Bethkis

BETHKIS is contraindicated in patients with a known hypersensitivity to any aminoglycoside. BETHKIS is contraindicated in patients with a known hypersensitivity to any aminoglycoside. ( 4 )

• Caution should be exercised when prescribing BETHKIS to patients with known or suspected auditory, vestibular, renal, or neuromuscular dysfunction.
• ( 5.1 , 5.2 , 5.3 and 5.5 ) Aminoglycoside may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function.
• ( 5.3 ) Bronchospasm can occur with inhalation of BETHKIS.
• ( 5.4 ) Audiograms, serum concentration, and renal function should be monitored as appropriate.
• ( 5.2 and 5.5 ) Fetal harm can occur when aminoglycosides are administered to a pregnant woman.
• Apprise women of the potential hazard to the fetus.
• ( 5.6 )
• 5.1 Ototoxicity Ototoxicity with use of BETHKIS 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 [see Adverse Reactions ( 6.2 )] , 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.
• Patients with known or suspected auditory or vestibular dysfunction should be closely monitored when taking BETHKIS.
• Monitoring may include obtaining audiometric evaluations and serum tobramycin levels.
• If ototoxicity is noted, the patient should be managed as medically appropriate, including potentially discontinuing BETHKIS.
• 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.
• 5.2 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.
• Patients with known or suspected renal dysfunction or taking concomitant nephrotoxic drugs along with BETHKIS should have serum concentrations of tobramycin and laboratory measurements of renal function obtained at the discretion of the treating physician.
• If nephrotoxicity develops, the patient should be managed as medically appropriate, including potentially discontinuing BETHKIS 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 normal laboratory ranges.
• Patients who experience an increase in serum creatinine during treatment with BETHKIS should have their renal function closely monitored.
• 5.3 Neuromuscular Disorders BETHKIS should be used cautiously in patients with muscular disorders.
• Aminoglycosides, including tobramycin, may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function.
• Neuromuscular blockade, respiratory failure, and prolonged respiratory paralysis may occur more commonly in patients with underlying neuromuscular disorders, such as myasthenia gravis or Parkinson’s disease.
• Prolonged respiratory paralysis may also occur in patients receiving concomitant neuromuscular blocking agents.
• If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts but mechanical assistance may be necessary.
• 5.4 Bronchospasm Bronchospasm has been reported 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.
• 5.5 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 Clinical Pharmacology ( 12.3 )] .
• The serum concentration of tobramycin should only be monitored through venipuncture and not finger prick blood sampling.
• Contamination of the skin of the fingers with tobramycin may lead to falsely increased measurements of serum levels of the drug.
• This contamination cannot be completely avoided by hand washing before testing.
• 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.
• 5.6 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 .
• Patients who use BETHKIS during pregnancy, or become pregnant while taking BETHKIS should be apprised of the potential hazard to the fetus [see Use in Specific Populations ( 8.1 )] .
• 5.7 Concomitant Use of Systemic Aminoglycosides Patients receiving concomitant BETHKIS and parenteral aminoglycoside therapy should be monitored as clinically appropriate for toxicities associated with aminoglycosides as a class.
• Serum tobramycin levels should be monitored.

• Risk Summary Aminoglycosides can cause fetal harm.
• Published literature reports that use of streptomycin, an aminoglycoside, can cause total, irreversible, bilateral congenital deafness when administered to a pregnant woman [Warnings and Precautions ( 5.6 )] .
• Although there are no available data on use of BETHKIS in pregnant women to be able to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, systemic absorption of tobramycin following inhaled administration is expected to be minimal [see Clinical Pharmacology ( 12.3 )] .
• There are risks to the mother associated with cystic fibrosis in pregnancy (see Clinical Considerations) .
• In animal reproduction studies with subcutaneous administration of tobramycin in pregnant rats and rabbits during organogenesis there were no adverse developmental outcomes; however, ototoxicity was not evaluated in the offspring from these studies (see Data ) .
• Advise pregnant women of the potential risk to a fetus.
• The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown.
• All pregnancies have a background risk of birth defect, 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 2 to 4% and 15 to 20%, respectively.
• Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Cystic fibrosis may increase the risk for preterm delivery.
• Data Animal Data No reproduction toxicology studies have been conducted with inhaled tobramycin.
• However, subcutaneous administration of tobramycin at doses of up to 100 (rat) or 20 (rabbit) mg/kg/day during organogenesis was not associated with adverse developmental outcomes.
• Subcutaneous doses of tobramycin ≥ 40mg/kg/day were severely maternally toxic to rabbits and precluded the evaluation of adverse developmental outcomes.
• Ototoxicity was not evaluated in offspring during nonclinical reproductive toxicity studies with tobramycin.
• IN SPECIFIC POPULATIONS Aminoglycosides can cause fetal harm when administered to a pregnant woman.
• ( 8.1 ) Nursing mothers:
• discontinue drug or nursing, taking into consideration the importance of the drug to a mother.
• ( 8.2 ) __________________________________________________________________
• 8.1 Pregnancy Risk Summary Aminoglycosides can cause fetal harm.
• Published literature reports that use of streptomycin, an aminoglycoside, can cause total, irreversible, bilateral congenital deafness when administered to a pregnant woman [Warnings and Precautions ( 5.6 )] .
• Although there are no available data on use of BETHKIS in pregnant women to be able to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, systemic absorption of tobramycin following inhaled administration is expected to be minimal [see Clinical Pharmacology ( 12.3 )] .
• There are risks to the mother associated with cystic fibrosis in pregnancy (see Clinical Considerations) .
• In animal reproduction studies with subcutaneous administration of tobramycin in pregnant rats and rabbits during organogenesis there were no adverse developmental outcomes; however, ototoxicity was not evaluated in the offspring from these studies (see Data ) .
• Advise pregnant women of the potential risk to a fetus.
• The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown.
• All pregnancies have a background risk of birth defect, 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 2 to 4% and 15 to 20%, respectively.
• Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Cystic fibrosis may increase the risk for preterm delivery.
• Data Animal Data No reproduction toxicology studies have been conducted with inhaled tobramycin.
• However, subcutaneous administration of tobramycin at doses of up to 100 (rat) or 20 (rabbit) mg/kg/day during organogenesis was not associated with adverse developmental outcomes.
• Subcutaneous doses of tobramycin ≥ 40mg/kg/day were severely maternally toxic to rabbits and precluded the evaluation of adverse developmental outcomes.
• Ototoxicity was not evaluated in offspring during nonclinical reproductive toxicity studies with tobramycin.
• 8.2 Lactation Risk Summary There are no data on the presence of tobramycin in either human or animal milk, the effects on the breastfed infant, or the effects on milk production following oral inhalation of BETHKIS.
• 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 [see Clinical Pharmacology ( 12.3 )] .
• Tobramycin may cause alteration in the intestinal flora of the breastfeeding infant (see Clinical Considerations) .
• The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BETHKIS and any potential adverse effects on the breastfed child from BETHKIS or from the underlying maternal condition.
• Clinical Considerations Tobramycin may cause intestinal flora alteration.
• Advise a woman to monitor the breastfed infant for loose or bloody stools and candidiasis (thrush, diaper rash).
• 8.4 Pediatric Use The safety and efficacy of BETHKIS have not been studied in pediatric cystic fibrosis patients under six years of age.
• 8.5 Geriatric Use Clinical studies of BETHKIS did not include patients aged 65 years and over.
• Tobramycin is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function.
• Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function [see Warnings and Precautions ( 5.2 , 5.5 )] .
• 8.6 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 ( 5.2 , 5.5 )] .
• 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.

• Concurrent and/or sequential use of BETHKIS with other drugs with neurotoxic, nephrotoxic or ototoxic potential should be avoided.
• ( 7.1 ) BETHKIS should not be administered concomitantly with ethacrynic acid, furosemide, urea, or intravenous mannitol.
• ( 7.2 )
• 7.1 Drugs with Neurotoxic, Nephrotoxic, or Ototoxic Potential Concurrent and/or sequential use of BETHKIS with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided.
• 7.2 Diuretics 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 intravenous mannitol.
• The interaction between inhaled mannitol and BETHKIS has not been evaluated.

• 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, 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.
• 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.