Tobramycin Inhalation (Page 2 of 7)

Renal Function

The clinical studies of Tobramycin Inhalation Solution 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 Tobramycin Inhalation Solution 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. However, systemic absorption of tobramycin following inhaled administration is expected to be minimal [see Clinical Pharmacology (12.3)]. Patients who use Tobramycin Inhalation Solution during pregnancy, or become pregnant while taking Tobramycin Inhalation Solution 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 Tobramycin Inhalation Solution and parenteral aminoglycoside therapy should be monitored as clinically appropriate for toxicities associated with aminoglycosides as a class. Serum tobramycin levels should be monitored.

6 ADVERSE REACTIONS

6.1 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 Tobramycin Inhalation Solution in two placebo-controlled studies in 305 cystic fibrosis patients. Patients receiving Tobramycin Inhalation Solution ranged in age from 6 to 31 years.

In Study 1, an eight week study, 29 patients received Tobramycin Inhalation Solution 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 Tobramycin Inhalation Solution group (23% [7/30] vs 3.4% [1/29], respectively). Five patients in the placebo group compared to none in the Tobramycin Inhalation Solution 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 Tobramycin Inhalation Solution 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 6-12 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 Tobramycin Inhalation Solution group (9.4% [8/85] vs 4.3% [7/161], respectively). Of these, 3 patients in the Tobramycin Inhalation Solution 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 Tobramycin Inhalation Solution- and placebo-treated patients. The following adverse reactions were reported in at least 5% of Tobramycin Inhalation Solution-treated patients and at rates ≥ 2% more common 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 Tobramycin Inhalation Solution Patients

Adverse Reactions

Tobramycin Inhalation SolutionN=190(%)

PlaceboN=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

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of tobramycin inhalation solution. 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.

Ear and labyrinth disorders: Hearing loss, Tinnitus [see Warnings and Precautions (5.1)]

Skin and subcutaneous tissue disorders: Hypersensitivity, pruritus, urticaria, rash

Nervous system disorders: Aphonia, dysgeusia

Respiratory, thoracic, and mediastinal disorders: Bronchospasm [see Warnings and Precautions (5.4)] , oropharyngeal pain

Metabolism and Nutrition Disorders: Decreased appetite

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