Tobramycin Inhalation Solution

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 O3-amino-3-deoxy-α-D-glucopyranosyl-(1→4)-O-[2,6-diamino- 2,3,6-trideoxy-α-D-ribohexopyranosyl-( 1→6)]-2-deoxy-Lstreptamine. 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.

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. aeruginosam. Only 13% were either initially or intermittently colonized with P. aeruginosam 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 reported in at least 5% of Bethkis-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 BETHKIS Patients

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, Ototoxicity)

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

Nervous system disorders: Aphonia, dysgeusia

Respiratory, thoracic, and mediastinal disorders: Bronchospasm (see WARNINGS AND PRECAUTIONS, Bronchospasm), oropharyngeal pain

Metabolism and Nutrition Disorders: Decreased appetite

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Change in balance.
• Dizziness or passing out.
• Fever.
• Muscle weakness.
• Ringing in the ears, hearing loss, or any other changes in hearing.
• Wheezing.
• Cough that does not go away.
• Coughing up blood.
• Trouble breathing that is new or worse.
• Chest pain.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about tobramycin inhalation solution, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about tobramycin inhalation solution. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using tobramycin inhalation solution.

Review Date: October 4, 2017

Tobramycin Inhalation Solution, USP is contraindicated in patients with a known hypersensitivity to any aminoglycoside.

Caution should be exercised when prescribing Tobramycin Inhalation Solution to patients with known or suspected renal, auditory, vestibular, or neuromuscular dysfunction. Patients receiving concomitant parenteral aminoglycoside therapy should be monitored as clinically appropriate.

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 Tobramycin Inhalation Solution during pregnancy, or become pregnant while taking Tobramycin Inhalation Solution should be apprised of the potential hazard to the fetus.

Ototoxicity

Ototoxicity, as measured by complaints of hearing loss or by audiometric evaluations, did not occur with Tobramycin Inhalation Solution therapy during clinical studies. However, transient tinnitus occurred in eight Tobramycin Inhalation Solution-treated patients versus no placebo patients in the clinical studies. Tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants caution (see ADVERSE REACTIONS). Ototoxicity, manifested as both auditory and vestibular toxicity, has been reported with parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness.

In postmarketing experience, patients receiving tobramycin inhalation solution 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.

Nephrotoxicity

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

Muscular Disorders

Tobramycin Inhalation Solution 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.

Bronchospasm

Bronchospasm has been reported with inhalation of Tobramycin Inhalation Solution. In clinical studies of Tobramycin Inhalation Solution, changes in FEV1 measured after the inhaled dose were similar in the Tobramycin Inhalation Solution and placebo groups. Bronchospasm should be treated as medically appropriate.

Signs and symptoms of acute toxicity from overdosage of intravenous (IV) 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.

Tobramycin Inhalation Solution, USP 300 mg is supplied in 5 mL single-use ampules.
It is available as follows:

5 mL single-dose ampule packaged in cartons containing 56 ampules

(14 pouches, each containing 4 ampules)                    NDC 65162-914-46

Storage

Tobramycin Inhalation Solution, USP should be stored under refrigeration at 2º to 8ºC (36º to 46ºF). Upon removal from the refrigerator, or if refrigeration is unavailable, Tobramycin Inhalation Solution, USP pouches (opened or unopened) may be stored at room temperature (up to 25ºC/77ºF) for up to 28 days. Tobramycin Inhalation Solution, USP should not be used beyond the expiration date stamped on the ampule when stored under refrigeration (2º to 8ºC/36º to 46ºF) or beyond 28 days when stored at room temperature (25ºC/77ºF).

Tobramycin Inhalation Solution, USP ampules should not be exposed to intense light. The solution in the ampule is slightly 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.

Clinical Studies

Two identically designed, double-blind, randomized, placebo-controlled, parallel group, 24-week clinical studies (Study 1 and Study 2) at a total of 69 cystic fibrosis centers in the United States were conducted in cystic fibrosis patients with P. aeruginosa. Subjects who were less than 6 years of age, had a baseline creatinine of >2 mg/dL, or had Burkholderia cepacia isolated from sputum were excluded. All subjects had baseline FEV1 % predicted between 25% and 75%. In these clinical studies, 258 patients received Tobramycin Inhalation Solution therapy on an outpatient basis (see Table 2) using a hand-held PARI LC PLUS Reusable Nebulizer with a DeVilbiss Pulmo-Aide compressor.

All patients received either Tobramycin Inhalation Solution or placebo (saline with 1.25 mg quinine for flavoring) in addition to standard treatment recommended for cystic fibrosis patients, which included oral and parenteral anti-pseudomonal therapy, β2-agonists, cromolyn, inhaled steroids, and airway clearance techniques. In addition, approximately 77% of patients were concurrently treated with dornase alfa (PULMOZYME, Genentech).

In each study, Tobramycin Inhalation Solution-treated patients experienced significant improvement in pulmonary function. Improvement was demonstrated in the Tobramycin Inhalation Solution group in Study 1 by an average increase in FEV1 % predicted of about 11% relative to baseline (Week 0) during 24 weeks compared to no average change in placebo patients. In Study 2, Tobramycin Inhalation Solution-treated patients had an average increase of about 7% compared to an average decrease of about 1% in placebo patients. Figure 1 shows the average relative change in FEV1% predicted over 24 weeks for both studies.

Figure 1: Relative Change From Baseline in FEV1% Predicted

In each study, Tobramycin Inhalation Solution therapy resulted in a significant reduction in the number of P. aeruginosa colony forming units (CFUs) in sputum during the on-drug periods. Sputum bacterial density returned to baseline during the off-drug periods. Reductions in sputum bacterial density were smaller in each successive cycle (see Figure 2).

Figure 2: Absolute Change From Baseline in Log10 CFUs

Patients treated with Tobramycin Inhalation Solution were hospitalized for an average of 5.1 days compared to 8.1 days for placebo patients. Patients treated with Tobramycin Inhalation Solution required an average of 9.6 days of parenteral anti-pseudomonal antibiotic treatment compared to 14.1 days for placebo patients. During the 6 months of treatment, 40% of Tobramycin Inhalation Solution patients and 53% of placebo patients were treated with parenteral anti-pseudomonal antibiotics.

The relationship between in vitro susceptibility test results and clinical outcome with Tobramycin Inhalation Solution therapy is not clear. However, 4 Tobramycin Inhalation Solution patients who began the clinical trial with P. aeruginosa isolates having MIC values ≥128 mcg/mL did not experience an improvement in FEV1 or a decrease in sputum bacterial density.

Treatment with Tobramycin Inhalation Solution did not affect the susceptibility of the majority of P. aeruginosa isolates during the 6-month studies. However, some P. aeruginosa isolates did exhibit increased tobramycin MICs. The percentage of patients with P. aeruginosa isolates with tobramycin MICs ≥16 mcg/mL was 13% at the beginning, and 23% at the end of 6 months of the Tobramycin Inhalation Solution regimen.

Do not take this medicine with any of the following medications:

• cidofovir
• cisplatin
• colistin
• ethacrynic acid
• furosemide
• mannitol
• other aminoglycoside antibiotics
• polymyxin
• urea
• vancomycin
• viomycin

This medicine may also interact with the following medications:

• birth control pills
• diuretics