* (Inhalation solution; Tobi(R)) safety and efficacy not established in patients with an FEV1 less than 25% or greater than 75% predicted.
* (Inhalation solution; Tobi(R)) safety and efficacy not established in patients with an FEV1 less than 25% or greater than 75% predicted.
* (Inhalation solution; Tobramycin(R)) safety and efficacy not established in patients with an FEV1 less than 40% or greater than 80% predicted.
* (Inhalation solution; Tobramycin(R)) safety and efficacy not established in patients with an FEV1 less than 40% or greater than 80% predicted.
* Cystic fibrosis - Infection due to Pseudomonas aeruginosa: 6 years or older, 300 mg (1 ampule) INHALED via nebulizer twice daily every 12 hours (28 days on, 28 days off); do not take less than 6 hours apart.
* [[Cystic fibrosis]] - [[Infection]] due to [[Pseudomonas aeruginosa]]: 6 years or older, 300 mg (1 ampule) INHALED via nebulizer twice daily every 12 hours (28 days on, 28 days off); do not take less than 6 hours apart.
* Cystic fibrosis - Infection due to Pseudomonas aeruginosa: 6 years or older, 112 mg (4 capsules) INHALED via Podhaler(TM) twice daily (28 days on, 28 days off); do not take less than 6 hours apart.
* [[Cystic fibrosis]] - [[Infection]] due to [[Pseudomonas aeruginosa]]: 6 years or older, 112 mg (4 capsules) INHALED via Podhaler(TM) twice daily (28 days on, 28 days off); do not take less than 6 hours apart.
* Eye infection, External: (2 months or older) ophthalmic ointment, apply half-inch ribbon OPHTHALMICALLY 2 to 3 times daily for a mild to moderate infection OR every 3 to 4 hours until improvement (then reduce prior to discontinuation) for a severe [[infection]].
* Eye infection, External: (2 months or older) ophthalmic ointment, apply half-inch ribbon OPHTHALMICALLY 2 to 3 times daily for a mild to moderate infection OR every 3 to 4 hours until improvement (then reduce prior to discontinuation) for a severe [[infection]].
* Eye infection, External: (2 months or older) ophthalmic solution, instill 1 to 2 drops OPHTHALMICALLY every 4 hours for a mild to moderate infection OR hourly until improvement (then reduce prior to discontinuation) for a severe infection.
* Eye infection, External: (2 months or older) ophthalmic solution, instill 1 to 2 drops OPHTHALMICALLY every 4 hours for a mild to moderate infection OR hourly until improvement (then reduce prior to discontinuation) for a severe infection.
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The recommended dosage for patients six years of age and older is to administer one single-use ampule (300 mg/4 mL) twice daily by oral inhalation in repeated cycles of 28 days on drug, followed by 28 days off drug. The doses should be taken as close to 12 hours apart as possible and not less than 6 hours apart.
The 300 mg/4 mL dose of BETHKIS is the same for patients regardless of age or weight. Tobramycin has not been studied in patients less than six years old.
Administration
Tobramycin is administered by oral inhalation. Do not use by any other route.
Tobramycin is administered by inhalation using a hand‑held PARI LC PLUS Reusable Nebulizer with a PARI Vios Air compressor over an approximately 15 minute period and until sputtering from the output of the nebulizer has occurred for at least one minute.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
(Inhalation) safety and efficacy not established in patients colonized with Burkholderia cepacia.
(Inhalation powder; Tobi(R) Podhaler(TM)) safety and efficacy not established in patients with an FEV1 less than 25% or greater than 80% predicted.
(Inhalation solution; Tobi(R)) safety and efficacy not established in patients with an FEV1 less than 25% or greater than 75% predicted.
(Inhalation solution) safety and efficacy not established in patients with an FEV1 less than 40% or greater than 80% predicted.
Cystic fibrosis - Infection due to Pseudomonas aeruginosa: 300 mg (1 ampule) INHALED via nebulizer twice daily every 12 hours (28 days on, 28 days off); do not take less than 6 hours apart.
Cystic fibrosis - Infection due to Pseudomonas aeruginosa: 112 mg (4 capsules) INHALED via Podhaler(TM) twice daily every 12 hours (28 days on, 28 days off); do not take less than 6 hours apart.
Eye infection, External: ophthalmic ointment, apply half-inch ribbon OPHTHALMICALLY 2 to 3 times daily for a mild to moderate infection OR every 3 to 4 hours until improvement (then reduce prior to discontinuation) for a severe infection.
Eye infection, External: ophthalmic solution, instill 1 to 2 drops OPHTHALMICALLY every 4 hours for a mild to moderate infection OR hourly until improvement (then reduce prior to discontinuation) for a severe infection.
There is limited information regarding FDA-Labeled Use of Tobramycin (inhalation) in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
(Ophthalmic) safety and efficacy not established in patients less than 2 months of age.
(Inhalation) safety and efficacy not established in children younger than 6 years or in patients colonized with Burkholderia cepacia.
(Inhalation powder; Tobi(R) Podhaler(TM)) safety and efficacy not established in patients with an FEV1 less than 25% or greater than 80% predicted.
(Inhalation solution; Tobi(R)) safety and efficacy not established in patients with an FEV1 less than 25% or greater than 75% predicted.
(Inhalation solution; Tobramycin(R)) safety and efficacy not established in patients with an FEV1 less than 40% or greater than 80% predicted.
Cystic fibrosis - Infection due to Pseudomonas aeruginosa: 6 years or older, 300 mg (1 ampule) INHALED via nebulizer twice daily every 12 hours (28 days on, 28 days off); do not take less than 6 hours apart.
Cystic fibrosis - Infection due to Pseudomonas aeruginosa: 6 years or older, 112 mg (4 capsules) INHALED via Podhaler(TM) twice daily (28 days on, 28 days off); do not take less than 6 hours apart.
Eye infection, External: (2 months or older) ophthalmic ointment, apply half-inch ribbon OPHTHALMICALLY 2 to 3 times daily for a mild to moderate infection OR every 3 to 4 hours until improvement (then reduce prior to discontinuation) for a severe infection.
Eye infection, External: (2 months or older) ophthalmic solution, instill 1 to 2 drops OPHTHALMICALLY every 4 hours for a mild to moderate infection OR hourly until improvement (then reduce prior to discontinuation) for a severe infection.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tobramycin (inhalation) in pediatric patients.
Contraindications
Tobramycin is contraindicated in patients with a known hypersensitivity to any aminoglycoside.
Warnings
Ototoxicity
Caution should be exercised when prescribing tobramycin to patients with known or suspected auditory or vestibular dysfunction.
Findings related to ototoxicity as measured by audiometric evaluations and auditory adverse event reports were similar between tobramycin and placebo in controlled clinical trials.
Hearing loss was reported in two (1.1%) tobramycin-treated patients and in one (0.9%) placebo-treated patient during clinical studies. Additionally, dizziness and vertigo, both of which may be manifestations of vestibular forms of ototoxicity, were observed in similar numbers of Tobramycin- and placebo-treated patients.
Dizziness occurred in two (1.1%) Tobramycin-treated patients and one (0.9%) placebo-treated patient and vertigo occurred in two (1.1%) Tobramycin‑treated patients versus no placebo patients in clinical studies.
None of the tobramycin patients discontinued their therapy due to hearing loss, dizziness or vertigo.
Tinnitus may be a sentinel symptom of ototoxicity. No reports of tinnitus occurred in patients during clinical studies with tobramycin, but because it has been observed with inhaled tobramycin solutions, onset of this symptom warrants caution.
Caution should be exercised when prescribing tobramycin to patients with known or suspected renal dysfunction.
Nephrotoxicity was not seen during tobramycin clinical studies but has been associated with aminoglycosides as a class. If nephrotoxicity occurs in a patient receiving tobramycin, therapy should be discontinued until serum concentrations fall below 2 mcg/mL.
Twenty-six (14%) tobramycin patients and 15 (13%) placebo patients had increases in serum creatinine of at least 50% over baseline. Follow-up values were obtained for 17 of the 26 tobramycin patients, all of which decreased to serum creatinine values that were within the upper limit of normal.
Patients who experience an increase in serum creatinine during treatment with tobramycin should have their renal function closely monitored.
Neuromuscular Disorders
BETHKIS should be used cautiously in patients with muscular 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.
Bronchospasm
Bronchospasm can occur with inhalation of tobramycin. In clinical studies with tobramycin, bronchospasm was observed in one (0.5%) tobramycin-treated patient and in no placebo-treated patients.
Wheezing occurred in ten (5%) tobramycin-treated patients and four (4%) placebo-treated patients. Bronchospasm and wheezing should be treated as medically appropriate.
Laboratory Tests
Audiograms
Clinical studies of inhaled tobramycin solutions did not identify hearing loss using audiometric tests which evaluated hearing up to 8000 Hz.
Physicians should consider an audiogram for patients who show any evidence of auditory dysfunction, or who are at increased risk for auditory dysfunction.Tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants caution.
Serum Concentrations
In patients with normal renal function treated with tobramycin, serum tobramycin concentrations range from approximately 0.06-1.89 mcg/mL one hour after dose administration and do not require routine monitoring.
Serum concentrations of tobramycin in patients with renal dysfunction or patients treated with concomitant parenteral tobramycin should be monitored at the discretion of the treating physician.
Renal Function
The clinical studies of tobramycin did not reveal any imbalance in the percentage of patients who experienced at least a 50% rise in serum creatinine from baseline in either the tobramycin group (n=26, 14%) or the placebo group (n=15, 13%).
Laboratory tests of urine and renal function should be conducted at the discretion of the treating physician.
Use in Pregnancy
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. Patients who use tobramycin during pregnancy, or become pregnant while taking tobramycin should be apprised of the potential hazard to the fetus.
Adverse Reactions
Clinical Trials Experience
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of drugs cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect exposure to tobramycin in two placebo-controlled studies in 305 cystic fibrosis patients. Patients receiving tobramycin ranged in age from 6 to 31 years.
In Study 1, an eight week study, 29 patients received tobramycin versus 30 patients who received placebo for a total of four weeks on drug and four weeks off drug.
All patients were ≤ 30 years of age (mean age 12.6 years) and 46% were females. 52.5% of patients were 6 to 12 years of age while 30.5% of patients were 13-17 years old. Only 16.5% of patients were adults (> 17 years old).
Eighty percent (80%) of patients were chronically colonized with Pseudomonas aeruginosa while 20.3% of patients were initially or intermittently colonized with [[]Pseudomonas aeruginosa]] during the study.
More patients in the placebo group discontinued/dropped out of Study 1 than in the tobramycin group (23% [7/30] vs 3.4% [1/29], respectively). Five patients in the placebo group compared to none in the tobramycin group discontinued/dropped out because of treatment-emergent adverse events (TEAEs) such as pulmonary exacerbations and respiratory disorders.
In Study 2, a 24 week study, 161 patients received tobramycin versus 85 patients who received placebo in alternating four week on-off cycles for three cycles.
All patients were ≤ 46 years of age (mean age 14.8 years) and 45% were females. 41% of patients were 6-12 years old while 29% of patients were 13-17 years old. Only 30% were adults (>17 years).
Eighty-seven percent (87%) of patients were chronically colonized with P. aeruginosa. Only 13% were either initially or intermittently colonized with P. aeruginosa during the study.
More patients in the placebo group discontinued/dropped out of Study 2 than in the tobramycin group (9.4% [8/85] vs 4.3% [7/161], respectively). Of these, 3 patients in the tobramycin group (1.9%) compared to 2 patients in the placebo group (2.4%) withdrew due to a TEAE.
The most common TEAEs causing patients to discontinue from the study drug are respiratory, thoracic, and mediastinal disorders.
The most common adverse experiences reported were respiratory disorders, consistent with the underlying disease in the patient population being evaluated and these were similarly distributed between both tobramycin- and placebo-treated patients.
The following adverse reactions were more commonly reported in ≥ 2% of the tobramycin-treated patients compared to the placebo-treated patients: decreased forced expiratory volume, rales, red blood cell sedimentation rate increased, and dysphonia (Table 1).
This image is provided by the National Library of Medicine.
This image is provided by the National Library of Medicine.
Postmarketing Experience
In postmarketing experience, some patients receiving inhaled tobramycin have reported hearing loss. Some of these reports occurred in patients with previous or concomitant treatment with systemic aminoglycosides. Patients with hearing loss frequently reported tinnitus.
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.
Drug Interactions
Drugs with Neurotoxic or Ototoxic Potential
Concurrent and/or sequential use of tobramycin with other drugs with neurotoxic or ototoxic potential should be avoided.
No reproduction toxicology studies have been conducted with inhaled tobramycin. However, subcutaneous administration of tobramycin at doses of 100 mg or 20 mg/kg/day during organogenesis was not teratogenic in rats or rabbits, respectively.
Subcutaneous doses of tobramycin ≥ 40mg/kg/day were severely maternally toxic to rabbits and precluded the evaluation of teratogenicity.
Aminoglycosides can cause fetal harm (e.g., congenital deafness) when administered to a pregnant woman. Ototoxicity was not evaluated in offspring during nonclinical reproduction toxicity studies with tobramycin.
If tobramycin is used during pregnancy, or if the patient becomes pregnant while taking tobramycin, the patient should be apprised of the potential hazard to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tobramycin (inhalation) in women who are pregnant.
Labor and Delivery
The safety and efficacy of tobramycin have not been studied in the puerperal patient.
Nursing Mothers
It is not known if tobramycin will reach sufficient concentrations after administration by inhalation to be excreted in human breast milk. Because of the potential for ototoxicity and nephrotoxicity in infants, a decision should be made whether to terminate nursing or discontinue tobramycin therapy, taking into account the importance of the drug to the mother.
Pediatric Use
The safety and efficacy of tobramycin have not been studied in pediatric cystic fibrosis patients under six years of age.
Geriatic Use
There is no FDA guidance on the use of Tobramycin (inhalation) with respect to geriatric patients.
Gender
There is no FDA guidance on the use of Tobramycin (inhalation) with respect to specific gender populations.
Race
There is no FDA guidance on the use of Tobramycin (inhalation) with respect to specific racial populations.
Renal Impairment
Tobramycin is primarily excreted unchanged in the urine and renal function is expected to affect the exposure of tobramycin. The risk of adverse reactions to this drug may be greater in patients with impaired renal function.
Patients with serum creatinine > 2mg/dL and blood urea nitrogen (BUN) > 40mg/dL have not been included in clinical studies and there are no data in this population to support a recommendation for or against dose adjustment
Serum concentrations of tobramycin in patients with renal dysfunction, or patients treated with concomitant parenteral tobramycin should be monitored at the discretion of the treating physician.
Hepatic Impairment
There is no FDA guidance on the use of Tobramycin (inhalation) in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tobramycin (inhalation) in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Tobramycin (inhalation) in patients who are immunocompromised.
There is limited information regarding Tobramycin (inhalation) Monitoring in the drug label.
IV Compatibility
There is limited information regarding IV Compatibility of Tobramycin (inhalation) in the drug label.
Overdosage
No overdoses have been reported with tobramycin in clinical trials. Signs and symptoms of acute toxicity from overdosage of intravenous tobramycin might include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, and neuromuscular blockade.
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.
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.
Tobramycin, an aminoglycoside antimicrobial, acts primarily by disrupting protein synthesis in the bacterial cell which eventually leads to death of the cell.
Tobramycin has activity against a wide range of gram-negative bacteria including P. aeruginosa. It is bactericidal at or above the minimal inhibitory concentration (MIC) needed to inhibit growth of bacteria.
Mechanism of Resistance
The predominant mechanism of resistance to tobramycin in P. aeruginosa isolated from CF patients is impermeability and to a lesser extent enzymatic modification and other mechanisms which cumulatively lead to decreased susceptibility of P. aeruginosa to tobramycin.
Cross Resistance
Cross resistance between aminoglycosides exists but the cross resistance is variable.
Development of Resistance
Treatment for six months with BETHKIS in one clinical trial did not affect the susceptibility of the majority of P. aeruginosa isolates tested; however, increases in minimal inhibitory concentrations (MIC) were noted in some patients.
The clinical significance of this information has not been clearly established in the treatment of cystic fibrosis patients.
Susceptibility Testing
The clinical microbiology laboratory should provide cumulative results of the in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physicians as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens.
These reports should aid the physician in selecting the most effective antimicrobial.
Susceptibility Testing Techniques
Dilution Techniques
Quantitative methods can be used to determine the minimum inhibitory concentration (MIC) of tobramycin that will inhibit the growth of the bacteria being tested.
The MIC provides an estimate of the susceptibility of bacteria to tobramycin. The MIC should be determined using a standardized procedure.3, 5 * Standardized procedures are based on a dilution method (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of tobramycin powder.
Diffusion Techniques
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds.
One such standardized procedure requires the use of standardized inoculum concentrations.5,5 This procedure uses paper disks impregnated with 10 mcg of tobramycin to test the susceptibility of bacteria to tobramycin.
Susceptibility Test Interpretive Criteria
In vitro susceptibility test interpretive criteria for inhaled tobramycin have not been determined. The relation of the in vitro MIC and/or disk diffusion susceptibility test results to clinical efficacy of inhaled tobramycin against the bacteria tested should be monitored.
Quality Control Parameters for Susceptibility Testing
In vitro susceptibility test quality control parameters exist for tobramycin so that laboratories that test the susceptibility of bacterial isolates to tobramycin can determine if the susceptibility test is performing correctly.
Standardized dilution techniques and diffusion methods require the use of laboratory control bacteria to monitor the technical aspects of the laboratory procedures.
Standard tobramycin powder should provide the following MIC and a 10 mcg tobramycin disk should produce the following zone diameters with the indicated quality control strains.
This image is provided by the National Library of Medicine.
Other
No trends in the treatment-emergent isolation of other bacterial respiratory pathogens such as Burkholderia cepacia, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, or Staphylococcus aureus were observed in clinical trials of tobramycin relative to placebo.
There was a slight increase in isolation of Candida spp in sputum at the end of the BETHKIS treatment cycle in clinical trials.
There is limited information regarding Tobramycin (inhalation) Pharmacodynamics in the drug label.
Pharmacokinetics
BETHKIS contains tobramycin, a cationic polar molecule that does not readily cross epithelial membranes.1 The bioavailability of BETHKIS may vary because of individual differences in nebulizer performance and airway pathology.2 Following administration of BETHKIS, tobramycin remains concentrated primarily in the airways.
Sputum Concentrations: Thirty minutes after inhalation of the first 300 mg dose of BETHKIS, the maximum geometric mean concentration of tobramycin was 814 mcg/g (ranging from 23 to 2843 mcg/g) in sputum. High variability of tobramycin concentration in sputum was observed. Three hours after inhalation started, sputum tobramycin concentrations declined to approximately 15% of those observed at 30 minutes. After four weeks of therapy with BETHKIS average mean sputum tobramycin concentrations obtained 10 minutes following administration were 717 mcg/g.
Elimination: The elimination half-life of tobramycin from serum is approximately two hours after intravenous (IV) administration. The elimination half-life following the inhalation of BETHKIS is approximately 4.4 hours. Assuming tobramycin absorbed following inhalation behaves similarly to tobramycin following intravenous administration, systemically absorbed tobramycin is eliminated principally by glomerular filtration. Unabsorbed tobramycin following inhalation is likely eliminated in expectorated sputum.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
A two-year rat inhalation toxicology study to assess carcinogenic potential of an inhaled solution of tobramycin has been completed. Rats were exposed to tobramycin for up to 1.5 hours per day for 95 weeks.
Serum levels of tobramycin up to 35 mcg/mL were measured in rats, 35x the average 1 mcg/mL exposure levels observed in cystic fibrosis patients in clinical trials. There was no drug-related increase in the incidence of any variety of tumors.
Additionally, tobramycin has been evaluated for genotoxicity in a battery of in vitro and in vivo tests. The Ames bacterial reversion test, conducted with five tester strains, failed to show a 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 Studies
Two, double-blind, randomized, placebo-controlled, parallel group clinical studies (Study 1 and Study 2), which randomized and dosed 306 patients, were conducted in cystic fibrosis patients with P. aeruginosa.
The osmolality of the drug formulation used in these studies differed from the to-be-marketed product. To rely upon the efficacy and safety established in the placebo-controlled studies, an additional study was conducted as a bridge to the to-be-marketed drug.
The bridging study assessed the efficacy and tolerability of aerosolized Tobramycin Inhalation Solution with osmolality similar to BETHKIS over a 4-week treatment in 324 patients with cystic fibrosis.
Results of this study showed that the Tobramycin Inhalation Solution in this study had similar efficacy as that seen in the placebo-controlled studies.
The compressors in the placebo-controlled studies and the bridging study differed from the PARI VIOS compressor to be used with BETHKIS.
In vitro cascade impaction studies demonstrated that the various compressors used in the clinical trials delivered equivalent doses and respirable fractions of the to-be-marketed BETHKIS and TOBI with the marketed compressor (PARI VIOS) when used with the same nebulizer (PARI LC Plus Reusable nebulizer).
All subjects enrolled in both efficacy studies had baseline FEV1 % predicted ≥ 40% and ≤ 80% (mean baseline FEV1 of 60% of predicted normal) and infected with P. aeruginosa.
Subjects who were less than 6 years of age, or who had a baseline creatinine of ≥ 1.5 mg/dL, or who had Burkholderia cepacia isolated from sputum were excluded.
A total of 190 patients, 29 in Study 1 and 161 in Study 2, received BETHKIS therapy on an outpatient basis. Of these, 55% were males and 45% were females.
Eighty-two (43.2%) patients were between 6 and 12 years of age, 54 (28.4%) patients were between 13 and 17 years of age, and the remaining 54 (28.4%) patients were greater than 17 years of age. Of the patients who received BETHKIS, only 89.7% of patients in Study 1 had at least one concomitant medication, while all patients in Study 2 also received at least one concomitant medication. These concomitant medications include mucolytics, steroidal and nonsteroidal anti-inflammatory drugs, bronchodilators, rehabilitative physiotherapies and if necessary, antibiotics for bacterial infections other than P. aeruginosa.
Study 1
Study 1 was a double-blind, single cycle study that randomized 59 patients to receive BETHKIS (n=29) or placebo (n=30) for one cycle of treatment (28 days on treatment followed by 28 days off treatment).
All patients were ≤ 30 years of age (mean age 12.6 years) and 46% were females. All randomized patients were included in the primary analysis except for one patient who had missing baseline information.
BETHKIS significantly improved lung function compared with placebo as measured by the absolute change in FEV1 % predicted from baseline to the end of Cycle 1 dosing in the primary analysis population. Treatment with BETHKIS and placebo resulted in absolute increases in FEV1 % predicted of 16% and 5%, respectively (LS mean difference = 11%; 95% CI: 3, 19; p=0.003). This analysis is adjusted for the covariate of baseline FEV1 % predicted, using multiple imputation for missing data. Figure 1 shows the average change in FEV1 % predicted over eight weeks.
Study 2
Study 2 was a randomized, double-blind, 3-cycle, placebo-controlled trial. A total of 247 eligible patients were randomized 2:1 to receive three cycles of BETHKIS (n=161) or placebo (n=86). As in Study 1, each cycle comprised 28 days on treatment followed by 28 days off treatment.
All patients were ≤46 years of age (mean age 14.8 years) and 44.9% were females. In this study, two randomized patients in the placebo group were not included in the primary efficacy analysis; one withdrew consent without taking any trial medication and the other withdrew due to an adverse drug reaction.
BETHKIS significantly improved lung function compared with placebo as measured by the absolute change in FEV1 % predicted from baseline to the end of Cycle 3 “ON” period.
Treatment with BETHKIS and placebo resulted in absolute increases in FEV1 % predicted of 7% and 1%, respectively (LS mean difference = 6%; 95% CI: 3, 10; p<0.001). This analysis is adjusted for the covariate of baseline FEV1 % predicted, using multiple imputation for missing data. Figure 1 shows the average change in FEV1 % predicted over 24 weeks from Study 2.
This image is provided by the National Library of Medicine.
How Supplied
BETHKIS 300 mg/4 mL is a clear, colorless to pale yellow solution and is available as follows:
NDC 10122-820-56: 4 mL single-use ampule (carton of 14 foil pouches each containing four ampules)
NDC 10122-820-28: 4 mL single-use ampule (carton of 7 foil pouches each containing four ampules)
Storage
Storage
BETHKIS should be stored under refrigeration at 36‑46 °F/2‑8 °C. Upon removal from the refrigerator, or if refrigeration is unavailable, BETHKIS pouches (opened or unopened) may be stored at room temperature (up to 77 °F/25 °C) for up to 28 days.
BETHKIS should not be used beyond the expiration date stamped on the ampule when stored under refrigeration (36‑46 °F/2‑8 °C) or beyond 28 days when stored at room temperature (77 °F/25 °C).
BETHKIS ampules should not be exposed to intense light. BETHKIS is light sensitive; unopened ampules should be returned to the foil pouch. The solution in the ampule is colorless to pale 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.
Images
Drug Images
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Package and Label Display Panel
This image is provided by the National Library of Medicine.This image is provided by the National Library of Medicine.This image is provided by the National Library of Medicine.This image is provided by the National Library of Medicine.
Information on the long term efficacy and safety of BETHKIS is limited. There is no information in patients with severe cystic fibrosis (FEV1 < 40% predicted).
Patients should be advised to complete a full 28-day course of BETHKIS, even if they are feeling better. After 28 days of therapy, patients should stop BETHKIS therapy for the next 28 days, and then resume therapy for the next 28 day on and 28 day off cycle.
For patients taking several different inhaled medications and/or performing chest physiotherapy, advise the patient regarding the order they should take the therapies. It is recommended that BETHKIS be taken last.
BETHKIS is to be used with the PARI LC PLUS reusable nebulizer and the PARI VIOS air compressor. Refer to the manufacturer’s instructions for care and use of the nebulizer and compressor.
Ototoxicity
Inform patients that ototoxicity, as measured by complaints of hearing loss or tinnitus, was reported by patients treated with tobramycin. Physicians should consider an audiogram at baseline, particularly for patients at increased risk of auditory dysfunction.
If a patient reports tinnitus or hearing loss during BETHKIS therapy, the physician should refer that patient for audiological assessment.
Patients should be reminded that vestibular toxicity may manifest as vertigo, ataxia, or dizzines.
Bronchospasm
Inform patients that bronchospasm can occur with inhalation of tobramycin.
Risks Associated with Aminoglycosides
Inform patients of adverse reactions associated with aminoglycosides such as nephrotoxicity and neuromuscular disorders.
Laboratory Tests
Inform patients of the need to monitor hearing, serum concentrations of tobramycin, or renal function as necessary during treatment with BETHKIS.
Pregnancy
Inform patients that aminoglycosides can cause fetal harm when administered to a pregnant woman. Advise them to inform their doctor if they are pregnant, become pregnant, or plan to become pregnant.
Storage Instructions
You should store BETHKIS ampules in a refrigerator (36-46 °F or 2-8 °C). However, when you don’t have a refrigerator available (e.g., transporting your BETHKIS), you may store the foil pouches (opened or unopened) at room temperature (up to 77 °F/25 °C) for up to 28 days.
BETHKIS is light sensitive; unopened ampules should be returned to the foil pouch. Avoid exposing BETHKIS ampules to intense light. Unrefrigerated BETHKIS, which is normally colorless to pale yellow, may darken with age; however, the color change does not indicate any change in the quality of the product.
You should not use BETHKIS 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. * You should not use BETHKIS beyond the expiration date stamped on the ampule.
Precautions with Alcohol
Alcohol-Tobramycin (inhalation) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
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