Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied TOBI is supplied as a sterile, clear, slightly yellow, non-pyrogenic, aqueous solution packaged in a 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 49502-345-73 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.; PRINCIPAL DISPLAY PANEL – 300 mg / 5 mL Ampules NDC 49502-345-73 TOBI ® Tobramycin Inhalation Solution, USP 300 mg / 5 mL Ampules 56 Single-Use Ampules (28-Day Supply) Rx only Store In Refrigerator Contents: Each foil pouch contains four sterile, non-pyrogenic, single-use ampules. Each 5 mL ampule contains one 300 mg dose of Tobramycin, USP and 11.25 mg Sodium Chloride in 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 full prescribing information. Storage: Store in a refrigerator at 2-8°C/36-46°F. Protect from intense light. See package insert for additional information. For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX). Manufactured for: Mylan Specialty L.P. Morgantown, WV 26505 U.S.A. Manufactured by: Woodstock Sterile Solutions, Inc. Woodstock, IL 60098 U.S.A. © 2021 Viatris Inc. TOBI is a registered trademark of BGP Products Operations GmbH, a Viatris Company. WS:345:56C:R1 PCR-700-13894 Tobramycin Inhalation Solution Carton Label
- 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied TOBI is supplied as a sterile, clear, slightly yellow, non-pyrogenic, aqueous solution packaged in a 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 49502-345-73 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.
- PRINCIPAL DISPLAY PANEL – 300 mg / 5 mL Ampules NDC 49502-345-73 TOBI ® Tobramycin Inhalation Solution, USP 300 mg / 5 mL Ampules 56 Single-Use Ampules (28-Day Supply) Rx only Store In Refrigerator Contents: Each foil pouch contains four sterile, non-pyrogenic, single-use ampules. Each 5 mL ampule contains one 300 mg dose of Tobramycin, USP and 11.25 mg Sodium Chloride in 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 full prescribing information. Storage: Store in a refrigerator at 2-8°C/36-46°F. Protect from intense light. See package insert for additional information. For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX). Manufactured for: Mylan Specialty L.P. Morgantown, WV 26505 U.S.A. Manufactured by: Woodstock Sterile Solutions, Inc. Woodstock, IL 60098 U.S.A. © 2021 Viatris Inc. TOBI is a registered trademark of BGP Products Operations GmbH, a Viatris Company. WS:345:56C:R1 PCR-700-13894 Tobramycin Inhalation Solution Carton Label
Overview
TOBI ® 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 g/mol. 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 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. Tobramycin Structural Formula
Indications & Usage
TOBI 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) ]. TOBI 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 ampoule (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 TOBI is for oral inhalation only [see Dosage and Administration (2.2) ] . The recommended dosage of TOBI for both adults and pediatric patients 6 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 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 TOBI 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. 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 manufacturer’s 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.
Warnings & Precautions
• Bronchospasm: Can occur with inhalation of TOBI. Treat as medically appropriate, if it occurs. ( 5.1 ) • Ototoxicity: Tinnitus and hearing loss have been reported in patients receiving TOBI. If noted, manage as medically appropriate, including potentially discontinuing TOBI. ( 5.2 ) • Nephrotoxicity: Has been associated with aminoglycosides as a class. If nephrotoxicity develops, manage the patient as medically appropriate, including potentially discontinuing TOBI. ( 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 TOBI. In clinical studies with TOBI, changes in FEV 1 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 with use of TOBI 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 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 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. 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 TOBI but has been associated with aminoglycosides as a 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 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 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 a class. Serum tobramycin levels should be monitored.
Contraindications
TOBI 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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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. TOBI was studied in two Phase 3 clinical studies involving 258 cystic fibrosis patients ranging in age from 6 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 a total of 24 weeks. Table 1 lists the percent of patients with selected adverse reactions that occurred in >5% of TOBI patients during the two Phase 3 studies. Table 1: Percent of Patients With Selected Adverse Reactions Occurring in >5% of TOBI 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 Includes reported decreases in pulmonary function tests or decreased lung volume on chest radiograph associated with intercurrent illness or study drug administration. 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 TOBI: 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 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 Creatinine Nine (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 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 TOBI 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 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.
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