TOBRAMYCIN

Brand names: TOBI Podhaler, Tobramycin, tobramycin, Kitabis Pak, TOBI, TOBRAMYCIN, BETHKIS, TOBREX, Tobramycin Inhalation Solution Pak

Boxed warning

WARNINGS Patients treated with Tobramycin for injection, USP and other aminoglycosides should be under close clinical observation, because these drugs have an inherent potential for causing ototoxicity and nephrotoxicity. Neurotoxicity, manifested as both auditory and vestibular ototoxicity, can occur. The auditory changes are irreversible, are usually bilateral, and may be partial or total. Eighth-nerve impairment and nephrotoxicity may develop, primarily in patients having preexisting renal damage and in those with normal renal function to whom aminoglycosides are administered for longer periods or in higher doses than those recommended. Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching, and convulsions. The risk of aminoglycoside-induced hearing loss increases with the degree of exposure to either high peak or high trough serum concentrations. Patients who develop cochlear damage may not have symptoms during therapy to warn them of eighth-nerve toxicity, and partial or total irreversible bilateral deafness may continue to develop after the drug has been discontinued. Rarely, nephrotoxicity may not become apparent until the first few days after cessation of therapy. Aminoglycoside-induced nephrotoxicity usually is reversible. Renal and eighth-nerve function should be closely monitored in patients with known or suspected renal impairment and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy. Peak and trough serum concentrations of aminoglycosides should be monitored periodically during therapy to assure adequate levels and to avoid potentially toxic levels. Prolonged serum concentrations above 12 mcg/mL should be avoided. Rising trough levels (above 2 mcg/mL) may indicate tissue accumulation. Such accumulation, excessive peak concentrations, advanced age, and cumulative dose may contribute to ototoxicity and nephrotoxicity (see PRECAUTIONS ). Urine should be examined for decreased specific gravity and increased excretion of protein, cells, and casts. Blood urea nitrogen, serum creatinine, and creatinine clearance should be measured periodically. When feasible, it is recommended that serial audiograms be obtained in patients old enough to be tested, particularly high-risk patients. Evidence of impairment of renal, vestibular, or auditory function requires discontinuation of the drug or dosage adjustment. Tobramycin should be used with caution in premature and neonatal infants because of their renal immaturity and the resulting prolongation of serum half-life of the drug. Concurrent and sequential use of other neurotoxic and/or nephrotoxic antibiotics, particularly other aminoglycosides (e.g., amikacin, streptomycin, neomycin, kanamycin, gentamicin, and paromomycin), cephaloridine, viomycin, polymyxin B, colistin, cisplatin, and vancomycin, should be avoided. Other factors that may increase patient risk are advanced age and dehydration. Aminoglycosides should not be given concurrently with potent diuretics, such as ethacrynic acid and furosemide. Some diuretics themselves cause ototoxicity, and intravenously administered diuretics enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. Aminoglycosides can cause fetal harm when administered to a pregnant woman (see PRECAUTIONS ).

Warnings

5 WARNINGS AND PRECAUTIONS • Caution should be exercised when prescribing TOBI Podhaler to patients with known or suspected auditory, vestibular, renal, or neuromuscular dysfunction ( 5.2 , 5.3 , 5.4 ) • Ototoxicity, as measured by complaints of hearing loss or tinnitus, was reported in clinical trials ( 5.2 ) • Aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function ( 5.6 ) • Bronchospasm can occur with inhalation of TOBI Podhaler ( 5.1 ) • Audiograms, serum concentrations, and renal function should be monitored as appropriate ( 5.3 , 5.5 , 5.6 ) • Embryo-Fetal Toxicity: Aminoglycosides can cause fetal harm Apprise women of the potential hazard to the fetus ( 5.6 , 8.1 ) 5.1 Bronchospasm Bronchospasm has been reported with inhalation of TOBI Podhaler [see Adverse Reactions (6.1) ] . Bronchospasm should be treated as medically appropriate. 5.2 Ototoxicity Ototoxicity with use of TOBI Podhaler Caution should be exercised when prescribing TOBI Podhaler to patients with known or suspected auditory or vestibular dysfunction. Ototoxicity, as measured by complaints of hearing loss or tinnitus, was reported by patients in the TOBI Podhaler clinical studies [see Adverse Reactions (6.1) ] . Tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants caution. Ototoxicity, manifested as both auditory (hearing loss) and vestibular toxicity, has been reported with parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness. 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 Caution should be exercised when prescribing TOBI Podhaler to patients with known or suspected renal dysfunction. Nephrotoxicity was not observed during TOBI Podhaler clinical studies but has been associated with aminoglycosides as a class. 5.4 Neuromuscular Disorders Caution should be exercised when prescribing TOBI Podhaler to patients with known or suspected neuromuscular dysfunction. TOBI Podhaler should be used cautiously in patients with neuromuscular disorders, such as myasthenia gravis or Parkinson’s disease, since aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function. 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 Podhaler during pregnancy, or become pregnant while taking TOBI Podhaler 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

4 CONTRAINDICATIONS Tobramycin inhalation solution is contraindicated in patients with a known hypersensitivity to any aminoglycoside. Known hypersensitivity to any aminoglycoside (4)

Overdose

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 tobramycin inhalation solution, 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.

Drug interactions

7 DRUG INTERACTIONS Concurrent and/or sequential use of tobramycin inhalation solution 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 inhalation solution 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 inhalation solution should not be administered concomitantly with ethacrynic acid, furosemide, urea, or intravenous mannitol. The interaction between inhaled mannitol and tobramycin inhalation solution has not been evaluated.

Uses

1 INDICATIONS AND USAGE TOBI Podhaler is indicated for the management of cystic fibrosis patients 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 >80% predicted, or patients colonized with Burkholderia cepacia [see Clinical Studies (14) ] . TOBI Podhaler is an aminoglycoside antibacterial indicated for the management of cystic fibrosis patients 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 >80%, or patients colonized with Burkholderia cepacia ( 1 )

Dosage forms & strengths

INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION POWDER SOLUTION SOLUTION/ DROPS INJECTION INJECTION, POWDER, FOR SOLUTION CAPSULE OINTMENT INJECTION, SOLUTION

TOBRAMYCIN SULFATE 1.2 g/30mL TOBRAMYCIN 1 kg/kg TOBRAMYCIN 3 mg/mL TOBRAMYCIN 300 mg/5mL TOBRAMYCIN SULFATE 40 mg/mL TOBRAMYCIN 1200 mg/30mL TOBRAMYCIN SULFATE 10 mg/mL TOBRAMYCIN 100 kg/100kg TOBRAMYCIN 300 mg/4mL TOBRAMYCIN 28 mg/1 TOBRAMYCIN 3 mg/g

2 DOSAGE AND 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.

All identified pills

Side effects

6 ADVERSE REACTIONS The most common adverse reactions (≥10 % of TOBI Podhaler and TOBI patients in primary safety population) are cough, lung disorder, productive cough, dyspnea, pyrexia, oropharyngeal pain, dysphonia, hemoptysis, and headache ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Viatris 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 Podhaler has been evaluated for safety in 425 cystic fibrosis patients exposed to at least one dose of TOBI Podhaler, including 273 patients who were exposed across three cycles (6 months) of treatment. Each cycle consisted of 28 days on-treatment (with 112 mg administered twice-daily) and 28 days off-treatment. Patients with serum creatinine ≥2 mg/dL and blood urea nitrogen (BUN) ≥40 mg/dL were excluded from clinical studies. There were 218 males and 207 females in this population, and reflecting the cystic fibrosis population in the U.S., the vast majority of patients were Caucasian. There were 221 patients ≥20 years old, 121 patients ≥13 to <20 years old, and 83 patients ≥6 to <13 years old. There were 239 patients with screening FEV 1 % predicted ≥50%, 156 patients with screening FEV 1 % predicted <50%, and 30 patients with missing FEV 1 % predicted. The primary safety population reflects patients from Study 1, an open-label study comparing TOBI Podhaler with TOBI (tobramycin inhalation solution, USP) over three cycles of 4 weeks on treatment followed by 4 weeks off treatment. Randomization, in a planned 3:2 ratio, resulted in 308 patients treated with TOBI Podhaler and 209 patients treated with TOBI. For both the TOBI Podhaler and TOBI groups, mean exposure to medication for each cycle was 28 to 29 days. The mean age for both arms was between 25 and 26 years old. The mean baseline FEV 1 % predicted for both arms was 53%. Table 1 displays adverse drug reactions reported by at least 2% of TOBI Podhaler patients in Study 1, inclusive of all cycles (on and off treatment). Adverse drug reactions are listed according to MedDRA system organ class and sorted within system organ class group in descending order of frequency. Table 1: Adverse Reactions Reported in Study 1 (Occurring in ≥2% of TOBI Podhaler Patients) Primary System Organ Class Preferred Term TOBI Podhaler N=308 % TOBI N=209 % Respiratory, thoracic, and mediastinal disorders Cough 48.4 31.1 Lung disorder This includes adverse events of pulmonary or cystic fibrosis exacerbations 33.8 30.1 Productive cough 18.2 19.6 Dyspnea 15.6 12.4 Oropharyngeal pain 14.0 10.5 Dysphonia 13.6 3.8 Hemoptysis 13.0 12.4 Nasal congestion 8.1 7.2 Rales 7.1 6.2 Wheezing 6.8 6.2 Chest discomfort 6.5 2.9 Throat irritation 4.5 1.9 Gastrointestinal disorders Nausea 7.5 9.6 Vomiting 6.2 5.7 Diarrhea 4.2 1.9 Dysgeusia 3.9 0.5 Infections and infestations Upper respiratory tract infection 6.8 8.6 Investigations Pulmonary function test decreased 6.8 8.1 Forced expiratory volume decreased 3.9 1.0 Blood glucose increased 2.9 0.5 Vascular disorders Epistaxis 2.6 1.9 Nervous system disorders Headache 11.4 12.0 General disorders and administration site conditions Pyrexia 15.6 12.4 Musculoskeletal and connective tissue disorders Musculoskeletal chest pain 4.5 4.8 Skin and subcutaneous tissue disorders Rash 2.3 2.4 Adverse drug reactions that occurred in <2% of patients treated with TOBI Podhaler in Study 1 were: bronchospasm (TOBI Podhaler 1.6%, TOBI 0.5%); deafness including deafness unilateral (reported as mild to moderate hearing loss or increased hearing loss) (TOBI Podhaler 1.0%, TOBI 0.5%); and tinnitus (TOBI Podhaler 1.9%, TOBI 2.4%). Discontinuations in Study 1 were higher in the TOBI Podhaler arm compared to TOBI (27% TOBI Podhaler versus 18% TOBI). This was driven primarily by discontinuations due to adverse events (14% TOBI Podhaler versus 8% TOBI). Higher rates of discontinuation were seen in subjects ≥20 years old and those with baseline FEV 1 % predicted <50%. Respiratory related hospitalizations occurred in 24% of the patients in the TOBI Podhaler arm and 22% of the patients in the TOBI arm. There was an increased new usage of antipseudomonal medication in the TOBI Podhaler arm (65% TOBI Podhaler versus 55% TOBI). This included oral antibiotics in 55% of TOBI Podhaler patients and 40% of TOBI patients and intravenous antibiotics in 35% of TOBI Podhaler patients and 33% of TOBI patients. Median time to first antipseudomonal usage was 89 days in the TOBI Podhaler arm and 112 days in the TOBI arm. The supportive safety population reflects patients from two studies: Study 2, a double-blind, placebo-controlled design for the first treatment cycle, followed by all patients receiving TOBI Podhaler (replaced placebo) for two additional cycles, and Study 3, a double-blind, placebo-controlled trial for one treatment cycle only. Placebo in these studies was inhaled powder without the active ingredient, tobramycin. The patient population for these studies was much younger than in Study 1 (mean age 13 years old). Adverse drug reactions reported more frequently by TOBI Podhaler patients in the placebo-controlled cycle (Cycle 1) of Study 2, which included 46 TOBI Podhaler and 49 placebo patients, were: Respiratory, thoracic, and mediastinal disorders Pharyngolaryngeal pain (TOBI Podhaler 10.9%, placebo 0%); dysphonia (TOBI Podhaler 4.3%, placebo 0%) Gastrointestinal disorders Dysgeusia (TOBI Podhaler 6.5%, placebo 2.0%) Adverse drug reactions reported more frequently by TOBI Podhaler patients in Study 3, which included 30 TOBI Podhaler and 32 placebo patients, were: Respiratory, thoracic, and mediastinal disorders Cough (TOBI Podhaler 10%, placebo 0%) Ear and labyrinth disorders Hypoacusis (TOBI Podhaler 10%, placebo 6.3%) Audiometric Assessment In Study 1, audiology testing was performed in a subset of approximately 25% of TOBI Podhaler (n=78) and TOBI (n=45) patients. Using the criteria for either ear of ≥10 dB loss at two consecutive frequencies, ≥20 dB loss at any frequency, or loss of response at three consecutive frequencies where responses were previously obtained, five TOBI Podhaler patients and three TOBI patients were judged to have ototoxicity, a ratio similar to the planned 3:2 randomization for this study. Audiology testing was also performed in a subset of patients in both Study 2 (n=13 from the TOBI Podhaler group and n=9 from the placebo group) and Study 3 (n=14 from the TOBI Podhaler group and n=11 from the placebo group). In Study 2, no patients reported hearing complaints but two TOBI Podhaler patients met the criteria for ototoxicity. In Study 3, three TOBI Podhaler and two placebo patients had reports of ‘hypoacusis.’ One TOBI Podhaler and two placebo patients met the criteria for ototoxicity. In some patients, ototoxicity was transient or may have been related to a conductive defect. Cough Cough is a common symptom in cystic fibrosis, reported in 42% of the patients in Study 1 at baseline. Cough was the most frequently reported adverse event in Study 1 and was more common in the TOBI Podhaler arm (48% TOBI Podhaler versus 31 % TOBI). There was a higher rate of cough adverse event reporting during the first week of active treatment with TOBI Podhaler (i.e., the first week of Cycle 1). The time to first cough event in the TOBI Podhaler and TOBI groups were similar thereafter. In some patients, cough resulted in discontinuation of TOBI Podhaler treatment. Sixteen patients (5%) receiving treatment with TOBI Podhaler discontinued study treatment due to cough events compared with 2 (1%) in the TOBI treatment group. Children and adolescents coughed more than adults when treated with TOBI Podhaler, yet the adults were more likely to discontinue: of the 16 patients on TOBI Podhaler in Study 1 who discontinued treatment due to cough events, 14 were ≥20 years of age, one patient was between the ages of 13 and <20, and one was between the ages of 6 and <13. The rates of bronchospasm (as measured by ≥20% decrease in FEV 1 % predicted post-dose) were approximately 5% in both treatment groups, and none of these patients experienced concomitant cough. In Study 2, cough was the most commonly reported adverse event during the first cycle of treatment (the double blind period of treatment) and occurred more frequently in placebo-treated patients (26.5%) than patients treated with TOBI Podhaler (13%). Similar percentages of patients in both treatment groups reported cough as a baseline symptom. In Study 3, cough events were reported by three patients in the TOBI Podhaler group (10%) and none in the placebo group (0%). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of TOBI Podhaler. 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. Respiratory, thoracic, and mediastinal disorders Aphonia, Sputum discolored General disorders and administration site conditions Malaise

Official source

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