PRECAUTIONS Information for Patients NOTE: In addition to information provided below, a Patient Medication Guide providing instructions for proper use of TOBI is contained inside the package. Safety Information TOBI 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 TOBI 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 TOBI, you should talk with your doctor about the possibility of TOBI causing any harm. Nursing Mothers: If you are nursing a baby, you should talk with your doctor before using TOBI. TOBI Packaging TOBI comes in a single dose, ready-to-use ampule containing 300 mg tobramycin. Each foil pouch contains 4 ampules, for 2 days of TOBI therapy. Dosage The 300 mg dose of TOBI is the same for patients regardless of age or weight. TOBI 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 TOBI with dornase alfa (PULMOZYME®, Genentech) 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, TOBI. Treatment Schedule You should take TOBI in repeated cycles of 28 days on drug followed by 28 days off drug. You should take TOBI twice a day during the 28-day period on drug. How To Administer TOBI THIS INFORMATION IS NOT INTENDED TO REPLACE CONSULTATION WITH YOUR PHYSICIAN AND CF CARE TEAM ABOUT PROPERLY TAKING MEDICATION OR USING INHALATION EQUIPMENT. TOBI is specifically formulated for inhalation using a PARI LC PLUS™ Reusable Nebulizer and a DeVilbiss® Pulmo-Aide® air compressor. TOBI 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 TOBI. You will need the following supplies: TOBI 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 TOBI therapy. Note: Please refer to the manufacturers’ care and use instructions for important information. Preparing Your TOBI for Inhalation 1. Wash your hands thoroughly with soap and water. 2a. TOBI 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 TOBI 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. TOBI 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 TOBI 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 TOBI treatment should take approximately 15 minutes to complete. Note: If you are interrupted, need to cough or rest during your TOBI 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 TOBI ampules in a refrigerator (2°C–8°C or 36°F –46°F). However, when you don’t have a refrigerator available (e.g., transporting your TOBI), 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 TOBI ampules to intense light. Unrefrigerated TOBI, 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 TOBI 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 TOBI beyond the expiration date stamped on the ampule. Additional Information Nebulizer: 1-800-327-8632 Compressor: 1-800-338-1988 TOBI: 1-888-NOW-NOVA (1-888-669-6682) Laboratory Tests Audiograms Clinical studies of TOBI 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 TOBI, serum tobramycin concentrations are approximately 1 mcg/mL 1 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. 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 TOBI did not reveal any imbalance in the percentage of patients in the TOBI 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 TOBI, patients taking TOBI 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 TOBI 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 should not be administered concomitantly with ethacrynic acid, furosemide, urea, or intravenous mannitol. The interaction between inhaled mannitol and TOBI has not been evaluated. Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year rat inhalation toxicology study to assess carcinogenic potential of TOBI has been completed. Rats were exposed to TOBI 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 tobramycin 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, TOBI 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. Tobramycin 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 tobramycin 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 TOBI. However, subcutaneous administration of tobramycin at doses of 100 or 20 mg/kg/day during organogenesis was not teratogenic in rats or rabbits, respectively. Doses of tobramycin ≥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 tobramycin. If TOBI is used during pregnancy, or if the patient becomes pregnant while taking TOBI, the patient should be apprised of the potential hazard to the fetus. Nursing Mothers It is not known if TOBI 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 TOBI. Pediatric Use The safety and efficacy of TOBI have not been studied in pediatric patients under 6 years of age. Geriatric Use Clinical studies of TOBI 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 – Nephrotoxicity; PRECAUTIONS – Serum Concentrations).