Drug: Bethkis

BETHKIS is a sterile, clear, colorless to pale yellow, non-pyrogenic, aqueous solution with pH and salinity adjusted. BETHKIS is administered by a compressed air driven reusable nebulizer. The chemical formula for tobramycin is C18H37N5O9 and the molecular weight is 467.52. 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-deoxyL-streptamine. The structural formula for tobramycin is: Each single-use 4 mL ampule of BETHKIS contains one 300 mg dose of tobramycin, with sodium chloride and sulfuric acid in water for injection. Sulfuric acid and sodium hydroxide are used to adjust the pH, as needed, to 5.0. Nitrogen is used for sparging, filling and pouching. The formulation contains no preservatives. BETHKIS does not comply with the USP with regard to pH, absorbance and osmolality. 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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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 BETHKIS in two placebo-controlled studies in 305 cystic fibrosis patients. Patients receiving BETHKIS ranged in age from 6 to 31 years. In Study 1, an eight week study, 29 patients received BETHKIS 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 BETHKIS group (23% [7/30] vs 3.4% [1/29], respectively). Five patients in the placebo group compared to none in the BETHKIS 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 BETHKIS 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 612 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 BETHKIS group (9.4% [8/85] vs 4.3% [7/161], respectively). Of these, 3 patients in the BETHKIS 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 BETHKIS-and placebo-treated patients. The following adverse reactions were more commonly reported in ≥ 2% of the BETHKIS-treated patients compared to the placebo-treated patients: decreased forced expiratory volume, rales, red blood cell sedimentation rate increased, and dysphonia (Table 1). Table 1: Patients with Selected Treatment-Emergent Adverse Reactions Occurring in ≥ 2% of BETHKIS Patients
Adverse Reactions BETHKIS
N=190 (%) Placebo
N=115 (%) Forced expiratory volume decreased 59 (31%) 33 (29%) Rales 36 (19%) 18 (16%) Red blood cell sedimentation rate increased 16 (8%) 6 (5%) Dysphonia 11 (6%) 2 (2%) Wheezing 10 (5%) 4 (4%) Epistaxis 6 (3%) 0 Pharyngolaryngeal pain 5 (3%) 2 (2%) Bronchitis 5 (3%) 1 (1%) Tonsillitis 4 (2%) 0 Diarrhea 3 (2%) 1 (1%) Eosinophilia 3 (2%) 0 Immunoglobulins increased 3 (2%) 0 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 (see WARNINGS AND PRECAUTIONS, Ototoxicity). 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. Read the Bethkis (tobramycin inhalation solution) Side Effects Center for a complete guide to possible side effectsLearn More »

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Dosing Information 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. BETHKIS has not been studied in patients less than six years old. Administration BETHKIS is administered by oral inhalation. Do not use by any other route. BETHKIS 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. Further patient instructions on how to administer BETHKIS are provided in the PATIENT INFORMATION section.

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Drugs with Neurotoxic or Ototoxic Potential Concurrent and/or sequential use of BETHKIS with other drugs with neurotoxic or ototoxic potential should be avoided. Ethacrynic Acid, Furosemide, Urea, or Mannitol Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. Therefore, BETHKIS should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol. Last reviewed on RxList: 10/26/2012
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

BETHKIS 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 six years, patients with FEV1 less than 40% or greater than 80% predicted, or patients colonized with Burkholderia cepacia.(See Clinical Studies)

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BETHKIS is contraindicated in patients with a known hypersensitivity to any aminoglycoside. Last reviewed on RxList: 10/26/2012
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

No overdoses have been reported with BETHKIS 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.

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Dosage Forms And Strengths 4 mL single-use ampules containing 300 mg of tobramycin. Storage And Handling 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) 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. REFERENCES 4. CLSI Performance Standards for Antimicrobial Susceptibility Testing: 22ND Informational supplement CLSI document M100-S22. CLSI 2012. 6. PARI Vios Aerosol Delivery System with LC Plus Nebulizer: Instructions for Use. PARI Respiratory Equipment, Inc. 2010; 310D0028 Rev A 6-10. Manufactured for Cornerstone Therapeutics Inc. by Catalent Pharma Solutions, LLC, Woodstock, Illinois 60098. Issued: 10/2012 Last reviewed on RxList: 10/26/2012
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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.

Source: http://www.rxlist.com

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