Cayston

1 INDICATIONS AND USAGE CAYSTON ® is indicated to improve respiratory symptoms in cystic fibrosis (CF) patients with Pseudomonas aeruginosa . Safety and effectiveness have not been established in pediatric patients below the age of 7 years, patients with FEV 1 <25% or >75% predicted, or patients colonized with Burkholderia cepacia [see Clinical Studies (14) ]. To reduce the development of drug-resistant bacteria and maintain the effectiveness of CAYSTON and other antibacterial drugs, CAYSTON should be used only to treat patients with CF known to have Pseudomonas aeruginosa in the lungs. CAYSTON is a monobactam antibacterial indicated to improve respiratory symptoms in cystic fibrosis (CF) patients with Pseudomonas aeruginosa . Safety and effectiveness have not been established in pediatric patients below the age of 7 years, patients with FEV 1 <25% or >75% predicted, or patients colonized with Burkholderia cepacia . ( 1 )

2 DOSAGE AND ADMINISTRATION Administer one dose (one single use vial and one ampule of diluent) 3 times a day for 28 days. ( 2.1 ) Use dose immediately after reconstitution. ( 2.2 ) Administer only with the Altera ® Nebulizer System. Do not administer with any other type of nebulizer. ( 2.3 ) 2.1 Dosing Information The recommended dose of CAYSTON for both adults and pediatric patients 7 years of age and older is one single-use vial (75 mg of aztreonam) reconstituted with 1 mL of sterile diluent administered 3 times a day for a 28-day course (followed by 28 days off CAYSTON therapy). Dosage is not based on weight or adjusted for age. Doses should be taken at least 4 hours apart. CAYSTON is administered by inhalation using an Altera ® Nebulizer System. Patients should use a bronchodilator before administration of CAYSTON. 2.2 Instructions for CAYSTON Reconstitution CAYSTON should be administered immediately after reconstitution. Do not reconstitute CAYSTON until ready to administer a dose. Take one amber glass vial containing CAYSTON and one diluent ampule from the carton. To open the glass vial, carefully remove the blue cap and metal ring and remove the gray rubber stopper. Twist the tip off the diluent ampule and squeeze the liquid into the glass vial. Replace the rubber stopper, then gently swirl the vial until contents have completely dissolved. The empty vial, stopper, and diluent ampule should be disposed of properly upon completion of dosing. 2.3 Instructions for CAYSTON Administration CAYSTON is administered by inhalation using an Altera Nebulizer System. CAYSTON should not be administered with any other nebulizer. CAYSTON should not be mixed with any other drugs in the Altera Nebulizer Handset. CAYSTON is not for intravenous or intramuscular administration. Patients should use a bronchodilator before administration of CAYSTON. Short-acting bronchodilators can be taken between 15 minutes and 4 hours prior to each dose of CAYSTON. Alternatively, long-acting bronchodilators can be taken between 30 minutes and 12 hours prior to administration of CAYSTON. For patients taking multiple inhaled therapies, the recommended order of administration is as follows: bronchodilator, mucolytics, and lastly, CAYSTON. To administer CAYSTON, pour the reconstituted solution into the handset of the nebulizer system. Turn the unit on. Place the mouthpiece of the handset in your mouth and breathe normally only through your mouth. Administration typically takes between 2 and 3 minutes. Further patient instructions on how to administer CAYSTON are provided in the FDA-approved patient labeling. Instructions on testing nebulizer functionality and cleaning the handset are provided in the Instructions for Use included with the nebulizer system.

4 CONTRAINDICATIONS CAYSTON is contraindicated in patients with a known allergy to aztreonam. Contraindicated in patients with a known allergy to aztreonam. ( 4 )

5 WARNINGS AND PRECAUTIONS Allergic reaction to CAYSTON was seen in clinical trials. Stop treatment if an allergic reaction occurs. Use caution when CAYSTON is administered to patients with a known allergic reaction to beta-lactams. ( 5.1 ) Bronchospasm has been reported with CAYSTON. Stop treatment if chest tightness develops during nebulizer use. ( 5.2 ) 5.1 Allergic Reactions Severe allergic reactions have been reported following administration of aztreonam for injection to patients with no known history of exposure to aztreonam. In addition, allergic reaction with facial rash, facial swelling, and throat tightness was reported with CAYSTON in clinical trials. If an allergic reaction to CAYSTON occurs, stop administration of CAYSTON and initiate treatment as appropriate. Caution is advised when administering CAYSTON to patients if they have a history of beta-lactam allergy, although patients with a known beta-lactam allergy have received CAYSTON in clinical trials and no severe allergic reactions were reported. A history of allergy to beta-lactam antibiotics, such as penicillins, cephalosporins, and/or carbapenems, may be a risk factor, since cross-reactivity may occur. 5.2 Bronchospasm Bronchospasm is a complication associated with nebulized therapies, including CAYSTON. Reduction of 15% or more in forced expiratory volume in 1 second (FEV 1 ) immediately following administration of study medication after pretreatment with a bronchodilator was observed in 3% of patients treated with CAYSTON. 5.3 Decreases in FEV 1 After 28-Day Treatment Cycle In clinical trials, patients with increases in FEV 1 during a 28-day course of CAYSTON were sometimes treated for pulmonary exacerbations when FEV 1 declined after the treatment period. Healthcare providers should consider a patient's baseline FEV 1 measured prior to CAYSTON therapy and the presence of other symptoms when evaluating whether post-treatment changes in FEV 1 are caused by a pulmonary exacerbation. 5.4 Development of Drug-Resistant Bacteria Prescribing CAYSTON in the absence of known Pseudomonas aeruginosa infection in patients with CF is unlikely to provide benefit and increases the risk of development of drug-resistant bacteria.

7 DRUG INTERACTIONS No formal clinical studies of drug interactions with CAYSTON have been conducted.

6 ADVERSE REACTIONS Common adverse reactions (more than 5%) occurring more frequently in CAYSTON patients are cough, nasal congestion, wheezing, pharyngolaryngeal pain, pyrexia, chest discomfort, abdominal pain and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD5, option 3 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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 safety of CAYSTON was evaluated in 344 patients from two placebo-controlled trials and one open-label follow-on trial. In controlled trials, 146 patients with CF received 75 mg CAYSTON 3 times a day for 28 days. Table 1 displays adverse reactions reported in more than 5% of patients treated with CAYSTON 3 times a day in placebo-controlled trials. The listed adverse reactions occurred more frequently in CAYSTON-treated patients than in placebo-treated patients. Table 1 Adverse Reactions Reported in more than 5% of Patients Treated with CAYSTON in the Placebo-Controlled Trials Event (Preferred Term) Placebo (N=160) n (%) CAYSTON 75 mg 3 times a day (N=146) n (%) Cough 82 (51%) 79 (54%) Nasal congestion 19 (12%) 23 (16%) Wheezing 16 (10%) 23 (16%) Pharyngolaryngeal pain 17 (11%) 18 (12%) Pyrexia 9 (6%) 19 (13%) Chest discomfort 10 (6%) 11 (8%) Abdominal Pain 8 (5%) 10 (7%) Vomiting 7 (4%) 9 (6%) Adverse reactions that occurred in less than 5% of patients treated with CAYSTON were bronchospasm (3%) [see Warnings and Precautions (5.2) ] and rash (2%). 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following possible adverse reactions have been identified during post-approval use of CAYSTON. Because these events have been reported voluntarily from a population of unknown size, estimates of frequency cannot be made. MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Arthralgia, joint swelling

8.1 Pregnancy Risk Summary Available data on CAYSTON use in pregnant women is insufficient to inform a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes; however, systemic absorption of aztreonam following inhaled administration is expected to be minimal [see Clinical Pharmacology (12.3) ]. There are risks to the mother associated with cystic fibrosis in pregnancy (see Clinical Considerations ) . In animal reproduction studies with aztreonam for injection administered parenterally to pregnant rats and rabbits during organogenesis, there was no evidence of developmental toxicity. A peri/postnatal study in rats revealed no drug-induced changes in maternal, fetal, or neonatal parameters. The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Cystic fibrosis may increase the risk for preterm delivery. Data Animal Data No reproductive toxicity studies have been conducted with CAYSTON. However, studies were conducted with aztreonam for injection. No evidence of developmental toxicity has been shown in studies with pregnant rats and rabbits that received parenteral doses of aztreonam during organogenesis of up to 1800 and 1200 mg/kg/day, respectively. In rats receiving aztreonam for injection during late gestation and lactation at up to 1800 mg/kg/day, no drug induced changes in maternal, fetal or neonatal parameters were observed. These animal reproduction and developmental toxicity studies used parenteral routes of administration that would provide systemic exposures significantly greater than the average peak plasma levels measured in humans following CAYSTON therapy.