Safety Tolerability

Safety & Tolerability

TOBI PODHALER safety considerations for patients

In a head-to-head study, TOBI PODHALER was evaluated for safety vs TOBI^® (Tobramycin Inhalation Solution, USP)^1,*

Adverse reactions (≥10%)	TOBI PODHALER (n=308)	TOBI (n=209)
Cough	48.4%	31.1%
Lung disorder^†	33.8%	30.1%
Productive cough	18.2%	19.6%
Dyspnea	15.6%	12.4%
Pyrexia	15.6%	12.4%
Oropharyngeal pain	14.0%	10.5%
Dysphonia	13.6%	3.8%
Hemoptysis	13.0%	12.4%
Headache	11.4%	12.0%

Discontinuations due to adverse events were higher in the TOBI PODHALER arm (14%) than in the TOBI arm (8%)¹

^†This includes adverse events of pulmonary or CF exacerbations.¹ *The EAGER study was a randomized, open-label, parallel-group study in 517 patients with cystic fibrosis (CF) and Pseudomonas aeruginosa (Pa) (within 6 months of screening) aged ≥6 years with FEV₁ ≥25% to ≤75% predicted. The study consisted of 3 cycles; each cycle consisted of 28 days on treatment followed by 28 days off treatment, for a total duration of 24 weeks. Patients were randomized (3:2) to receive TOBI PODHALER 112 mg BID (n=308) or TOBI 300 mg/5 mL BID (n=209).^1,2 In a double-blind, phase-III trial patients aged 6 to 21 years with CF, Pa and FEV₁ ≥25% and ≤80% predicted at screening were randomized 1:1 to receive TOBI PODHALER (n=46) [4 times 28 mg capsules twice-daily] or placebo (n=49). Of the 79 patients included in the prespecified interim analysis, 18 were excluded due to a failure to meet spirometry quality review criteria, which resulted in a total of 61 patients included in the primary analysis. Cough was the most commonly reported adverse event during the first cycle of treatment and occurred more frequently in placebo-treated patients (26.5%) than patients treated with TOBI PODHALER (13%). In a 24-week, randomized, open-label trial patients aged ≥6 years with CF, Pa and FEV₁ ≥25% and ≤80% predicted within 6 months of screening were randomized 3:2 to receive TOBI PODHALER (n=308) [four capsules/112 mg tobramycin twice-daily] or TOBI solution (n=209) [300 mg/5 mL tobramycin twice-daily]. Cough was the most frequently reported adverse event and was more common in the TOBI PODHALER arm (48% TOBI PODHALER versus 31% TOBI solution). Discontinuations due to adverse events were 14% for TOBI PODHALER versus 8% for TOBI solution. EAGER, Establish a new gold standard efficacy and safety with tobramycin in cystic fibrosis.

Bronchospasm

Bronchospasm can occur with inhalation of TOBI PODHALER. Bronchospasm should be treated as medically appropriate¹

EAGER study

Similar rates of bronchospasm were seen in the 2 treatment groups (≈5% in each treatment group, as defined by a ≥20% decrease in FEV₁% predicted postdose)¹
None of these patients experienced concomitant cough¹

Ototoxicity

Caution should be exercised when prescribing TOBI PODHALER to patients with known or suspected auditory or vestibular dysfunction. Ototoxicity, as measured by complaints of hearing loss or tinnitus, was reported by patients in the TOBI PODHALER clinical studies. Tinnitus may be a sentinel symptom of ototoxicity, and therefore the 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 dizziness¹

Nephrotoxicity

Caution should be exercised when prescribing TOBI PODHALER to patients with known or suspected renal dysfunction. Nephrotoxicity was not observed during TOBI PODHALER clinical studies but has been associated with aminoglycosides as a class¹

Neuromuscular disorders

Caution should be exercised when prescribing TOBI PODHALER to patients with known or suspected neuromuscular dysfunction. TOBI PODHALER should be used cautiously in patients with neuromuscular disorders, such as myasthenia gravis or Parkinson’s disease, since aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function¹

Use in pregnancy

References

TOBI^® PODHALER^® [Prescribing Information, 2023].
Konstan MW, Flume PA, Kappler M, et al. Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: the EAGER trial. J Cyst Fibros. 2011;10(1):54-61.

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INDICATION

TOBI^® PODHALER^® (Tobramycin Inhalation Powder) 28 mg per capsule 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 6 years, patients with forced expiratory volume in 1 second (FEV₁) <25% or >80% predicted, or patients colonized with Burkholderia cepacia.

IMPORTANT SAFETY INFORMATION

TOBI PODHALER is contraindicated in patients with known hypersensitivity to any aminoglycoside.

Bronchospasm can occur with inhalation of TOBI PODHALER. Bronchospasm should be treated as medically appropriate.

Caution should be exercised when prescribing TOBI PODHALER to patients with known or suspected auditory, vestibular, renal, or neuromuscular dysfunction.

Ototoxicity, as measured by complaints of hearing loss or tinnitus, was reported by patients in the TOBI PODHALER clinical studies. Tinnitus may be a sentinel symptom of ototoxicity, and therefore the 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.

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.

TOBI PODHALER should be used cautiously in patients with neuromuscular 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.

Aminoglycosides can cause fetal harm when administered to a pregnant woman. Patients who use TOBI PODHALER during pregnancy, or who become pregnant while taking TOBI PODHALER, should be apprised of the potential hazard to the fetus. The amount of tobramycin excreted in human breast milk is unknown. However, systemic absorption of tobramycin following inhaled administration is expected to be minimal. A decision should be made whether to discontinue nursing or TOBI PODHALER. TOBI may cause intestinal flora alteration. Advise a woman to monitor the breastfed infant for loose or bloody stools and candidiasis.

Patients receiving concomitant TOBI and parenteral aminoglycoside therapy should be monitored as clinically appropriate for toxicities associated with aminoglycosides as a class. Serum tobramycin levels should be monitored.

Concurrent and/or sequential use of TOBI PODHALER with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. TOBI PODHALER should not be administered concomitantly with ethacrynic acid, furosemide, urea, or mannitol.

In a clinical trial, the most commonly observed adverse events with TOBI PODHALER occurring at a frequency of at least 10%, were cough, lung disorder, productive cough, dyspnea, pyrexia, oropharyngeal pain, dysphonia, hemoptysis, and headache.