Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Tobramycin inhalation solution USP is supplied as a sterile, clear, slightly yellow, non-pyrogenic, aqueous solution packaged in a 5 mL single-dose ampule (300 mg tobramycin) for nebulization. It is available as follows: 5 mL single-dose ampule packaged in cartons containing 56 ampules (14 pouches, each containing 4 ampules) NDC 65162-914-46 16.2 Storage and Handling Tobramycin inhalation solution should be stored under refrigeration at 2º to 8ºC or 36º to 46ºF. Upon removal from the refrigerator, or if refrigeration is unavailable, tobramycin inhalation solution pouches (opened or unopened) may be stored at room temperature (up to 25ºC/77ºF) for up to 28 days. Tobramycin inhalation solution should not be used beyond the expiration date stamped on the ampule when stored under refrigeration (2º to 8ºC or 36º to 46ºF) or beyond 28 days when stored at room temperature (25ºC/77ºF). Tobramycin inhalation solution ampules should not be exposed to intense light. The solution in the ampule 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.; PRINCIPAL DISPLAY PANEL NDC 65162-914-46 Tobramycin inhalation solution USP, 300 mg 5 mL single-dose ampoule Rx only Amneal Pharmaceuticals LLC NDC 65162-914-46 Tobramycin inhalation solution USP, 300 mg Rx only Amneal Pharmaceuticals LLC Carton label NDC 65162-914-46 Tobramycin inhalation solution USP, 300 mg Rx only Amneal Pharmaceuticals LLC Carton label 10 10 10
- 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Tobramycin inhalation solution USP is supplied as a sterile, clear, slightly yellow, non-pyrogenic, aqueous solution packaged in a 5 mL single-dose ampule (300 mg tobramycin) for nebulization. It is available as follows: 5 mL single-dose ampule packaged in cartons containing 56 ampules (14 pouches, each containing 4 ampules) NDC 65162-914-46 16.2 Storage and Handling Tobramycin inhalation solution should be stored under refrigeration at 2º to 8ºC or 36º to 46ºF. Upon removal from the refrigerator, or if refrigeration is unavailable, tobramycin inhalation solution pouches (opened or unopened) may be stored at room temperature (up to 25ºC/77ºF) for up to 28 days. Tobramycin inhalation solution should not be used beyond the expiration date stamped on the ampule when stored under refrigeration (2º to 8ºC or 36º to 46ºF) or beyond 28 days when stored at room temperature (25ºC/77ºF). Tobramycin inhalation solution ampules should not be exposed to intense light. The solution in the ampule 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.
- PRINCIPAL DISPLAY PANEL NDC 65162-914-46 Tobramycin inhalation solution USP, 300 mg 5 mL single-dose ampoule Rx only Amneal Pharmaceuticals LLC NDC 65162-914-46 Tobramycin inhalation solution USP, 300 mg Rx only Amneal Pharmaceuticals LLC Carton label NDC 65162-914-46 Tobramycin inhalation solution USP, 300 mg Rx only Amneal Pharmaceuticals LLC Carton label 10 10 10
Overview
Tobramycin inhalation solution, USP is a tobramycin solution for inhalation. It is a sterile, clear, slightly yellow, non-pyrogenic, aqueous solution with the pH and salinity adjusted specifically for administration by a compressed air driven reusable nebulizer. The chemical formula for tobramycin is C 18 H 37 N 5 O 9 and the molecular weight is 467.52. Tobramycin is O-3-amino-3-deoxy-α- D-glucopyranosyl-(1→4)-O-[2,6-diamino-2,3,6- trideoxy-α-D- ribo -hexopyranosyl-(1→6)]-2-deoxy-L-streptamine. The structural formula for tobramycin is: Each single-dose 5 mL ampule contains 300 mg tobramycin, USP 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. 10
Indications & Usage
Tobramycin inhalation solution is indicated for the management of cystic fibrosis in adults and pediatric patients 6 years of age and older with Pseudomonas aeruginosa . Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with forced expiratory volume in 1 second (FEV 1 ) < 25% or > 75% predicted, or patients colonized with Burkholderia cepacia [see Clinical Studies (14) ]. Tobramycin is an aminoglycoside antibacterial indicated for the management of cystic fibrosis in adults and pediatric patients 6 years of age and older with Pseudomonas aeruginosa . ( 1 ) Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with forced expiratory volume in 1 second (FEV 1 ) < 25% or > 75% predicted, or patients colonized with Burkholderia cepacia. ( 1 )
Dosage & Administration
For oral inhalation only. ( 2.1 ) The recommended dosage for adults and pediatric patients 6 years of age and older is one single-dose ampule (300 mg) twice daily by oral inhalation in alternating periods of 28 days on drug, followed by 28 days off drug. ( 2.1 ) Dosage is not adjusted by weight. ( 2.1 ) Take doses as close to 12 hours apart as possible; but not less than 6 hours apart. ( 2.1 ) Administer each 300 mg dose by inhalation using a hand-held PARI LC PLUS Reusable Nebulizer with a DeVilbiss Pulmo-Aide compressor. ( 2.2 ) 2.1 Dosage Tobramycin inhalation solution is for oral inhalation only [see Dosage and Administration (2.2) ] . The recommended dosage of tobramycin inhalation solution for both adults and pediatric patients 6 years of age and older is one single-dose ampule (300 mg) administered twice daily for 28 days. Dosage is not adjusted by weight. All patients should be administered 300 mg twice daily. Tobramycin inhalation solution is administered twice daily in alternating periods of 28 days. After 28 days of therapy, patients should stop tobramycin inhalation solution therapy for the next 28 days, and then resume therapy for the next 28 day on/28 day off cycle. The doses should be taken as close to 12 hours apart as possible; they should not be taken less than 6 hours apart. If patients miss a dose, they should take it as soon as possible anytime up to 6 hours prior to their next scheduled dose. If less than 6 hours remain before the next dose, wait until their next scheduled dose. 2.2 Administration Instructions Tobramycin inhalation solution is administered by oral inhalation over an approximately 15-minute period, using a hand-held PARI LC PLUS Reusable Nebulizer with a DeVilbiss Pulmo-Aide compressor. Tobramycin inhalation solution should not be diluted or mixed with dornase alfa or other medications in the nebulizer. Tobramycin inhalation solution is not for subcutaneous, intravenous or intrathecal administration. Prior to administration of tobramycin inhalation solution, read the Patient Information/Instructions for Use for tobramycin inhalation solution for detailed information on how to use tobramycin inhalation solution, and follow the manufacturer’s instructions for use and care of the PARI LC PLUS Reusable Nebulizer and DeVilbiss Pulmo-Aide air compressor. Tobramycin inhalation solution is inhaled while the patient is sitting or standing upright and breathing normally through the mouthpiece of the nebulizer. Nose clips may help the patient breathe through the mouth. Instruct patients on multiple therapies to take their medications, prior to inhaling tobramycin inhalation solution or as directed by their physician. Tobramycin inhalation solution should not be used if it is cloudy, if there are particles in the solution, or if it has been stored at room temperature for more than 28 days.
Warnings & Precautions
Bronchospasm: Can occur with inhalation of tobramycin. Treat as medically appropriate, if it occurs. ( 5.1 ) Ototoxicity: Tinnitus and hearing loss have been reported in patients receiving tobramycin. If noted, manage as medically appropriate, including potentially discontinuing tobramycin. ( 5.2 ) Nephrotoxicity: Has been associated with aminoglycosides as a class. If nephrotoxicity develops, manage the patient as medically appropriate, including potentially discontinuing tobramycin. ( 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. In clinical studies with tobramycin, changes in FEV 1 measured after the inhaled dose was similar in tobramycin inhalation solution and placebo groups. Bronchospasm that occurs during the use of tobramycin should be treated as medically appropriate. 5.2 Ototoxicity Ototoxicity with use of tobramycin inhalation solution Ototoxicity, manifested as both auditory and vestibular toxicity, has been reported with parenteral aminoglycosides. Transient tinnitus occurred in eight tobramycin 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. Ototoxicity, as measured by complaints of hearing loss or by audiometric evaluations, did not occur with tobramycin therapy during clinical studies, however in post-marketing experience, patients receiving tobramycin 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 tobramycin. 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. 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 but has been associated with aminoglycosides as a class. Patients with known or suspected renal dysfunction or taking concomitant nephrotoxic drugs along with tobramycin 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. 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 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 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 during pregnancy, or become pregnant while taking tobramycin 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 and parenteral aminoglycoside therapy should be monitored as clinically appropriate for toxicities associated with aminoglycosides as a class. Serum tobramycin levels should be monitored.
Contraindications
Tobramycin inhalation solution is contraindicated in patients with a known hypersensitivity to any aminoglycoside. Known hypersensitivity to any aminoglycoside. ( 4 )
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) ] Nephrotoxicity [see Warnings and Precautions (5.3) ] Neuromuscular Disorders [see Warnings and Precautions (5.4) ] Embryo-fetal Toxicity [see Warnings and Precautions (5.5) ] Concomitant 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 Amneal Pharmaceuticals LLC at 1-877-835-5472 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 was studied in two Phase 3 clinical studies involving 258 cystic fibrosis patients ranging in age from 6 to 48 years. Patients received tobramycin 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. Table 1 lists the percent of patients with selected adverse reactions that occurred in > 5% of tobramycin patients during the two Phase 3 studies. Table 1: Percent of Patients With Selected Adverse Reactions Occurring in > 5% of Tobramycin Patients 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 Decreased 1 16.3 15.3 Voice Alteration 12.8 6.5 Taste Perversion 6.6 6.9 Rash 5.4 6.1 1 Includes reported decreases in pulmonary function tests or decreased lung volume on chest radiograph associated with intercurrent illness or study drug administration. Selected adverse reactions that occurred in less than or equal to 5% of patients treated with tobramycin: Ear and Labyrinth Disorders: Tinnitus Musculoskeletal and Connective Tissue disorders: Myalgia Infections and Infestations: Laryngitis Voice Alteration and Tinnitus Voice alteration and tinnitus were the only adverse reactions reported by significantly more tobramycin-treated patients. Thirty-three patients (13%) treated with tobramycin 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 group (3%) reported tinnitus compared to no placebo patients. All episodes were transient, resolved without discontinuation of the tobramycin 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 tobramycin and placebo groups. Changes in Serum Creatinine Nine (3%) patients in the tobramycin 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 tobramycin group, creatinine decreased at the next visit. 6.2 Post-marketing Experience The following adverse reactions have been identified during post-approval use of tobramycin. 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 Metabolism and Nutrition Disorders Decreased appetite
Drug Interactions
Concurrent and/or sequential use of tobramycin with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided. ( 7.1 ) Concomitant 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 tobramycin 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. Tobramycin should not be administered concomitantly with ethacrynic acid, furosemide, urea, or intravenous mannitol. The interaction between inhaled mannitol and tobramycin has not been evaluated.
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