo-Aide compressor. (2.2). 2.1 Dosage. TOBI is for oral inhalation only [see Dosage and Administration (2.2) ]. The recommended dosage of TOBI for both adults and pediatric patients years of age and older is one single-dose ampoule (300 mg) administered twice daily for 28 days. Dosage is not adjusted by weight. All patients should be administered 300 mg twice daily.TOBI is administered twice daily in alternating periods of 28 days. After 28 days of therapy, patients should stop TOBI 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 hours apart.If patients miss dose, they should take it as soon as possible anytime up to hours prior to their next scheduled dose. If less than hours remain before the next dose, wait until their next scheduled dose.. 2.2 Administration Instructions. TOBI is administered by oral inhalation over an approximately 15-minute period, using hand-held PARI LC PLUS Reusable Nebulizer with DeVilbiss Pulmo-Aide compressor. TOBI should not be diluted or mixed with dornase alfa or other medications in the nebulizer. TOBI is not for subcutaneous, intravenous or intrathecal administration.Prior to administration of TOBI, read the Patient Information/Instructions for Use for TOBI for detailed information on how to use TOBI, and follow the manufacturers instructions for use and care of the PARI LC PLUS Reusable Nebulizer and DeVilbiss Pulmo-Aide air compressor. TOBI 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 TOBI or as directed by their physician.TOBI 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. TOBI is supplied as sterile inhalational solution for nebulization in single-dose mL ampoules. Each mL ampoule contains 300 mg of tobramycin.. oInhalation Solution: 300 mg per mL solution in single-dose ampoule (3). oInhalation Solution: 300 mg per mL solution in single-dose ampoule (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oConcurrent and/or sequential use of TOBI with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided. (7.1)oConcomitant administration with ethacrynic acid, furosemide, urea, or intravenous mannitol is not recommended due to possible enhancement of aminoglycoside toxicity. (7.2). oConcurrent and/or sequential use of TOBI with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided. (7.1). oConcomitant administration with ethacrynic acid, furosemide, urea, or intravenous mannitol is not recommended due to possible enhancement of aminoglycoside toxicity. (7.2). 7.1 Drugs with Neurotoxic, Nephrotoxic or Ototoxic Potential. Concurrent and/or sequential use of TOBI with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided.. 7.2 Diuretics. Some diuretics can enhance aminoglycoside toxicity by altering aminoglycoside concentrations in serum and tissue. TOBI should not be administered concomitantly with ethacrynic acid, furosemide, urea, or intravenous mannitol. The interaction between inhaled mannitol and TOBI has not been evaluated.

GERIATRIC USE SECTION.

8.5 Geriatric Use Clinical studies of TOBI 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 (5.3) ].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. TOBI is supplied as sterile, clear, slightly yellow, non-pyrogenic, aqueous solution packaged in 5 mL single-dose ampoule (300 mg tobramycin) for nebulization.TOBI 300 mg is available as follows:5 mL single-dose ampoule (carton of 56) NDC 0078-0494-71. 16.2 Storage and Handling. TOBI should be stored under refrigeration at 2oC-8oC/36oF-46oF. Upon removal from the refrigerator, or if refrigeration is unavailable, TOBI pouches (opened or unopened) may be stored at room temperature (up to 25oC/77oF) for up to 28 days. TOBI should not be used beyond the expiration date stamped on the ampoule when stored under refrigeration (2oC-8oC/36oF-46oF) or beyond 28 days when stored at room temperature (25oC/77oF).TOBI ampoules should not be exposed to intense light. The solution in the ampoule 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.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE TOBI is indicated for the management of cystic fibrosis in adults and pediatric patients years of age and older with Pseudomonas aeruginosa.Safety and efficacy have not been demonstrated in patients under the age of years, patients with forced expiratory volume in second (FEV1) 25% or 75% predicted, or patients colonized with Burkholderia cepacia [see Clinical Studies (14)]. TOBI is an aminoglycoside antibacterial indicated for the management of cystic fibrosis in adults and pediatric patients years of age and older with Pseudomonas aeruginosa.Safety and efficacy have not been demonstrated in patients under the age of years, patients with forced expiratory volume in second (FEV1) 25% or 75% predicted, or patients colonized with Burkholderia cepacia.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).Difficulty Breathing:Advise patients to inform their physicians if they experience shortness of breath or wheezing after administration of tobramycin inhalation solution. Tobramycin inhalation solution can cause narrowing of the airway [see Warnings and Precautions (5.1) ].Hearing Loss:Advise patients to inform their physician if they experience ringing in the ears, dizziness, or any changes in hearing because tobramycin inhalation solution has been associated with hearing loss [see Warnings and Precautions (5.2) ].Kidney Damage:Advise patients to inform their physician if they have any history of kidney problems because tobramycin inhalation solution is in class of drugs that have caused kidney damage [see Warnings and Precautions (5.3) ].Embryo-fetal Toxicity:Advise pregnant women that aminoglycosides can cause irreversible congenital deafness when administered to pregnant woman [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1) ].Lactation:Advise woman to monitor their breastfed infants for diarrhea and/or bloody stools [see Use in Specific Populations (8.2) ].Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936(C) NovartisT2018-120.

LABORATORY TESTS SECTION.

5.5 Embryo-fetal Toxicity. Aminoglycosides can cause fetal harm when administered to 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 TOBI during pregnancy, or become pregnant while taking TOBI should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1) ].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of TOBI 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 (12.3) ]. Tobramycin may cause alteration in the intestinal flora of the breastfeeding infant (see Clinical Considerations ). The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for TOBI and any potential adverse effects on the breastfed infant from TOBI or from the underlying maternal condition.Clinical ConsiderationsTobramycin may cause intestinal flora alteration. Advise woman to monitor the breastfed infant for loose or bloody stools and candidiasis (thrush, diaper rash).

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Tobramycin is an aminoglycoside antibacterial [see Microbiology (12.4)].

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of ActionTobramycin is an aminoglycoside antibacterial produced by Streptomyces tenebrarius. (1)It acts primarily by disrupting protein synthesis, leading to altered cell membrane permeability, progressive disruption of the cell envelope, and eventual cell death.(3) Tobramycin has in vitro activity against gram-negative bacteria including Pseudomonas aeruginosa. It is bactericidal in vitro at concentrations equal to or slightly greater than the minimum inhibitory concentration (MIC).ResistanceTreatment for months with TOBI in two clinical studies did not affect the susceptibility of the majority of P. aeruginosa isolates tested; however, increased minimum inhibitory concentrations (MICs) were noted in some patients. The clinical significance of this information has not been clearly established in the treatment of P. aeruginosa in cystic fibrosis patients [see Clinical Studies (14) ].Susceptibility Test MethodsInterpretive criteria for inhaled antibacterial products are not defined. The in vitro antimicrobial susceptibility test methods used for parenteral tobramycin therapy can be used to monitor the susceptibility of P. aeruginosa isolated from cystic fibrosis patients. If decreased susceptibility is noted, the results should be reported to the clinician.Susceptibility breakpoints established for parenteral administration of tobramycin do not apply to aerosolized administration of TOBI. The relationship between in vitro susceptibility test results and clinical outcome with TOBI therapy is not clear.A single sputum sample from cystic fibrosis patient may contain multiple morphotypes of Pseudomonas aeruginosa and each morphotype may have different level of in vitro susceptibility to tobramycin.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. two-year rat inhalation toxicology study to assess carcinogenic potential of TOBI has been completed. Rats were exposed to TOBI 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 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 battery of in vitro and in vivo tests. The Ames bacterial reversion test, conducted with tester strains, failed to show significant increase in revertants with or without metabolic activation in all strains. Tobramycin was negative in the mouse lymphoma forward mutation assay, did not induce chromosomal aberrations in Chinese hamster ovary cells, and was negative in the mouse micronucleus test.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.

OVERDOSAGE SECTION.

10 OVERDOSAGE Signs and symptoms of acute toxicity from overdosage of intravenous (IV) tobramycin might include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, neuromuscular blockade, and renal impairment. 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 overdosage.Acute toxicity should be treated with immediate withdrawal of TOBI, and baseline tests of renal function should be undertaken.In all cases of suspected overdosage, physicians should contact the Regional Poison Control Center for information about effective treatment. In the case of any overdosage, the possibility of drug interactions with alterations in drug disposition should be considered.Hemodialysis may be helpful in removing tobramycin from the body.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 300 mg 5 mL Ampules. NDC 0078-0494-71TOBI(R) Tobramycin Inhalation Solution, USP300 mg 5 mL Ampules56 Single-Use Ampules (28-Day Supply) Rx Only Store In RefrigeratorContents: Each foil pouch contains four sterile, non-pyrogenic, single-use ampules. Each5 mL ampule contains one 300 mg dose of Tobramycin USP and 11.25 mg Sodium Chloridein Sterile Water for Injection.Dosage and Administration: Each single-use ampule contains one 300 mg dose.For inhalation only using required type of nebulizer. See package insert for fullprescribing information.Storage: Store in refrigerator at 2-8C/36-46F. Protect from intense light. See packageinsert for additional information.U.S. Patent 5,508,269; other patents pending.Store In RefrigeratorFor more information, call1-888-NOW-NOVA (1-888-669-6682)Manufactured by:Catalent Pharma Solution, LLCWoodstock, Illinois 60098Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936PCR-700-11544 US. Rx Only TOBI(R) 300 mg/5 mL Ampules Carton Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use The safety and efficacy of TOBI in pediatric patients under years of age has not been established. The use of TOBI is not indicated in children 6 years of age [see Indications and Usage (1) and Dosage and Administration (2) ].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionTOBI contains tobramycin, cationic polar molecule that does not readily cross epithelial membranes. (1)The bioavailability of TOBI may vary because of individual differences in nebulizer performance and airway pathology. (2)Following administration of TOBI, tobramycin remains concentrated primarily in the airways.Serum ConcentrationsThe average serum concentration of tobramycin one hour after inhalation of single 300-mg dose of TOBI by cystic fibrosis patients was 0.95 mcg/mL. After 20 weeks of therapy on the TOBI regimen, the average serum tobramycin concentration one hour after dosing was 1.05 mcg/mL.Sputum ConcentrationsTen minutes after inhalation of the first 300-mg dose of TOBI 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 TOBI 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.DistributionFollowing administration of TOBI, tobramycin remains concentrated primarily in the airways. Binding of tobramycin to serum proteins is negligible.EliminationMetabolismTobramycin is not metabolized.ExcretionThe elimination half-life of tobramycin from serum is approximately and 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 TOBI administration, is probably eliminated primarily in expectorated sputum.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAminoglycosides can cause fetal harm. Published literature reports that use of streptomycin, an aminoglycoside, can cause total, irreversible, bilateral congenital deafness when administered to pregnant woman [see Warnings and Precautions (5.5) ]. Although there are no available data on TOBI use in pregnant women to inform drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes, systemic absorption of tobramycin following inhaled administration is expected to be minimal [see Clinical Pharmacology (12.3) ]. There are risks to the mother associated with cystic fibrosis in pregnancy (see Clinical Considerations ). In animal reproduction studies with subcutaneous administration of tobramycin in pregnant rats and rabbits during organogenesis, there were no adverse developmental outcomes; however, ototoxicity was not evaluated in the offspring from these studies (see Data ). Advise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. 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 ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskCystic fibrosis may increase the risk for preterm delivery.DataAnimal DataNo reproductive toxicity studies have been conducted with TOBI (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.

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions, Ototoxicity (5.2) 10/2018.

REFERENCES SECTION.

15 REFERENCES. 1.Neu HC. Tobramycin: an overview. [Review]. Infect Dis 1976; Suppl 134:S3-19.2.Weber A, Smith A, Williams-Warren et al. Nebulizer delivery of tobramycin to the lower respiratory tract. Pediatr Pulmonol 1994; 17 (5):331-9.3.Bryan LE. Aminoglycoside resistance. Bryan LE, Ed. Antimicrobial drug resistance. Orlando, FL: Academic Press, 1984: 241-77.. 1.Neu HC. Tobramycin: an overview. [Review]. Infect Dis 1976; Suppl 134:S3-19.. 2.Weber A, Smith A, Williams-Warren et al. Nebulizer delivery of tobramycin to the lower respiratory tract. Pediatr Pulmonol 1994; 17 (5):331-9.. 3.Bryan LE. Aminoglycoside resistance. Bryan LE, Ed. Antimicrobial drug resistance. Orlando, FL: Academic Press, 1984: 241-77.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONTOBI (TOH-bee)(tobramycin inhalation solution)for oral inhalation useWhat is TOBITOBI is prescription medicine that is used to treat people with cystic fibrosis who have bacterial infection called Pseudomonas aeruginosa. TOBI contains an antibacterial medicine called tobramycin (an aminoglycoside).It is not known if TOBI is safe and effective:oin children under years of ageoin people who have an FEV1 less than 25% or greater than 75% predictedoin people who are colonized with bacterium called Burkholderia cepaciaDo not take TOBI if you are allergic to tobramycin, any of the ingredients in TOBI, or to any other aminoglycoside antibacterial.See the end of this Patient Information for complete list of ingredients in TOBI.Before you take TOBI, tell your healthcare provider about all of your medical conditions, including if you:ohave or have had hearing problems (including noises in your ears such as ringing or hissing)ohave dizzinessohave or have had kidney problemsohave or have had problems with muscle weakness such as myasthenia gravis or Parkinsons diseaseohave or have had breathing problems such as wheezing, coughing, or chest tightnessoare pregnant or plan to become pregnant. TOBI is in class of drugs that can harm your unborn baby.oare breastfeeding or plan to breastfeed. It is not known if TOBI passes into your breast milk.oare receiving aminoglycoside therapy by injection or through vein (intravenous) while taking TOBI. Your blood levels of tobramycin will be checked.Tell your healthcare provider about all the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements.How should take TOBIoSee the step-by-step Instructions for Use about the right way to take your TOBI.oTake TOBI exactly as your healthcare provider tells you. Do not change your dose or stop taking TOBI unless your healthcare provider tells you to.oThe usual dose for adults and children over years of age is:o1 single-use ampule of TOBI inhaled times each day using hand-held PARI LC PLUS(TM) Reusable Nebulizer ana DeVilbiss(R) Pulmo-Aide(R) air compressor.oEach dose of TOBI should be taken as close to 12 hours apart as possible.oYou should not take your dose less than hours apart.oTOBI is taken as breathing treatment (inhalation) with hand-held PARI LC PLUS Reusable Nebulizer with DeVilbiss Pulmo-Aide compressor. Do not use any other nebulizer for your TOBI treatment.oDo not mix or dilute TOBI with dornase alfa or other medicines in your nebulizer system.oEach treatment should take about 15 minutes.oTOBI 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.oIf you forget to take TOBI and there are at least 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.oAfter using TOBI for 28 days, you should stop using it and wait 28 days. After you have stopped using TOBI for 28 days, you should start using TOBI 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.If you are taking several medicines or treatments to treat your cystic fibrosis, you should take your medicines or other treatments before inhaling TOBI or as directed by your healthcare provider. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter prescription medicines, vitamins, and herbal supplements.Using TOBI with certain other medicines can cause serious side effects.If you are using TOBI, you should discuss with your healthcare provider if you should take:oother medicines that may harm your nervous system, kidneys, or hearingowater pills (diuretics) such as ethacrynic acid, furosemide, or intravenous mannitoloureaAsk your healthcare provider or pharmacist for list of these medicines, if you are not sure.Know the medicines you take. Keep list of them and show it to your healthcare provider and pharmacist when you get new medicine.What are the possible side effects of TOBITOBI may cause serious side effects, including:osevere breathing problems (bronchospasm). Tell your healthcare provider right away if you get any of these symptoms of bronchospasm with using TOBI: oshortness of breath with wheezingocoughing and chest tightnessohearing 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. oworsening kidney problems (nephrotoxicity). TOBI is in class of drugs which may cause worsening kidney problems, especially in people with known or suspected kidney problems. Your healthcare provider may do blood test to check how your kidneys are working while you are using TOBI.oworsening muscle weakness (neuromuscular disorder). TOBI is in class of drugs which can cause muscle weakness to get worse in people who already have problems with muscle weakness (myasthenia gravis or Parkinsons disease).The most common side effects of TOBI include: oincreased coughocoughing up bloodovoice changesosore throatodecreased lung functionoloss or change in tasteoincreased sputumotrouble breathingorashThese are not all of the possible side effects of TOBI.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of TOBIMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use TOBI for condition for which it was not prescribed. Do not give it to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for more information about TOBI that is written for health professionals.What are the ingredients in TOBIActive ingredient: tobramycin Inactive ingredients: sodium chloride in sterile water for injection, sulfuric acid, sodium hydroxide, and nitrogen What is Pseudomonas aeruginosaIt is 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. Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936 For more information, go to www.pharma.us.novartis.com or call 1-888-669-6682.This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 10/2018(C) NovartisT2018-121Instructions for UseTOBI (TOH-bee) (tobramycin inhalation solution) for oral inhalation use Read this Instructions for Use before you start using TOBI inhalation solution and each time you get 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. TOBI is made for inhalation using PARI LC PLUS(TM) Reusable Nebulizer and DeVilbiss(R) Pulmo-Aide(R) air compressor. TOBI can be taken at home, school, or at work. The following instructions tell you how to use the DeVilbiss Pulmo-Aide air compressor and PARI LC PLUS Reusable Nebulizer to administer TOBI.You will need the following supplies (See Figure A):o1 TOBI plastic ampule (TOBI is packaged with ampules in each foil pouch)oDeVilbiss Pulmo-Aide air compressor oPARI LC PLUS Reusable Nebulizer oTubing to connect the nebulizer and compressoroClean paper or cloth towelsoNose clips (optional)(Figure A)It is important that your nebulizer and compressor function properly before starting your TOBI therapy.Note: Read the manufacturer care and use instructions for important information.Prepare Your TOBI for Inhalation TherapyStep 1: Wash your hands thoroughly with soap and water.Step 2: Open the foil pouch.Step 3: Separate TOBI ampule by gently pulling apart at the bottom tabs (See Figure B). Place the remaining TOBI ampules in the refrigerator.(Figure B)Step 4: Check the expiration date stamped on the TOBI ampule (See Figure C). Do not use the TOBI ampule if the expiration date has passed.(Figure C)Step 5: Check that the TOBI ampule medicine is clear and does not have particles. oUnrefrigerated TOBI, 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.oDo not use the TOBI ampule if the medicine is cloudy or has particles. oThrow it away and get new one.Step 6: Lay out the parts of PARI LC PLUS Reusable Nebulizer package on clean, dry paper or cloth towel. You should have the following parts (See Figure D):oNebulizer Top and Bottom (Nebulizer Cup) AssemblyoInspiratory Valve CapoMouthpiece with ValveoTubing(Figure D)Step 7: Remove the Nebulizer Top from the Nebulizer Cup by twisting the Nebulizer Top counter-clockwise, and then lifting off (See Figure E). (Figure E)Step 8: Place the Nebulizer Top on the clean paper or cloth towel by standing the Nebulizer Cup upright on the towel (See Figure F). (Figure F)Step 9: Connect one end of the tubing to the compressor air outlet (See Figure G). The tubing should fit tightly. (Figure G)Step 10: Plug in your compressor to an electrical outlet (See Figure H).(Figure H)Step 11: Open the TOBI ampule by holding the bottom tab with hand and twisting off the top of the TOBI ampule with the other hand (See Figure I). Be careful not to squeeze the TOBI ampule until you are ready to empty all the medicine into the Nebulizer Cup.(Figure I)Step 12: Squeeze all the medicine of the TOBI ampule into the Nebulizer Cup (See Figure J).(Figure J)Step 13: Replace the Nebulizer Top. To replace the Nebulizer Top insert the Nebulizer Top into the Nebulizer Cup with the semi-circle halfway down the stem of the Nebulizer Top facing the Nebulizer Outlet. Turn the Nebulizer Top clockwise until securely fastened to the nebulizer Cup. (See Figure K). (Figure K)Step 14: Push the Mouthpiece straight onto the Nebulizer Outlet (See Figure L). (Figure L)Step 15: Firmly push the Inspiratory Valve Cap straight down onto the Nebulizer Top (See Figure M). The Inspiratory Valve Cap will fit tightly.(Figure M)Step 16: Hold the Nebulizer Cup upright and firmly push the free end of the tubing from the compressor to the Air Intake on the bottom of the Nebulizer Cup (See Figure N). Make sure to keep the Nebulizer Cup upright. (Figure N)Giving your TOBI Inhalation TherapyStep 17: Turn on the compressor (See Figure O).(Figure O)Step 18: Check for steady mist from the Mouthpiece (See Figure P). If there is no mist, check all tubing connections and make sure that the compressor is working properly.(Figure P)Step 19: Sit or stand in an upright position that will allow you to breathe normally. Place the Mouthpiece between your teeth and on top of your tongue and breathe normally only through your mouth (See Figure Q). Nose clips may help you breathe through your mouth and not through your nose. Do not block the airflow with your tongue.(Figure Q)Step 20: Keep breathing in your TOBI medicine for at least 15 minutes to get your full dose. Continue therapy until all your TOBI medicine is gone, and there is no longer any mist being made. You may hear sputtering sound coming from the Mouthpiece when the Nebulizer Cup is empty. The entire TOBI therapy should take about 15 minutes to complete. If you are interrupted, need to cough or rest during your TOBI 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 TOBI Inhalation TherapyCleaning Your NebulizerTo 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 nebulizer with 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 clean, lint-free cloth. Reassemble nebulizer when dry, and store.You can also wash all parts of the nebulizer in dishwasher (except tubing). 1)Place the nebulizer parts in 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 NebulizerYour nebulizer is for your use only. Do not share your nebulizer with other people. You must disinfect the nebulizer every other treatment day. Failure to disinfect the nebulizer every other treatment day could lead to serious or fatal illness.Clean the nebulizer as described above. Every other treatment day, disinfect the nebulizer parts (except tubing) by boiling them in water for full 10 minutes. Dry parts on clean, lint-free cloth.Care and Use of Your Pulmo-Aide CompressorFollow the manufacturer instructions for care and use of your compressor.Filter Change:oDeVilbiss Compressor filters should be changed every months or sooner if the filter turns completely gray in color.Compressor Cleaning:oWith power switch in the Off position, unplug power cord from wall outlet.oWipe outside of the compressor cabinet with clean, damp cloth every few days to keep dust free.Caution: Do not submerge in water because this will damage the compressor.How should store TOBIoStore TOBI ampules in refrigerator between 36F to 46F (2C to 8C) until needed.oYou may store the TOBI ampules in the foil pouches (opened or unopened) at room temperature 77F (25C) for up to 28 days. oDo not use TOBI ampules if they have been stored at room temperature for more than 28 days.oProtect TOBI ampules from light.Keep TOBI and all medicines out of the reach of children.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Additional InformationNebulizer: 1-800-327-8632Compressor: 1-800-338-1988TOBI: 1-888-NOW-NOVA (1-888-669-6682)Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936(C) NovartisIFU:TOBRIS:RX12/2018. oin children under years of age. oin people who have an FEV1 less than 25% or greater than 75% predicted. oin people who are colonized with bacterium called Burkholderia cepacia. ohave or have had hearing problems (including noises in your ears such as ringing or hissing). ohave dizziness. ohave or have had kidney problems. ohave or have had problems with muscle weakness such as myasthenia gravis or Parkinsons disease. ohave or have had breathing problems such as wheezing, coughing, or chest tightness. oare pregnant or plan to become pregnant. TOBI is in class of drugs that can harm your unborn baby.. oare breastfeeding or plan to breastfeed. It is not known if TOBI passes into your breast milk.. oare receiving aminoglycoside therapy by injection or through vein (intravenous) while taking TOBI. Your blood levels of tobramycin will be checked.. oSee the step-by-step Instructions for Use about the right way to take your TOBI.. oTake TOBI exactly as your healthcare provider tells you. Do not change your dose or stop taking TOBI unless your healthcare provider tells you to.. oThe usual dose for adults and children over years of age is:o1 single-use ampule of TOBI inhaled times each day using hand-held PARI LC PLUS(TM) Reusable Nebulizer ana DeVilbiss(R) Pulmo-Aide(R) air compressor.. o1 single-use ampule of TOBI inhaled times each day using hand-held PARI LC PLUS(TM) Reusable Nebulizer ana DeVilbiss(R) Pulmo-Aide(R) air compressor.. oEach dose of TOBI should be taken as close to 12 hours apart as possible.. oYou should not take your dose less than hours apart.. oTOBI is taken as breathing treatment (inhalation) with hand-held PARI LC PLUS Reusable Nebulizer with DeVilbiss Pulmo-Aide compressor. Do not use any other nebulizer for your TOBI treatment.. oDo not mix or dilute TOBI with dornase alfa or other medicines in your nebulizer system.. oEach treatment should take about 15 minutes.. oTOBI 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.. oIf you forget to take TOBI and there are at least 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.. oAfter using TOBI for 28 days, you should stop using it and wait 28 days. After you have stopped using TOBI for 28 days, you should start using TOBI 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.. oother medicines that may harm your nervous system, kidneys, or hearing. owater pills (diuretics) such as ethacrynic acid, furosemide, or intravenous mannitol. ourea. osevere breathing problems (bronchospasm). Tell your healthcare provider right away if you get any of these symptoms of bronchospasm with using TOBI: oshortness of breath with wheezingocoughing and chest tightness. oshortness of breath with wheezing. ocoughing and chest tightness. ohearing 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. oworsening kidney problems (nephrotoxicity). TOBI is in class of drugs which may cause worsening kidney problems, especially in people with known or suspected kidney problems. Your healthcare provider may do blood test to check how your kidneys are working while you are using TOBI.. oworsening muscle weakness (neuromuscular disorder). TOBI is in class of drugs which can cause muscle weakness to get worse in people who already have problems with muscle weakness (myasthenia gravis or Parkinsons disease).. oincreased cough. ocoughing up blood. ovoice changes. osore throat. odecreased lung function. oloss or change in taste. oincreased sputum. otrouble breathing. orash. o1 TOBI plastic ampule (TOBI is packaged with ampules in each foil pouch). oDeVilbiss Pulmo-Aide air compressor oPARI LC PLUS Reusable Nebulizer oTubing to connect the nebulizer and compressor. oClean paper or cloth towels. oNose clips (optional). oUnrefrigerated TOBI, 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.. oDo not use the TOBI ampule if the medicine is cloudy or has particles. oThrow it away and get new one.. oNebulizer Top and Bottom (Nebulizer Cup) Assembly. oInspiratory Valve Cap. oMouthpiece with Valve. oTubing. 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 clean, lint-free cloth. Reassemble nebulizer when dry, and store.. 1)Place the nebulizer parts in 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.. oDeVilbiss Compressor filters should be changed every months or sooner if the filter turns completely gray in color.. oWith power switch in the Off position, unplug power cord from wall outlet.. oWipe outside of the compressor cabinet with clean, damp cloth every few days to keep dust free.. oStore TOBI ampules in refrigerator between 36F to 46F (2C to 8C) until needed.. oYou may store the TOBI ampules in the foil pouches (opened or unopened) at room temperature 77F (25C) for up to 28 days. oDo not use TOBI ampules if they have been stored at room temperature for more than 28 days.. oProtect TOBI ampules from light.. Instructions for Use Figure A. Instructions for Use Figure B. Instructions for Use Figure C. Instructions for Use Figure D. Instructions for Use Figure E. Instructions for Use Figure F. Instructions for Use Figure G. Instructions for Use Figure H. Instructions for Use Figure I. Instructions for Use Figure J. Instructions for Use Figure K. Instructions for Use Figure L. Instructions for Use Figure M. Instructions for Use Figure N. Instructions for Use Figure O. Instructions for Use Figure P. Instructions for Use Figure Q.

SPL UNCLASSIFIED SECTION.

2.1 Dosage. TOBI is for oral inhalation only [see Dosage and Administration (2.2) ]. The recommended dosage of TOBI for both adults and pediatric patients years of age and older is one single-dose ampoule (300 mg) administered twice daily for 28 days. Dosage is not adjusted by weight. All patients should be administered 300 mg twice daily.TOBI is administered twice daily in alternating periods of 28 days. After 28 days of therapy, patients should stop TOBI 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 hours apart.If patients miss dose, they should take it as soon as possible anytime up to hours prior to their next scheduled dose. If less than hours remain before the next dose, wait until their next scheduled dose.

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling. TOBI should be stored under refrigeration at 2oC-8oC/36oF-46oF. Upon removal from the refrigerator, or if refrigeration is unavailable, TOBI pouches (opened or unopened) may be stored at room temperature (up to 25oC/77oF) for up to 28 days. TOBI should not be used beyond the expiration date stamped on the ampoule when stored under refrigeration (2oC-8oC/36oF-46oF) or beyond 28 days when stored at room temperature (25oC/77oF).TOBI ampoules should not be exposed to intense light. The solution in the ampoule 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAminoglycosides can cause fetal harm. Published literature reports that use of streptomycin, an aminoglycoside, can cause total, irreversible, bilateral congenital deafness when administered to pregnant woman [see Warnings and Precautions (5.5) ]. Although there are no available data on TOBI use in pregnant women to inform drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes, systemic absorption of tobramycin following inhaled administration is expected to be minimal [see Clinical Pharmacology (12.3) ]. There are risks to the mother associated with cystic fibrosis in pregnancy (see Clinical Considerations ). In animal reproduction studies with subcutaneous administration of tobramycin in pregnant rats and rabbits during organogenesis, there were no adverse developmental outcomes; however, ototoxicity was not evaluated in the offspring from these studies (see Data ). Advise pregnant women of the potential risk to fetus.The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. 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 ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskCystic fibrosis may increase the risk for preterm delivery.DataAnimal DataNo reproductive toxicity studies have been conducted with TOBI (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.. 8.2 Lactation. Risk SummaryThere are no data on the presence of TOBI 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 (12.3) ]. Tobramycin may cause alteration in the intestinal flora of the breastfeeding infant (see Clinical Considerations ). The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for TOBI and any potential adverse effects on the breastfed infant from TOBI or from the underlying maternal condition.Clinical ConsiderationsTobramycin may cause intestinal flora alteration. Advise woman to monitor the breastfed infant for loose or bloody stools and candidiasis (thrush, diaper rash).. 8.4 Pediatric Use The safety and efficacy of TOBI in pediatric patients under years of age has not been established. The use of TOBI is not indicated in children 6 years of age [see Indications and Usage (1) and Dosage and Administration (2) ].. 8.5 Geriatric Use Clinical studies of TOBI 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 (5.3) ].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oBronchospasm: Can occur with inhalation of TOBI. Treat as medically appropriate, if it occurs. (5.1)oOtotoxicity: Tinnitus and hearing loss have been reported in patients receiving TOBI. If noted, manage as medically appropriate, including potentially discontinuing TOBI. (5.2)oNephrotoxicity: Has been associated with aminoglycosides as class. If nephrotoxicity develops, manage the patient as medically appropriate, including potentially discontinuing TOBI. (5.3)oNeuromuscular Disorders: Aminoglycosides may aggravate muscle weakness because of 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)oEmbryo-fetal Toxicity: Aminoglycosides can cause fetal harm (5.5, 8.1). oBronchospasm: Can occur with inhalation of TOBI. Treat as medically appropriate, if it occurs. (5.1). oOtotoxicity: Tinnitus and hearing loss have been reported in patients receiving TOBI. If noted, manage as medically appropriate, including potentially discontinuing TOBI. (5.2). oNephrotoxicity: Has been associated with aminoglycosides as class. If nephrotoxicity develops, manage the patient as medically appropriate, including potentially discontinuing TOBI. (5.3). oNeuromuscular Disorders: Aminoglycosides may aggravate muscle weakness because of 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). oEmbryo-fetal Toxicity: Aminoglycosides can cause fetal harm (5.5, 8.1). 5.1 Bronchospasm. Bronchospasm can occur with inhalation of TOBI. In clinical studies with TOBI, changes in FEV1 measured after the inhaled dose were similar in tobramycin inhalation solution and placebo groups. Bronchospasm that occurs during the use of TOBI should be treated as medically appropriate.. 5.2 Ototoxicity. Ototoxicity, manifested as both auditory and vestibular toxicity, has been reported with parenteral aminoglycosides.Transient tinnitus occurred in eight TOBI treated patients versus no placebo patients in the clinical studies. Tinnitus may be sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants further clinical investigation. Ototoxicity, as measured by complaints of hearing loss or by audiometric evaluations, did not occur with TOBI therapy during clinical studies, however in postmarketing experience, patients receiving TOBI have reported hearing loss. 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 TOBI. 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 TOBI.. 5.3 Nephrotoxicity. Nephrotoxicity was not seen during clinical studies with TOBI but has been associated with aminoglycosides as class. Patients with known or suspected renal dysfunction or taking concomitant nephrotoxic drugs along with TOBI 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 TOBI.. 5.4 Neuromuscular Disorders. Aminoglycosides, including tobramycin, may aggravate muscle weakness because of 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 Parkinsons disease. Prolonged respiratory paralysis may also occur in patients receiving concomitant 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 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 TOBI during pregnancy, or become pregnant while taking TOBI 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 TOBI and parenteral aminoglycoside therapy should be monitored as clinically appropriate for toxicities associated with aminoglycosides as class. Serum tobramycin levels should be monitored.