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Tobrabact

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Published: 2021-11-11T10:10:10+00:00

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Tobrabact uses

Description
Clinical pharmacology
Indications and usage
Contraindications
Warnings
Precautions
Adverse reactions
Overdosage
Dosage and administration
How supplied
References
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DESCRIPTION

Tobrabact inhalation solution, USP is a Tobrabact solution for inhalation. It is a sterile, clear, slightly yellow, non-pyrogenic, aqueous solution with the pH and salinity adjusted specifically for administration by a compressed air driven reusable nebulizer. The chemical formula for Tobrabact, USP is C₁₈H₃₇N₅O₉ and the molecular weight is 467.52. Tobrabact, USP 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-deoxy-L-streptamine. The structural formula for Tobrabact, USP is:

Each single-use 5 mL ampule contains 300 mg Tobrabact, USP and 11.25 mg sodium chloride in sterile water for injection. Sulfuric acid and sodium hydroxide are added to adjust the pH to 6.0. Nitrogen is used for sparging. All ingredients meet USP requirements. The formulation contains no preservatives.

Tobrabact, USP is a solution for inhalation. It is a sterile, clear, slightly yellow, non-pyrogenic, aqueous solution with the pH and salinity adjusted specifically for administration by a compressed air driven reusable nebulizer. The chemical formula for Tobrabact, USP is C₁₈H₃₇N₅O₉ and the molecular weight is 467.52. Tobrabact, USP 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-deoxy-L-streptamine. The structural formula for Tobrabact, USP is:

Formulation

CLINICAL PHARMACOLOGY

Tobrabact inhalation solution is specifically formulated for administration by inhalation. When inhaled, Tobrabact is concentrated in the airways.

Pharmacokinetics

Tobrabact inhalation solution contains Tobrabact, a cationic polar molecule that does not readily cross epithelial membranes.⁽¹⁾ The bioavailability of Tobrabact inhalation solution may vary because of individual differences in nebulizer performance and airway pathology.⁽²⁾ Following administration of Tobrabact inhalation solution, Tobrabact remains concentrated primarily in the airways.

Sputum Concentrations: Ten minutes after inhalation of the first 300-mg dose of Tobrabact inhalation solution, the average concentration of Tobrabact was 1237 mcg/g (ranging from 35 to 7417 mcg/g) in sputum. Tobrabact does not accumulate in sputum; after 20 weeks of therapy with the Tobrabact inhalation solution regimen, the average concentration of Tobrabact at ten minutes after inhalation was 1154 mcg/g (ranging from 39 to 8085 mcg/g) in sputum. High variability of Tobrabact concentration in sputum was observed. Two hours after inhalation, sputum concentrations declined to approximately 14% of Tobrabact levels at ten minutes after inhalation.

Serum Concentrations: The average serum concentration of Tobrabact one hour after inhalation of a single 300-mg dose of Tobrabact inhalation solution by cystic fibrosis patients was 0.95 mcg/mL. After 20 weeks of therapy on the Tobrabact inhalation solution regimen, the average serum Tobrabact concentration one hour after dosing was 1.05 mcg/mL.

Elimination: The elimination half-life of Tobrabact from serum is approximately 2 hours after intravenous (IV) administration. Assuming Tobrabact absorbed following inhalation behaves similarly to Tobrabact following IV administration, systemically absorbed Tobrabact is eliminated principally by glomerular filtration. Unabsorbed Tobrabact, following Tobrabact inhalation solution administration, is probably eliminated primarily in expectorated sputum.

Microbiology

Tobrabact is an aminoglycoside antibiotic produced by Streptomyces tenebrarius.⁽¹⁾ It acts primarily by disrupting protein synthesis, leading to altered cell membrane permeability, progressive disruption of the cell envelope, and eventual cell death.⁽³⁾

Tobrabact has in vitro activity against a wide range of gram-negative organisms including Pseudomonas aeruginosa. It is bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.

Susceptibility Testing

A single sputum sample from a cystic fibrosis patient may contain multiple morphotypes of Pseudomonas aeruginosa and each morphotype may have a different level of in vitro susceptibility to Tobrabact. Treatment for 6 months with Tobrabact inhalation solution in two clinical studies did not affect the susceptibility of the majority of P. aeruginosa isolates tested; however, increased minimum inhibitory concentrations (MICs) were noted in some patients. The clinical significance of this information has not been clearly established in the treatment of P. aeruginosa in cystic fibrosis patients. For additional information regarding the effects of Tobrabact inhalation solution on P. aeruginosa MIC values and bacterial sputum density, please refer to the CLINICAL STUDIES section.

The in vitro antimicrobial susceptibility test methods used for parenteral Tobrabact therapy can be used to monitor the susceptibility of P. aeruginosa isolated from cystic fibrosis patients. If decreased susceptibility is noted, the results should be reported to the clinician.

Susceptibility breakpoints established for parenteral administration of Tobrabact do not apply to aerosolized administration of Tobrabact inhalation solution. The relationship between in vitro susceptibility test results and clinical outcome with Tobrabact inhalation solution therapy is not clear.

INDICATIONS AND USAGE

Tobrabact inhalation solution, USP 300 mg/5 mL is indicated for the management of cystic fibrosis patients with P. 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 >75% predicted, or patients colonized with Burkholderia cepacia (see CLINICAL STUDIES ).

CONTRAINDICATIONS

Tobrabact inhalation solution, USP is contraindicated in patients with a known hypersensitivity to any aminoglycoside.

WARNINGS

Caution should be exercised when prescribing Tobrabact 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 Tobrabact inhalation solution during pregnancy, or become pregnant while taking Tobrabact 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 Tobrabact inhalation solution therapy during clinical studies. However, transient tinnitus occurred in eight Tobrabact 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. 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 Tobrabact 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 Tobrabact inhalation solution clinical studies but has been associated with aminoglycosides as a class. If nephrotoxicity occurs in a patient receiving Tobrabact inhalation solution, Tobrabact therapy should be discontinued until serum concentrations fall below 2 mg/mL.

Muscular Disorders

Tobrabact 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 Tobrabact inhalation solution. In clinical studies of Tobrabact inhalation solution, changes in FEV₁ measured after the inhaled dose were similar in the Tobrabact inhalation solution and placebo groups. Bronchospasm should be treated as medically appropriate.

PRECAUTIONS

Information for Patients

NOTE: In addition to information provided below, a Patient Medication Guide providing instructions for proper use of Tobrabact inhalation solution is contained inside the package.

Safety Information

Tobrabact inhalation solution is in a class of antibiotics that have caused hearing loss, dizziness, kidney damage, and harm to a fetus. Ringing in the ears and hoarseness were two symptoms that were seen in more patients taking Tobrabact inhalation solution than placebo in research studies. Patients with cystic fibrosis can have many symptoms. Some of these symptoms may be related to your medications. If you have new or worsening symptoms, you should tell your doctor.

Hearing: You should tell your doctor if you have ringing in the ears, dizziness, or any changes in hearing.

Kidney Damage: Inform your doctor if you have any history of kidney problems.

Pregnancy: If you want to become pregnant or are pregnant while on Tobrabact inhalation solution, you should talk with your doctor about the possibility of Tobrabact inhalation solution causing any harm.

Nursing Mothers: If you are nursing a baby, you should talk with your doctor before using Tobrabact inhalation solution.

Tobrabact Inhalation Solution Packaging

Tobrabact inhalation solution comes in a single dose, ready-to-use ampule containing 300 mg Tobrabact. Each foil pouch contains 4 ampules, for 2 days of Tobrabact inhalation solution therapy.

Dosage

The 300 mg dose of Tobrabact inhalation solution is the same for patients regardless of age or weight. Tobrabact inhalation solution has not been studied in patients less than 6 years old. Doses should be inhaled as close to 12 hours apart as possible and not less than 6 hours apart.

You should not mix Tobrabact inhalation solution with dornase alfa in the nebulizer.

If you are taking several medications, the recommended order is as follows: bronchodilator first, followed by chest physiotherapy, then other inhaled medications and, finally, Tobrabact inhalation solution.

Treatment Schedule

You should take Tobrabact inhalation solution in repeated cycles of 28 days on drug followed by 28 days off drug. You should take Tobrabact inhalation solution twice a day during the 28-day period on drug.

How To Administer Tobrabact Inhalation Solution for Inhalation

THIS INFORMATION IS NOT INTENDED TO REPLACE CONSULTATION WITH YOUR PHYSICIAN AND CF CARE TEAM ABOUT PROPERLY TAKING MEDICATION OR USING INHALATION EQUIPMENT.

Tobrabact inhalation solution is specifically formulated for inhalation using a PARI LC PLUS Reusable Nebulizer and a DeVilbiss^® Pulmo-Aide^® air compressor. Tobrabact inhalation solution can be taken at home, school, or at work. The following are instructions on how to use the DeVilbiss Pulmo-Aide air compressor and PARI LC PLUS Reusable Nebulizer to administer Tobrabact Inhalation Solution for Inhalation.

You will need the following supplies:

- Tobrabact inhalation solution plastic ampule (vial)

- DeVilbiss Pulmo-Aide air compressor

- PARI LC PLUS Reusable Nebulizer

- Tubing to connect the nebulizer and compressor

- Clean paper or cloth towels

- Nose clips (optional)

It is important that your nebulizer and compressor function properly before starting your Tobrabact inhalation solution therapy.

Note: Please refer to the manufacturers’ care and use instructions for important information.

Preparing Your Tobrabact Inhalation Solution for Inhalation

1. Wash your hands thoroughly with soap and water.

2a. Tobrabact inhalation solution is packaged with 4 ampules per foil pouch.

2b. Separate one ampule by gently pulling apart at the bottom tabs. Store all remaining ampules in the refrigerator as directed.

3. Lay out the contents of a PARI LC PLUS Reusable Nebulizer package on a clean, dry paper or cloth towel. You should have the following parts:

- Nebulizer Top and Bottom (Nebulizer Cup) Assembly

- Inspiratory Valve Cap

- Mouthpiece with Valve

- Tubing

4. Remove the Nebulizer Top from the Nebulizer Cup by twisting the Nebulizer Top counter-clockwise, and then lifting off. Place the Nebulizer Top on the clean paper or cloth towel. Stand the Nebulizer Cup upright on the towel.

5. Connect one end of the tubing to the compressor air outlet. The tubing should fit snugly. Plug in your compressor to an electrical outlet.

6. Open the Tobrabact inhalation solution ampule by holding the bottom tab with one hand and twisting off the top of the ampule with the other hand. Be careful not to squeeze the ampule until you are ready to empty its contents into the Nebulizer Cup.

7. Squeeze all the contents of the ampule into the Nebulizer Cup.

8. Replace the Nebulizer Top. Note: In order to insert the Nebulizer Top into the

Nebulizer Cup, the semi-circle halfway down the stem of the Nebulizer Top should face the Nebulizer Outlet.

9. Attach the Mouthpiece to the Nebulizer Outlet. Then firmly push the Inspiratory Valve Cap in place on the Nebulizer Top. Note: the Inspiratory Valve Cap will fit snugly.

10. Connect the free end of the tubing from the compressor to the Air Intake on the bottom of the nebulizer, making sure to keep the nebulizer upright. Press the tubing on the Air Intake firmly.

Tobrabact Inhalation Solution Treatment

1. Turn on the compressor.

2. Check for a steady mist from the Mouthpiece. If there is no mist, check all tubing connections and confirm that the compressor is working properly.

3. Sit or stand in an upright position that will allow you to breathe normally.

4. Place Mouthpiece between your teeth and on top of your tongue and breathe normally only through your mouth. Nose clips may help you breathe through your mouth and not through your nose. Do not block airflow with your tongue.

5. Continue treatment until all your Tobrabact inhalation solution is gone, and there is no longer any mist being produced. You may hear a sputtering sound when the Nebulizer Cup is empty. The entire Tobrabact inhalation solution treatment should take approximately 15 minutes to complete. Note: if you are interrupted, need to cough or rest during your Tobrabact inhalation solution treatment, turn off the compressor to save your medication. Turn the compressor back on when you are ready to resume your therapy.

6. Follow the nebulizer cleaning and disinfecting instructions after completing therapy.

Cleaning Your Nebulizer

To reduce the risk of infection, illness or injury from contamination, you must thoroughly clean all parts of the nebulizer as instructed after each treatment. Never use a nebulizer with a clogged nozzle. If the nozzle is clogged, no aerosol mist is produced, which will alter the effectiveness of the treatment. Replace the nebulizer if clogging occurs.

1. Remove tubing from nebulizer and disassemble nebulizer parts.

2. Wash all parts (except tubing) with warm water and liquid dish soap.

3. Rinse thoroughly with warm water and shake out water.

4. Air dry or hand dry nebulizer parts on a clean, lint-free cloth. Reassemble nebulizer when dry, and store.

5. You can also wash all parts of the nebulizer in a dishwasher (except tubing). Place the nebulizer parts in a dishwasher basket, then place on the top rack of the dishwasher.

Remove and dry the parts when the cycle is complete.

Disinfecting Your Nebulizer

Your nebulizer is for your use only - Do not share your nebulizer with other people. You must regularly disinfect the nebulizer. Failure to do so could lead to serious or fatal illness.

Clean the nebulizer as described above. Every other treatment day, disinfect the nebulizer parts (except tubing) by boiling them in water for a full 10 minutes. Dry parts on a clean, lint-free cloth.

Care and Use of Your Pulmo-Aide Compressor

Follow the manufacturer’s instructions for care and use of your compressor.

Filter Change:

1. DeVilbiss Compressor filters should be changed every six months or sooner if filter turns completely gray in color.

Compressor Cleaning:

1. With power switch in the “Off” position, unplug power cord from wall outlet.

2. Wipe outside of the compressor cabinet with a clean, damp cloth every few days to keep dust free.

Caution: Do not submerge in water; doing so will result in compressor damage.

Storage Instructions

You should store Tobrabact inhalation solution ampules in a refrigerator (2°C to 8°C or 36°F to 46°F). However, when you don’t have a refrigerator available (e.g., transporting your Tobrabact inhalation solution), you may store the foil pouches (opened or unopened) at room temperature (up to 25°C/77°F) for up to 28 days.

Avoid exposing Tobrabact inhalation solution ampules to intense light.

Unrefrigerated Tobrabact inhalation solution, which is normally slightly yellow, may darken with age; however, the color change does not indicate any change in the quality of the product.

You should not use Tobrabact inhalation solution 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 Tobrabact inhalation solution beyond the expiration date stamped on the ampule.

Additional Information

Nebulizer: 1-800-327-8632

Compressor: 1-800-338-1988

Tobrabact Inhalation Solution: 1-877-835-5472

Laboratory Tests

Audiograms

Clinical studies of Tobrabact inhalation solution 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 Tobrabact inhalation solution, serum Tobrabact concentrations are approximately 1 mcg/mL 1 hour after dose administration and do not require routine monitoring. Serum concentrations of Tobrabact in patients with renal dysfunction or patients treated with concomitant parenteral Tobrabact should be monitored at the discretion of the treating physician.

The serum concentration of Tobrabact should only be monitored through venipuncture and not finger prick blood sampling. Contamination of the skin of the fingers with Tobrabact 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 Tobrabact inhalation solution did not reveal any imbalance in the percentage of patients in the Tobrabact inhalation solution and placebo groups who experienced at least a 50% rise in serum creatinine from baseline (see ADVERSE REACTIONS ). Laboratory tests of urine and renal function should be conducted at the discretion of the treating physician.

Drug Interactions

In clinical studies of Tobrabact inhalation solution, patients taking Tobrabact inhalation solution concomitantly with dornase alfa (PULMOZYME, Genentech), ß-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole.

Concurrent and/or sequential use of Tobrabact inhalation solution 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. Tobrabact inhalation solution should not be administered concomitantly with ethacrynic acid, furosemide, urea, or intravenous mannitol. The interaction between inhaled mannitol and Tobrabact inhalation solution has not been evaluated.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A two-year rat inhalation toxicology study to assess carcinogenic potential of Tobrabact inhalation solution has been completed. Rats were exposed to Tobrabact inhalation solution for up to 1.5 hours per day for 95 weeks. The clinical formulation of the drug was used for this carcinogenicity study. Serum levels of Tobrabact of up to 35 mcg/mL were measured in rats, in contrast to the average 1 mcg/mL levels observed in cystic fibrosis patients in clinical trials. There was no drug-related increase in the incidence of any variety of tumor.

Additionally, Tobrabact inhalation solution has been evaluated for genotoxicity in a battery of in vitro and in vivo tests. The Ames bacterial reversion test, conducted with 5 tester strains, failed to show a significant increase in revertants with or without metabolic activation in all strains. Tobrabact 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 Tobrabact did not affect mating behavior or cause impairment of fertility in male or female rats.

Pregnancy

Teratogenic Effects – Pregnancy Category D

(See WARNINGS )

No reproduction toxicology studies have been conducted with Tobrabact inhalation solution. However, subcutaneous administration of Tobrabact at doses of 100 or 20 mg/kg/day during organogenesis was not teratogenic in rats or rabbits, respectively. Doses of Tobrabact ≥40 mg/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 Tobrabact. If Tobrabact inhalation solution is used during pregnancy, or if the patient becomes pregnant while taking Tobrabact inhalation solution, the patient should be apprised of the potential hazard to the fetus.

Nursing Mothers

It is not known if Tobrabact inhalation solution 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 Tobrabact inhalation solution.

Pediatric Use

The safety and efficacy of Tobrabact inhalation solution have not been studied in pediatric patients under 6 years of age.

Geriatric Use

Clinical studies of Tobrabact inhalation solution did not include patients aged 65 years and over. Tobrabact 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 – Nephrotoxicity ; PRECAUTIONS – Serum Concentrations ).

ADVERSE REACTIONS

Tobrabact inhalation solution was generally well tolerated during two clinical studies in 258 cystic fibrosis patients ranging in age from 6 to 48 years. Patients received Tobrabact inhalation solution in alternating periods of 28 days on and 28 days off drug in addition to their standard cystic fibrosis therapy for a total of 24 weeks.

Voice alteration and tinnitus were the only adverse experiences reported by significantly more Tobrabact inhalation solution-treated patients. Thirty-three patients (13%) treated with Tobrabact inhalation solution complained of voice alteration compared to 17 (7%) placebo patients. Voice alteration was more common in the on-drug periods.

Eight patients from the Tobrabact inhalation solution group (3%) reported tinnitus compared to no placebo patients. All episodes were transient, resolved without discontinuation of the Tobrabact inhalation solution treatment regimen, and were not associated with loss of hearing in audiograms. Tinnitus is one of the sentinel symptoms of cochlear toxicity, and patients with this symptom should be carefully monitored for high frequency hearing loss. The numbers of patients reporting vestibular adverse experiences such as dizziness were similar in the Tobrabact inhalation solution and placebo groups.

Nine (3%) patients in the Tobrabact inhalation solution group and nine (3%) patients in the placebo group had increases in serum creatinine of at least 50% over baseline. In all nine patients in the Tobrabact inhalation solution group, creatinine decreased at the next visit.

Table 1 lists the percent of patients with treatment-emergent adverse experiences (spontaneously reported and solicited) that occurred in >5% of Tobrabact inhalation solution patients during the two Phase III studies.

Table 1: Percent of Patients With Treatment Emergent Adverse Experiences Occurring in >5% of Tobrabact Inhalation Solution Patients

Adverse Event

Tobrabact Inhalation Solution

(n=258)

Placebo

(n=262)

Cough Increased

46.1

47.3

Pharyngitis

39.3

Sputum Increased

37.6

39.7

Asthenia

35.7

39.3

Rhinitis

34.5

33.6

Dyspnea

33.7

38.5

Fever¹

32.9

43.5

Lung Disorder

31.4

31.3

Headache

26.7

32.1

Chest Pain

29.8

Sputum Discoloration

21.3

19.8

Hemoptysis

19.4

23.7

Anorexia

18.6

27.9

Lung Function Decreased²

16.3

15.3

Asthma

15.9

20.2

Vomiting

22.1

Abdominal Pain

12.8

23.7

Voice Alteration

12.8

6.5

Nausea

11.2

Weight Loss

10.1

15.3

Pain

8.1

12.6

Sinusitis

8.1

9.2

Ear Pain

7.4

8.8

Back Pain

Epistaxis

6.5

Taste Perversion

6.6

6.9

Diarrhea

6.2

10.3

Malaise

6.2

5.3

Lower Respiratory Tract Infection

5.8

Dizziness

5.8

7.6

Hyperventilation

5.4

9.9

Rash

5.4

6.1

¹ Includes subjective complaints of fever.

² Includes reported decreases in pulmonary function tests or decreased lung volume on chest radiograph associated with intercurrent illness or study drug administration.

Adverse drug reactions (<5%) occurring more frequently with Tobrabact inhalation solution in the placebo-controlled studies and assessed as drug-related in ≥1% of patients:

Ear and labyrinth disorders

Tinnitus (3.1%, vs 0% for placebo)

Musculoskeletal and connective tissue disorders

Myalgia (4.7%, vs 2.7% for placebo)

Infections and infestations

Laryngitis (4.3%, vs 3.1% for placebo)

Adverse drug reactions derived from spontaneous reports

The following adverse reactions have been identified during postapproval use of Tobrabact 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 (see WARNINGS – Ototoxicity )

Skin and subcutaneous tissue disorders

Hypersensitivity, pruritus, urticaria, rash

Nervous system disorders

Aphonia, dysgeusia

Respiratory, thoracic, and mediastinal disorders

Bronchospasm (see WARNINGS – Bronchospasm ), oropharyngeal pain

Metabolism and Nutrition Disorders

Decreased appetite

OVERDOSAGE

Signs and symptoms of acute toxicity from overdosage of intravenous (IV) Tobrabact 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 Tobrabact. Tobrabact is not significantly absorbed following oral administration. Tobrabact 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.

DOSAGE AND ADMINISTRATION

The recommended dosage for both adults and pediatric patients 6 years of age and older is 1 single-use ampule (300 mg) administered BID for 28 days. Dosage is not adjusted by weight. All patients should be administered 300 mg BID. The doses should be taken as close to 12 hours apart as possible; they should not be taken less than 6 hours apart.

Tobrabact inhalation solution, USP is inhaled while the patient is sitting or standing upright and breathing normally through the mouthpiece of the nebulizer. Nose clips may help the patient breathe through the mouth.

Tobrabact inhalation solution, USP is administered BID in alternating periods of 28 days. After 28 days of therapy, patients should stop Tobrabact inhalation solution, USP therapy for the next 28 days, and then resume therapy for the next 28 day on/28 day off cycle.

Tobrabact inhalation solution, USP is supplied as a single-use ampule and is administered by inhalation, using a hand-held PARI LC PLUS Reusable Nebulizer with a DeVilbiss Pulmo-Aide compressor. Tobrabact inhalation solution, USP is not for subcutaneous, intravenous or intrathecal administration.

Usage

Tobrabact inhalation solution, USP is administered by inhalation over an approximately 15-minute period, using a hand-held PARI LC PLUS Reusable Nebulizer with a DeVilbiss Pulmo-Aide compressor. Tobrabact inhalation solution, USP should not be diluted or mixed with dornase alfa (PULMOZYME, Genentech) or other medications in the nebulizer.

During clinical studies, patients on multiple therapies were instructed to take them first, followed by Tobrabact inhalation solution, USP.

HOW SUPPLIED

Tobrabact 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

NDC 65162-914-46

Storage

Tobrabact 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, Tobrabact inhalation solution, USP pouches (opened or unopened) may be stored at room temperature (up to 25ºC/77ºF) for up to 28 days. Tobrabact 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).

Tobrabact 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 Tobrabact inhalation solution therapy on an outpatient basis using a hand-held PARI LC PLUS Reusable Nebulizer with a DeVilbiss Pulmo-Aide compressor.

Table 2: Dosing Regimens in Clinical Studies
	Cycle 1	Cycle 2		Cycle 3
	28 days	28 days	28 days	28 days	28 days	28 days
Tobrabact Inhalation Solution regimen n=258	Tobrabact Inhalation Solution 300 mg BID	No drug	Tobrabact Inhalation Solution 300 mg BID	No drug	Tobrabact Inhalation Solution 300 mg BID	No drug
Placebo regimen n=262	placebo BID	No drug	placebo BID	No drug	placebo BID	No drug

All patients received either Tobrabact 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, Tobrabact inhalation solution-treated patients experienced significant improvement in pulmonary function. Improvement was demonstrated in the Tobrabact 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, Tobrabact 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, Tobrabact 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.

Figure 2: Absolute Change From Baseline in Log₁₀ CFUs

Patients treated with Tobrabact inhalation solution were hospitalized for an average of 5.1 days compared to 8.1 days for placebo patients. Patients treated with Tobrabact 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 Tobrabact 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 Tobrabact inhalation solution therapy is not clear. However, 4 Tobrabact 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 Tobrabact 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 Tobrabact MICs. The percentage of patients with P. aeruginosa isolates with Tobrabact MICs ≥16 mcg/mL was 13% at the beginning, and 23% at the end of 6 months of the Tobrabact inhalation solution regimen.

Figure 1 Figure 2

REFERENCES

1. Neu HC. Tobrabact: an overview. [Review]. J Infect Dis 1976; Suppl 134:S3-19.

2. Weber A, Smith A, Williams-Warren J et al. Nebulizer delivery of Tobrabact to the lower respiratory tract. Pediatr Pulmonol 1994; 17 (5):331-9.

3. Bryan LE. Aminoglycoside resistance. Bryan LE, Ed. Antimicrobial drug resistance. Orlando, FL: Academic Press, 1984: 241-77.

Distributed by:

Amneal Pharmaceuticals

Glasgow, KY 42141

Rev. 10-2015-01

Tobrabact Inhalation Solution, USP

Nebulizer Solution - For Inhalation Use Only

Information for Patients

Safety Information

Tobrabact inhalation solution is in a class of antibiotics that have caused hearing loss, dizziness, kidney damage and harm to a fetus. Ringing in the ears and hoarseness were two symptoms that were seen in more patients taking Tobrabact inhalation solution than placebo in research studies. Patients with cystic fibrosis can have many symptoms. Some of these symptoms may be related to your medications. If you have new or worsening symptoms, you should tell your doctor.

Hearing: You should tell your doctor if you have ringing in the ears, dizziness, or any changes in hearing.

Kidney Damage: Inform your doctor if you have any history of kidney problems.

Pregnancy: If you want to become pregnant or are pregnant while on Tobrabact inhalation solution, you should talk with your doctor about the possibility of Tobrabact inhalation solution causing any harm.

Nursing Mothers: If you are nursing a baby, you should talk with your doctor before using Tobrabact inhalation solution.

Tobrabact Inhalation Solution Packaging

Tobrabact inhalation solution comes in a single dose, ready-to-use ampule containing 300 mg Tobrabact. Each foil pouch contains 4 ampules, for 2 days of Tobrabact inhalation solution therapy.

Dosage

Treatment Schedule

How To Administer Tobrabact Inhalation Solution for Inhalation

THIS INFORMATION IS NOT INTENDED TO REPLACE CONSULTATION WITH YOUR PHYSICIAN AND CF CARE TEAM ABOUT PROPERLY TAKING MEDICATION OR USING INHALATION EQUIPMENT.

Tobrabact inhalation solution is specifically formulated for inhalation using a PARI LC PLUS Reusable Nebulizer and a DeVilbiss^® Pulmo-Aide^® air compressor. Tobrabact inhalation solution can be taken at home, school, or at work. The following are instructions on how to use the DeVilbiss^® Pulmo-Aide^® air compressor and PARI LC PLUS Reusable Nebulizer to administer Tobrabact Inhalation Solution for Inhalation.

You will need the following supplies:

- Tobrabact inhalation solution plastic ampule (vial)

- DeVilbiss^® Pulmo-Aide^® air compressor

- PARI LC PLUS Reusable Nebulizer

- Tubing to connect the nebulizer and compressor

- Clean paper or cloth towels

- Nose clips (optional)

It is important that your nebulizer and compressor function properly before starting your Tobrabact inhalation solution therapy.

Note: Please refer to the manufacturers’ care and use instructions for important information.

Preparing Your Tobrabact Inhalation Solution for Inhalation

1. Wash your hands thoroughly with soap and water.

2a. Tobrabact inhalation solution is packaged with 4 ampules per foil pouch.

2b. Separate one ampule by gently pulling apart at the bottom tabs. Store all remaining ampules in the refrigerator as directed.

3. Lay out the contents of a PARI LC PLUS Reusable Nebulizer package on a clean, dry paper or cloth towel. You should have the following parts:

- Nebulizer Top and Bottom

(Nebulizer Cup) Assembly

- Inspiratory Valve Cap

- Mouthpiece with Valve

- Tubing

4. Remove the Nebulizer Top from the Nebulizer Cup by twisting the Nebulizer Top counter-clockwise, and then lifting. Place the Nebulizer Top on the clean paper or cloth towel. Stand the Nebulizer Cup upright on the towel.

5. Connect one end of the tubing to the compressor air outlet. The tubing should fit snugly. Plug in your compressor to an electrical outlet.

7. Squeeze all the contents of the ampule into the Nebulizer Cup.

8. Replace the Nebulizer Top. Note: In order to insert the Nebulizer Top into the Nebulizer Cup, the semi-circle halfway down the stem of the Nebulizer Top should face the Nebulizer Outlet. Turn the Nebulizer Top clockwise until securely fastened to the Nebulizer Cup.

9. Attach the Mouthpiece to the Nebulizer Outlet. Then firmly push the Inspiratory Valve Cap in place on the Nebulizer Top. Note: The Inspiratory Valve Cap will fit snugly.

10. Connect the free end of the tubing to the Air Intake on the bottom of the nebulizer, making sure to keep the nebulizer upright. Press the tubing on the Air Intake firmly.

Tobrabact Inhalation Solution Treatment

1. Turn on the compressor.

2. Check for a steady mist from the Mouthpiece. If there is no mist, check all tubing connections and confirm that the compressor is working properly.

3. Sit or stand in an upright position that will allow you to breathe normally.

5. Continue treatment until all of your Tobrabact inhalation solution is gone, and there is no longer any mist being produced. You may hear a sputtering sound when the Nebulizer Cup is empty. The entire Tobrabact inhalation solution treatment should take approximately 15 minutes to complete. Note: If you are interrupted, need to cough or rest during your Tobrabact inhalation solution treatment, turn off the compressor to save your medication. Turn the compressor back on when you are ready to resume your therapy.

6. Follow the nebulizer cleaning and disinfecting instructions after completing therapy.

Cleaning Your Nebulizer

To reduce the risk of infection, illness or injury from contamination, you must thoroughly clean all parts of the nebulizer as instructed after each treatment. Never use a nebulizer with a clogged nozzle. If the nozzle is clogged, no aerosol mist is produced which will alter the effectiveness of the treatment. Replace the nebulizer if clogging occurs.

1. Remove tubing from nebulizer and disassemble nebulizer parts.

2. Wash all parts (except tubing) with warm water and liquid dish soap.

3. Rinse thoroughly with warm water and shake out water.

4. Air dry or hand dry nebulizer parts on a clean, lint-free cloth. Reassemble nebulizer when dry, and store.

5. You can also wash all parts of the nebulizer in a dishwasher (except tubing). Place the nebulizer parts in a dishwasher basket, then place on the top rack of the dishwasher. Remove and dry the parts when the cycle is complete.

Disinfecting Your Nebulizer

Your nebulizer is for your use only - Do not share your nebulizer with other people. You must regularly disinfect the nebulizer. Failure to do so could lead to serious or fatal illness.

Clean the nebulizer as described above. Every other treatment day, disinfect the nebulizer parts (except tubing) by boiling them in water for a full 10 minutes. Dry parts on a clean, lint-free cloth.

Care and Use of Your Pulmo-Aide^® Compressor

Follow the manufacturer’s instructions for care and use of your compressor.

Filter Change:

1. DeVilbiss^® Compressor filters should be changed every six months or sooner if filter turns completely gray in color.

Compressor Cleaning:

1. With power switch in the “Off” position, unplug power cord from wall outlet.

2. Wipe outside of the compressor cabinet with a clean, damp cloth every few days to keep dust free.

Caution: Do not submerge in water; doing so will result in compressor damage.

Storage Instructions

You should store Tobrabact inhalation solution ampules in a refrigerator (2° to 8°C or 36° to 46°F). However, when you don’t have a refrigerator available (e.g., transporting your Tobrabact inhalation solution), you may store the foil pouches (opened or unopened) at room temperature (up to 25°C/77°F) for up to 28 days.

Avoid exposing Tobrabact inhalation solution ampules to intense light.

Unrefrigerated Tobrabact inhalation solution, which is normally slightly yellow, may darken with age; however, the color change does not indicate any change in the quality of the product.

Additional Information

Nebulizer: 1-800-327-8632

Compressor: 1-800-338-1988

Tobrabact Inhalation Solution: 1-877-835-5472

Distributed by:

Amneal Pharmaceuticals

Glasgow, KY 42141

Rev. 03-2015-00

Printed in USA

Pic 1 Pic 2 Pic 3 Pic 4 Pic 5 Pic 6 Pic 7 Pic 8 Pic 9 Pic 10 Pic 11 300 mg/5 mL Ampules pouch carton

Tobrabact pharmaceutical active ingredients containing related brand and generic drugs:

Tobramycin

Tobrabact available forms, composition, doses:

Solution; Ophthalmic; Tobramycin 0.3%

Tobrabact destination | category:

Human:
Aminoglycosides
Antibacterials
Ear anti-infectives and antiseptics
Eye anti-infectives and antiseptics

Tobrabact Anatomical Therapeutic Chemical codes:

J01GB01 - Tobramycin
S01AA12 - Tobramycin

Tobrabact pharmaceutical companies:

References

Dailymed."TOBRAMYCIN SOLUTION [AMNEAL PHARMACEUTICALS LLC]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
Dailymed."TOBRAMYCIN SULFATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
"tobramycin". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Tobrabact?

Depending on the reaction of the Tobrabact after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Tobrabact not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Tobrabact addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

Review

sdrugs.com conducted a study on Tobrabact, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Tobrabact consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.