Bethkis

Description

BETHKIS is a sterile, clear, colorless to pale yellow, non-pyrogenic aqueous solution, with pH and salinity adjusted for optimal use. The formulation is designed for administration via a compressed air-driven reusable nebulizer. The active ingredient, tobramycin, has a chemical formula of C₁₈H₃₇N₅O₉ and a molecular weight of 467.52. Each single-use 4 mL ampule contains a 300 mg dose of tobramycin, along with sodium chloride and sulfuric acid in water for injection. The pH is adjusted to 5.0 using sulfuric acid and sodium hydroxide as necessary. Nitrogen is utilized for sparging, filling, and pouching the product. The formulation is preservative-free.

Uses and Indications

BETHKIS is an inhaled aminoglycoside antibacterial indicated for the management of cystic fibrosis patients with Pseudomonas aeruginosa infection.

Limitations of Use: The safety and efficacy of BETHKIS have not been established in patients under the age of six years, in patients with a forced expiratory volume in one second (FEV1) less than 40% or greater than 80% predicted, or in patients colonized with Burkholderia cepacia.

Dosage and Administration

For oral inhalation only. The entire contents of one ampule should be administered twice daily by oral inhalation. This regimen is to be followed in repeated cycles of 28 days on the drug, succeeded by 28 days off the drug.

Contraindications

BETHKIS is contraindicated in patients with a known hypersensitivity to any aminoglycoside. Use in these patients may lead to severe allergic reactions.

Warnings and Precautions

Caution should be exercised when prescribing BETHKIS to patients with known or suspected auditory, vestibular, renal, or neuromuscular dysfunction. The use of aminoglycosides, including BETHKIS, may exacerbate muscle weakness due to a potential curare-like effect on neuromuscular function, necessitating careful consideration in these populations.

Bronchospasm has been reported following the inhalation of BETHKIS. Healthcare professionals should be vigilant for signs of bronchospasm and manage accordingly.

Monitoring parameters are critical for the safe use of BETHKIS. Audiograms, serum concentrations, and renal function should be assessed as appropriate. Audiograms are particularly important for patients exhibiting any signs of auditory dysfunction or those at increased risk for such conditions. The presence of tinnitus may indicate ototoxicity, and its onset should prompt immediate caution and further evaluation.

In patients with renal dysfunction or those receiving concomitant parenteral tobramycin, serum concentrations of tobramycin should be monitored at the discretion of the treating physician. It is essential to note that serum concentration measurements should be obtained through venipuncture rather than finger prick blood sampling to ensure accuracy.

Additionally, laboratory tests assessing urine and renal function should be conducted as deemed necessary by the treating physician.

It is crucial to inform women of childbearing potential about the risks associated with aminoglycoside administration during pregnancy, as fetal harm may occur. The potential hazard to the fetus must be clearly communicated to ensure informed decision-making.

Side Effects

In clinical trials, participants receiving BETHKIS experienced several common adverse reactions. Notably, decreased forced expiratory volume was reported in 31% of subjects receiving BETHKIS compared to 29% in the placebo group. Rales occurred in 19% of those treated with BETHKIS versus 16% in the placebo group. An increase in red blood cell sedimentation rate was observed in 8% of patients on BETHKIS compared to 5% in the placebo cohort. Dysphonia was noted in 6% of BETHKIS recipients, while only 2% of placebo participants reported this reaction. Other adverse reactions included wheezing (5% in BETHKIS vs. 4% in placebo), epistaxis (3% vs. 0%), pharyngolaryngeal pain (3% vs. 2%), bronchitis (3% vs. 1%), tonsillitis (2% vs. 0%), diarrhea (2% vs. 1%), eosinophilia (2% vs. 0%), and increased immunoglobulins (2% vs. 0%).

Postmarketing experience has revealed additional adverse reactions. Patients have reported ear and labyrinth disorders, including hearing loss and tinnitus. Skin and subcutaneous tissue disorders such as hypersensitivity, pruritus, urticaria, and rash have also been noted. Nervous system disorders, including aphonia and dysgeusia, were reported, as well as respiratory, thoracic, and mediastinal disorders like bronchospasm and oropharyngeal pain. Metabolism and nutrition disorders, specifically decreased appetite, have been observed as well.

Caution is advised as bronchospasm can occur with the inhalation of BETHKIS. Additionally, BETHKIS is contraindicated in patients with a known hypersensitivity to any aminoglycoside.

Drug Interactions

Concurrent and/or sequential use of BETHKIS with other agents that possess neurotoxic, nephrotoxic, or ototoxic potential is contraindicated. This includes, but is not limited to, ethacrynic acid, furosemide, urea, and intravenous mannitol.

Healthcare professionals are advised to exercise caution and avoid co-administration of BETHKIS with these drugs to mitigate the risk of adverse effects associated with neurotoxicity, nephrotoxicity, or ototoxicity. Monitoring for potential toxic effects is recommended when considering the use of BETHKIS in patients who may require these medications.

Packaging & NDC

The table below lists all NDC Code configurations of Bethkis (tobramycin), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and efficacy of BETHKIS have not been established in pediatric patients with cystic fibrosis who are under six years of age. Therefore, caution is advised when considering the use of this medication in this age group. Further studies are needed to determine appropriate dosing and safety profiles for younger children.

Geriatric Use

Clinical studies of BETHKIS did not include elderly patients aged 65 years and over. Therefore, the safety and efficacy of BETHKIS in this population have not been established.

Tobramycin, the active ingredient in BETHKIS, is substantially excreted by the kidneys. Consequently, the risk of adverse reactions may be heightened in geriatric patients, particularly those with impaired renal function. Given that elderly patients are more likely to experience decreased renal function, it is advisable to monitor renal function closely in this demographic. This monitoring may help mitigate potential risks associated with the use of BETHKIS in elderly patients.

Pregnancy

Aminoglycosides, including tobramycin, have been associated with potential fetal harm. Published literature indicates that the use of streptomycin, an aminoglycoside, during pregnancy can lead to total, irreversible, bilateral congenital deafness. While there are no available data on the use of BETHKIS in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, it is important to note that systemic absorption of tobramycin following inhaled administration is expected to be minimal.

Pregnant women should be advised of the potential risks to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations remains unknown. However, it is acknowledged that all pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is approximately 2 to 4% and 15 to 20%, respectively.

Cystic fibrosis may pose additional risks during pregnancy, including an increased likelihood of preterm delivery. Although no reproduction toxicology studies have been conducted with inhaled tobramycin, subcutaneous administration of tobramycin at doses of up to 100 mg/kg/day in rats and 20 mg/kg/day in rabbits during organogenesis did not demonstrate adverse developmental outcomes. However, subcutaneous doses of tobramycin at or above 40 mg/kg/day were associated with severe maternal toxicity in rabbits, which limited the evaluation of potential adverse developmental outcomes. Ototoxicity was not assessed in offspring during nonclinical reproductive toxicity studies involving tobramycin.

Lactation

There are no data on the presence of tobramycin in either human or animal milk, nor on the effects of BETHKIS on the breastfed infant or on milk production following oral inhalation. Limited published data on other formulations of tobramycin in lactating women indicate that tobramycin is present in human milk; however, systemic absorption of tobramycin following inhaled administration is expected to be minimal.

Tobramycin may cause alterations in the intestinal flora of the breastfeeding infant. Therefore, the developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for BETHKIS and any potential adverse effects on the breastfed child from BETHKIS or from the underlying maternal condition.

Lactating mothers should be advised to monitor the breastfed infant for signs of loose or bloody stools and candidiasis (thrush, diaper rash).

Renal Impairment

Caution should be exercised when prescribing BETHKIS to patients with known or suspected renal dysfunction. It is important to monitor audiograms, serum concentration, and renal function as appropriate in this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

In clinical trials, no overdoses have been reported with BETHKIS. However, healthcare professionals should remain vigilant regarding the potential signs and symptoms of acute toxicity associated with intravenous tobramycin overdosage. These may include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory failure, neuromuscular blockade, and renal impairment.

It is important to note that the administration of tobramycin by inhalation results in low systemic bioavailability, and tobramycin is not significantly absorbed when administered orally. Therefore, the risk of systemic toxicity from inhalation or oral routes is considerably reduced.

Monitoring tobramycin serum concentrations can be beneficial in assessing potential overdosage. In all instances of suspected overdosage, it is imperative for physicians to contact the Regional Poison Control Center to obtain guidance on effective treatment options.

Additionally, healthcare professionals should consider the possibility of drug interactions that may alter drug disposition in cases of overdosage. This consideration is crucial for ensuring appropriate management and mitigating potential adverse effects.

Nonclinical Toxicology

A two-year inhalation toxicology study in rats was conducted to evaluate the carcinogenic potential of an inhaled solution of tobramycin. During the study, rats were exposed to tobramycin for up to 1.5 hours per day over a period of 95 weeks. Serum levels of tobramycin reached up to 35 mcg/mL, which is 35 times the average exposure levels of 1 mcg/mL observed in cystic fibrosis patients during clinical trials. The results indicated no drug-related increase in the incidence of any tumor types.

Tobramycin has also undergone a comprehensive assessment for genotoxicity through a series of in vitro and in vivo tests. The Ames bacterial reversion test, which utilized five tester strains, did not demonstrate a significant increase in revertants, both with and without metabolic activation across all strains. Furthermore, tobramycin was found to be negative in the mouse lymphoma forward mutation assay, did not induce chromosomal aberrations in Chinese hamster ovary cells, and yielded negative results in the mouse micronucleus test.

In terms of reproductive toxicity, subcutaneous administration of tobramycin at doses up to 100 mg/kg did not adversely affect mating behavior or result in impairment of fertility in either male or female rats.

Postmarketing Experience

During postapproval use of tobramycin inhalation solution, the following adverse reactions have been identified. These reactions were reported voluntarily from a population of uncertain size, making it challenging to reliably estimate their frequency or establish a causal relationship to drug exposure.

Ear and labyrinth disorders have included hearing loss and tinnitus.

Skin and subcutaneous tissue disorders reported include hypersensitivity, pruritus, urticaria, and rash.

Nervous system disorders have encompassed aphonia and dysgeusia.

Respiratory, thoracic, and mediastinal disorders have included bronchospasm and oropharyngeal pain.

Metabolism and nutrition disorders have been characterized by decreased appetite.

Patient Counseling

Advise patients to read the FDA-approved patient labeling, which includes the Patient Information and Instructions for Use. It is important to inform patients that information regarding the long-term efficacy and safety of BETHKIS is limited, particularly in patients with severe cystic fibrosis (FEV < 40% predicted).

Patients should be instructed to complete a full 28-day course of BETHKIS, even if they start to feel better. After this 28-day therapy, they should discontinue BETHKIS for the next 28 days before resuming therapy in a cycle of 28 days on and 28 days off.

For patients using multiple inhaled medications and/or performing chest physiotherapy, advise them on the appropriate order of administration, recommending that BETHKIS be taken last. BETHKIS is intended for use with the PARI LC PLUS reusable nebulizer and the PARI VIOS air compressor; therefore, it is essential to refer to the manufacturer’s instructions for the care and use of these devices.

Inform patients about the potential for ototoxicity, which may present as hearing loss or tinnitus, associated with tobramycin. Physicians should consider conducting an audiogram at baseline, especially for patients at increased risk of auditory dysfunction. If a patient reports tinnitus or hearing loss during BETHKIS therapy, they should be referred for audiological assessment. Additionally, patients should be reminded that vestibular toxicity may manifest as vertigo, ataxia, or dizziness.

Patients should be made aware that bronchospasm can occur with the inhalation of tobramycin. It is also important to inform them of adverse reactions associated with aminoglycosides, including nephrotoxicity and neuromuscular disorders. Monitoring of hearing, serum concentrations of tobramycin, and renal function may be necessary during treatment with BETHKIS.

Patients should be cautioned that aminoglycosides can cause fetal harm when administered to a pregnant woman. They should inform their healthcare provider if they are pregnant, become pregnant, or plan to become pregnant.

In the event that a dose of BETHKIS is missed, patients should be instructed to take the prescribed dose as soon as possible if there are at least 6 hours until the next dose. If less than 6 hours remain until the next dose, they should not take the missed dose and should resume their usual dosing schedule. Patients should also be encouraged to contact their healthcare provider if they have any questions.

BETHKIS ampules should be stored in a refrigerator at 36-46 °F (2-8 °C). However, if refrigeration is not available, the foil pouches (opened or unopened) may be stored at room temperature (up to 77 °F/25 °C) for up to 28 days. It is crucial to keep BETHKIS light-sensitive; unopened ampules should be returned to the foil pouch, and exposure to intense light should be avoided. Unrefrigerated BETHKIS, which is typically colorless to pale yellow, may darken with age, but this color change does not indicate a change in product quality. Patients should not use BETHKIS if it appears cloudy, contains particles, or has been stored at room temperature for more than 28 days. Additionally, BETHKIS should not be used beyond the expiration date stamped on the ampule.

Storage and Handling

BETHKIS is supplied in ampules that should be stored under refrigeration at a temperature range of 2°C to 8°C (36°F to 46°F). When removed from refrigeration or if refrigeration is unavailable, BETHKIS pouches, whether opened or unopened, may be stored at room temperature, not exceeding 25°C (77°F), for a maximum of 28 days.

It is imperative that BETHKIS is not used beyond the expiration date indicated on the ampule when stored under refrigeration or beyond 28 days when kept at room temperature. The ampules must be protected from intense light, and unopened ampules should be returned to their original foil pouch to maintain integrity.

The solution within the ampule is typically colorless to pale yellow; however, it may darken with age if not stored in the recommended refrigeration conditions. This color change does not signify a decline in product quality, provided the storage guidelines are adhered to.

Additional Clinical Information

Physicians should consider conducting audiograms for patients exhibiting signs of auditory dysfunction or those at increased risk, as tinnitus may indicate potential ototoxicity. In patients with normal renal function receiving BETHKIS, serum tobramycin concentrations typically range from 0.06 to 1.89 mcg/mL one hour post-administration, and routine monitoring is not necessary. However, for patients with renal dysfunction or those receiving concomitant parenteral tobramycin, serum concentrations should be monitored at the physician's discretion, using venipuncture rather than finger prick sampling. Additionally, urine and renal function tests may be performed as deemed appropriate by the treating physician.

Postmarketing experience has revealed various adverse effects, including ear and labyrinth disorders such as hearing loss and tinnitus, skin reactions like hypersensitivity and rash, nervous system issues including aphonia and dysgeusia, respiratory complications such as bronchospasm and oropharyngeal pain, and metabolic concerns like decreased appetite.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Bethkis as submitted by Chiesi USA, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)