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Bethkis

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Bethkis

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Ototoxicity

Caution should be exercised when prescribing BETHKIS 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 BETHKIS and placebo in controlled clinical trials. Hearing loss was reported in two (1.1%) BETHKIS-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 BETHKIS-and placebo-treated patients. Dizziness occurred in two (1.1%) BETHKIS-treated patients and one (0.9%) placebo-treated patient and vertigo occurred in two (1.1%) BETHKIS-treated patients versus no placebo patients in clinical studies. None of the BETHKIS 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 BETHKIS, but because it has been observed with inhaled tobramycin solutions, onset of this symptom warrants caution. Ototoxicity, manifested as both auditory and vestibular toxicity, has been reported with parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness.

Nephrotoxicity

Caution should be exercised when prescribing BETHKIS to patients with known or suspected renal dysfunction.

Nephrotoxicity was not seen during BETHKIS clinical studies but has been associated with aminoglycosides as a class. If nephrotoxicity occurs in a patient receiving BETHKIS, therapy should be discontinued until serum concentrations fall below 2 mcg/mL.

Twenty-six (14%) BETHKIS 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 BETHKIS 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 BETHKIS 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 BETHKIS, bronchospasm was observed in one (0.5%) BETHKIS-treated patient and in no placebo-treated patients. Wheezing occurred in ten (5%) BETHKIS-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 BETHKIS, 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. (See Pharmacokinetics)

Renal Function

The clinical studies of BETHKIS 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 BETHKIS 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 BETHKIS during pregnancy, or become pregnant while taking BETHKIS should be apprised of the potential hazard to the fetus.

Patient Counseling Information

See FDA Approved Patient Labeling

Information for Patients

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 dizziness.

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.

Additional Information

Nebulizers and Compressors: 1-800-327-8632 BETHKIS: 1-888-661-9260

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.

Use In Specific Populations

Pregnancy

Teratogenic Effects - Pregnancy Category D

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.

Labor and Delivery

The safety and efficacy of BETHKIS 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 BETHKIS have not been studied in pediatric cystic fibrosis patients under six years of age.

Geriatric Use

The safety and efficacy of BETHKIS have not been studied in adult cystic fibrosis patients over 31 years of age.

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 [see WARNINGS AND PRECAUTIONS].

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.

Last reviewed on RxList: 10/26/2012
This monograph has been modified to include the generic and brand name in many instances.

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