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Cayston

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These highlights do not include all the information needed to use CAYSTON safely and effectively. See full prescribing information for CAYSTON. CAYSTON (aztreonam for inhalation solution)Initial U.S. Approval: 1986

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 <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.

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.

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 metal ring by pulling the tab 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.

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.

A dose of CAYSTON consists of a single-use vial of sterile, lyophilized aztreonam (75 mg) reconstituted with a 1 mL ampule of sterile diluent (0.17% sodium chloride). Reconstituted CAYSTON is administered by inhalation.

CAYSTON is contraindicated in patients with a known allergy to aztreonam.

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.

Bronchospasm is a complication associated with nebulized therapies, including CAYSTON. Reduction of 15% or more in forced expiratory volume in 1 second (FEV) immediately following administration of study medication after pretreatment with a bronchodilator was observed in 3% of patients treated with CAYSTON.

In clinical trials, patients with increases in FEV during a 28-day course of CAYSTON were sometimes treated for pulmonary exacerbations when FEV declined after the treatment period. Healthcare providers should consider a patient's baseline FEV measured prior to CAYSTON therapy and the presence of other symptoms when eva luating whether post-treatment changes in FEV are caused by a pulmonary exacerbation.

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.

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 eva luated 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.

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%).

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%)

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

Pregnancy Category B

No reproductive toxicology studies have been conducted with CAYSTON. However, studies were conducted with aztreonam for injection. Aztreonam has been shown to cross the placenta and enter fetal circulation. No evidence of embryo or fetotoxicity or teratogenicity has been shown in studies with pregnant rats and rabbits. In rats receiving aztreonam for injection during late gestation and lactation, 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 far in excess of the average peak plasma levels measured in humans following CAYSTON therapy.

No adequate and well-controlled studies of aztreonam for injection or CAYSTON in pregnant women have been conducted. Because animal reproduction studies are not always predictive of human response, CAYSTON should be used during pregnancy only if clearly needed.

Following administration of aztreonam for injection, aztreonam is excreted in human milk at concentrations that are less than one percent of those determined in simultaneously obtained maternal serum. Peak plasma concentrations of aztreonam following administration of CAYSTON (75 mg) are approximately 1% of peak concentrations observed following IV aztreonam (500 mg). Therefore, use of CAYSTON during breastfeeding is unlikely to pose a risk to infants.

Patients 7 years and older were included in clinical trials with CAYSTON. Fifty-five patients under 18 years of age received CAYSTON in placebo-controlled trials. No dose adjustments were made for pediatric patients. Pyrexia was more commonly reported in pediatric patients than in adult patients. Safety and effectiveness in pediatric patients below the age of 7 years have not been established.

Clinical trials of CAYSTON did not include CAYSTON-treated patients aged 65 years of age and older to determine whether they respond differently from younger patients.

Aztreonam is known to be excreted by the kidney. Placebo-controlled clinical trials with CAYSTON excluded patients with abnormal baseline renal function (defined as serum creatinine greater than 2 times the upper limit of normal range). Given the low systemic exposure of aztreonam following administration of CAYSTON, clinically relevant accumulation of aztreonam is unlikely to occur in patients with renal impairment. Therefore, CAYSTON may be administered to patients with mild, moderate and severe renal impairment with no dosage adjustment.

No overdoses have been reported with CAYSTON in clinical trials to date. In clinical trials, 225 mg doses of CAYSTON via inhalation were associated with higher rates of drug-related respiratory adverse reactions, particularly cough. Since the peak plasma concentration of aztreonam following administration of CAYSTON (75 mg) is approximately 0.6 mcg/mL, compared to a serum concentration of 54 mcg/mL following administration of aztreonam for injection (500 mg), no systemic safety issues associated with CAYSTON overdose are anticipated.

A dose of CAYSTON consists of a 2 mL amber glass vial containing lyophilized aztreonam (75 mg) and lysine (46.7 mg), and a low-density polyethylene ampule containing 1 mL sterile diluent (0.17% sodium chloride). The reconstituted solution is for inhalation. The formulation contains no preservatives or arginine.

The active ingredient in CAYSTON is aztreonam, a monobactam antibacterial. The monobactams are structurally different from beta-lactam antibiotics (e.g., penicillins, cephalosporins, carbapenems) due to a monocyclic nucleus. This nucleus contains several side chains; sulfonic acid in the 1-position activates the nucleus, an aminothiazolyl oxime side chain in the 3-position confers specificity for aerobic Gram-negative bacteria including Pseudomonas spp., and a methyl group in the 4-position enhances beta-lactamase stability.

Aztreonam is designated chemically as (Z)-2-[[[(2-amino-4-thiazolyl)[[(2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]carbamoyl]methylene]amino]oxy]-2-methylpropionic acid. The structural formula is presented below:

CAYSTON is a white to off-white powder. CAYSTON is sterile, hygroscopic, and light sensitive. Once reconstituted with the supplied diluent, the pH range is 4.5 to 6.0.

Aztreonam is an antibacterial drug [see Clinical Pharmacology (12.4) ].

Sputum Concentrations

Sputum aztreonam concentrations exhibited considerable variability between patients receiving CAYSTON (75 mg) in clinical trials. The mean sputum concentration 10 minutes following the first dose of CAYSTON (n = 195 patients with CF) was 726 mcg/g. Mean sputum concentrations of aztreonam in patients receiving CAYSTON 3 times a day for 28 days were 984 mcg/g, 793 mcg/g, and 715 mcg/g 10 minutes after dose administration on Days 0, 14, and 28, respectively, indicating no accumulation of aztreonam in sputum.

Plasma Concentrations

Plasma aztreonam concentrations exhibited considerable variability between patients receiving CAYSTON (75 mg) in the clinical trials. The mean plasma concentration one hour following the first dose of CAYSTON (at approximately the peak plasma concentration) was 0.59 mcg/mL. Mean peak plasma concentrations in patients receiving CAYSTON 3 times a day for 28 days were 0.55 mcg/mL, 0.67 mcg/mL, and 0.65 mcg/mL on Days 0, 14, and 28, respectively, indicating no systemic accumulation of aztreonam. In contrast, the serum concentration of aztreonam following administration of aztreonam for injection (500 mg) is approximately 54 mcg/mL.

Absorption

eva luation of plasma and urine aztreonam concentrations following administration of CAYSTON indicates low systemic absorption of aztreonam. Approximately 10% of the total CAYSTON dose is excreted in the urine as unchanged drug, as compared to 60–65% following intravenous administration of aztreonam for injection.

Distribution

The protein binding of aztreonam in serum is approximately 56% and is independent of dose.

Metabolism

Following intramuscular administration of aztreonam for injection 500 mg every 8 hours for 7 days, approximately 6% of the dose was excreted as a microbiologically inactive open β-lactam ring hydrolysis product in an 8-hour urine collection on the last day of multiple dosing.

Excretion

The elimination half-life of aztreonam from plasma is approximately 2.1 hours following administration of CAYSTON to adult patients with CF, similar to what has been reported for aztreonam for injection. Approximately 10% of the total CAYSTON dose is excreted in the urine as unchanged drug. Systemically absorbed aztreonam is eliminated about equally by active tubular secretion and glomerular filtration. Following administration of a single intravenous dose of radiolabeled aztreonam for injection, about 12% of the dose was recovered in the feces.

Mechanism of Action

Aztreonam exhibits activity in vitro against Gram-negative aerobic pathogens including P. aeruginosa. Aztreonam binds to penicillin-binding proteins of susceptible bacteria, which leads to inhibition of bacterial cell wall synthesis and death of the cell. Aztreonam activity is not decreased in the presence of CF lung secretions.

Susceptibility Testing

A single sputum sample from a patient with CF may contain multiple morphotypes of P. aeruginosa and each morphotype may have a different level of in vitro susceptibility to aztreonam. There are no in vitro susceptibility test interpretive criteria for isolates of P. aeruginosa obtained from the sputum of CF patients.

Development of Resistance

No changes in the susceptibility of P. aeruginosa to aztreonam were observed following a 28-day course of CAYSTON in the placebo-controlled trials.

Cross-Resistance

No cross-resistance to other classes of antibiotics, including aminoglycosides, quinolones, and beta-lactams, was observed following a 28-day course of CAYSTON in the Phase 3 placebo-controlled trials or in an open-label follow-on trial of up to nine 28-day courses of 75 mg CAYSTON 3 times a day.

Other

No trends in the treatment-emergent isolation of other bacterial respiratory pathogens (Burkholderia cepacia, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Staphylococcus aureus) were observed in clinical trials. There was a slight increase in the isolation of Candida spp. following up to nine 28-day courses of CAYSTON therapy.

A 104-week rat inhalation toxicology study to assess the carcinogenic potential of aztreonam demonstrated no drug-related increase in the incidence of tumors. Rats were exposed to aztreonam for up to 4 hours per day. Peak plasma levels of aztreonam averaging approximately 6.8 mcg/mL were measured in rats at the highest dose level. This is approximately 12-fold higher than the average peak plasma level measured in humans following CAYSTON therapy.

Genetic toxicology studies performed in vitro demonstrated that aztreonam did not induce structural chromosome aberrations in CHO cells and did not induce mutations at the TK locus in mouse lymphoma L5178Y TK cells. Likewise, genetic toxicology studies performed in vivo did not reveal evidence of mutagenic potential.

Aztreonam did not impair the fertility of rats when administered at doses that would provide systemic exposures far in excess of peak plasma levels measured in humans following CAYSTON therapy.

CAYSTON was eva luated over a period of 28 days of treatment in a randomized, double-blind, placebo-controlled, multicenter trial that enrolled patients with CF and P. aeruginosa. This trial was designed to eva luate improvement in respiratory symptoms. Patients 7 years of age and older and with FEV of 25% to 75% predicted were enrolled. All patients received CAYSTON or placebo on an outpatient basis administered with the Altera Nebulizer System. All patients were required to take a dose of an inhaled bronchodilator (beta-agonist) prior to taking a dose of CAYSTON or placebo. Patients were receiving standard care for CF, including drugs for obstructive airway diseases.

The trial enrolled 164 patients with CF and P. aeruginosa. The mean age was 30 years, and the mean baseline FEV% predicted was 55%; 43% were females and 96% were Caucasian. These patients were randomized in a 1:1 ratio to receive either CAYSTON (75 mg) or volume-matched placebo administered by inhalation 3 times a day for 28 days. Patients were required to have been off antibiotics for at least 28 days before treatment with study drug. The primary efficacy endpoint was improvement in respiratory symptoms on the last day of treatment with CAYSTON or placebo. Respiratory symptoms were also assessed two weeks after the completion of treatment with CAYSTON or placebo. Changes in respiratory symptoms were assessed using a questionnaire that asks patients to report on symptoms like cough, wheezing, and sputum production.

Improvement in respiratory symptoms was noted for CAYSTON-treated patients relative to placebo-treated patients on the last day of drug treatment. Statistically significant improvements were seen in both adult and pediatric patients, but were substantially smaller in adult patients. Two weeks after completion of treatment, a difference in respiratory symptoms between treatment groups was still present, though the difference was smaller.

Pulmonary function, as measured by FEV (L), increased from baseline in patients treated with CAYSTON (see Figure 1). The treatment difference at Day 28 between CAYSTON-treated and placebo-treated patients for percent change in FEV (L) was statistically significant at 10% (95% CI: 6%, 14%). Improvements in FEV were comparable between adult and pediatric patients. Two weeks after completion of drug treatment, the difference in FEV between CAYSTON and placebo groups had decreased to 6% (95% CI: 2%, 9%).

Figure 1. Adjusted Mean Percent Change in FEV from Baseline to Study End (Days 0–42).

Each kit for a 28-day course of CAYSTON contains 84 sterile vials of CAYSTON and 88 ampules of sterile diluent packed in 2 cartons, each carton containing a 14-day supply. The four additional diluent ampules are provided in case of spillage.

Package Configuration	Dosage Strength	NDC No.
28-Day Kit	75 mg	61958-0901-1

CAYSTON vials and diluent ampules should be stored in the refrigerator at 2 °C to 8 °C (36 °F to 46 °F) until needed. Once removed from the refrigerator, CAYSTON and diluent may be stored at room temperature (up to 25 °C/77 °F) for up to 28 days. Do not separate the CAYSTON vials from the diluent ampules. CAYSTON should be protected from light.

Do not use CAYSTON if it has been stored at room temperature for more than 28 days. Do not use CAYSTON beyond the expiration date stamped on the vial. Do not use diluent beyond the expiration date embossed on the ampule.

CAYSTON should be used immediately upon reconstitution. Do not reconstitute more than one dose at a time.

Do not use diluent or reconstituted CAYSTON if it is cloudy or if there are particles in the solution.

See FDA-Approved Patient Labeling

Patients should be advised that CAYSTON is for inhalation use only and that CAYSTON should only be administered using the Altera Nebulizer System. Patients should be instructed only to reconstitute CAYSTON with the provided diluent and not mix other drugs with CAYSTON in the Altera Nebulizer System.

Patients should be advised to complete the full 28-day course of CAYSTON even if they are feeling better. Inform the patient that if they miss a dose, they should take all 3 daily doses as long as the doses are at least 4 hours apart.

Patients should be advised to use a bronchodilator prior to administration of CAYSTON. Patients taking several inhaled medications should be advised to use the medications in the following order of administration: bronchodilator, mucolytics, and lastly, CAYSTON.

Patients should be advised to tell their doctor if they have new or worsening symptoms. Patients who believe they are experiencing an allergic reaction to CAYSTON should be advised to contact their doctor immediately.

Patients should be counseled that antibacterial drugs including CAYSTON should only be used to treat bacterial infections. They do not treat viral infection (e.g., the common cold). When CAYSTON is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by CAYSTON or other antibacterial drugs in the future.

Manufactured by: Gilead Sciences, Inc., Foster City, CA 94404

CAYSTON is a trademark of Gilead Sciences, Inc. All other trademarks referenced herein are the property of their respective owners.

FDA-Approved Patient Labeling

Patient InformationCAYSTON (kay-stun)(aztreonam for inhalation solution)

Read this Patient Information before you start taking CAYSTON and each time you get a refill. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is CAYSTON?

CAYSTON is a prescription inhaled antibiotic. CAYSTON is used to improve breathing symptoms in people with cystic fibrosis (CF) who have Pseudomonas aeruginosa (P. aeruginosa) in their lungs.

CAYSTON is only for infections caused by bacteria. It is not for infections caused by viruses, such as the common cold.

CAYSTON is used only with the Altera Nebulizer System.

It is not known if CAYSTON is safe and effective in children under the age of 7.

Who should not take CAYSTON?

Do not take CAYSTON if you are allergic to aztreonam (AZACTAM).

What should I tell my doctor before taking CAYSTON?

Before taking CAYSTON, tell your doctor if you:

Tell your doctor about all the medicine you take, including prescription and non-prescription medicines, vitamins and herbal supplements.

Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take CAYSTON?

What are the possible side effects of CAYSTON?

CAYSTON can cause serious side effects, including:

Common side effects of CAYSTON include:

Tell your doctor if you have any new or worsening symptoms while taking CAYSTON. Tell your doctor about any side effect that bothers you or that does not go away.

These are not all the possible side effects of CAYSTON. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store CAYSTON?

Keep CAYSTON and all medicines out of the reach of children.

General information about CAYSTON

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use CAYSTON for a condition for which it was not prescribed. Do not give CAYSTON to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about CAYSTON. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about CAYSTON that is written for health professionals.

For more information, call 1-877-7CAYSTON (1-877-722-9786).

What are the ingredients in CAYSTON?

Active ingredient: aztreonam

Inactive ingredient: sodium chloride (diluent)

Patient Instructions for Use

CAYSTON (aztreonam for inhalation solution)

Be sure that you read, understand and follow the Patient Instructions for Use below for the right way to take CAYSTON. If you have any questions, ask your doctor or pharmacist.

You will need the following supplies (Figure 1):

Check to make sure that your Altera Nebulizer System works properly before starting your treatment with CAYSTON. See the manufacturer's instructions for use that comes with your Altera Nebulizer System. This should have complete information about how to put together (assemble), prepare, use, and care for your Altera Nebulizer System.

Step 1 Preparing your CAYSTON for inhalation

Step 2 Taking your CAYSTON treatment

See the manufacturer's instructions for use that comes with your Altera Nebulizer System for complete instructions on taking a treatment, and how to clean and disinfect your Altera Nebulizer Handset.

Manufactured by: Gilead Sciences, Inc., Foster City, CA 94404

CAYSTON is a trademark of Gilead Sciences, Inc. All other trademarks referenced herein are the property of their respective owners.