monocyclic beta-lactam antibiotic

aztreonam lysine

Cayston contains aztreonam lysine (formed in situ from 75 mg aztreonam) as a sterile lyophilised powder in a vial and a 1 ml ampoule of sterile solvent (0.17% w/v sodium chloride). After reconstitution of the powder in the solvent, the nebuliser solution contains 75 mg aztreonam (as lysine).

Powder and solvent for nebuliser solution. White to off-white, lyophilised powder.

Cayston is indicated for the suppressive therapy of chronic pulmonary infections due to Pseudomonas aeruginosa in patients with cystic fibrosis (CF) aged 18 years and older.

The primary support for this indication is based on two single 28-day course placebo-controlled studies. The data to support the sustainability of the observed short term benefit over subsequent courses of treatment are limited. Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Patients should use a bronchodilator before each dose of Cayston. Short acting bronchodilators can be taken between 15 minutes and 4 hours and long acting bronchodilators can be taken between 30 minutes and 12 hours prior to each dose of Cayston.

For patients receiving several respiratory therapies, the recommended order is:

1. bronchodilator

2. dornase alfa

3. chest physiotherapy

4. other inhaled medicinal products

5. Cayston.

Adults

The recommended dose for adults is 75 mg three times per 24 hours for 28 days.

Doses should be taken at least 4 hours apart.

Multiple course, controlled efficacy data are not yet available. Additional courses, beyond the initial 28-day course, should be considered only at the discretion of the physician. If additional courses are prescribed, a minimum of 28 days without Cayston is recommended.

Renal impairment

Aztreonam is known to be excreted renally and therefore administration of Cayston in patients with renal impairment (serum creatinine > 2 times upper limit of normal) should be undertaken with caution. No dose adjustment is necessary in cases of renal impairment since the systemic concentration of aztreonam following inhaled administration of Cayston is very low (approximately 1% of the concentration resulting from a dose of 500 mg aztreonam for injection).

Hepatic impairment

There are no data on the use of Cayston in patients with severe hepatic impairment (ALT or AST greater than 5 times the upper limit of normal). No dose adjustment is necessary in cases of hepatic impairment.

Method of administration

Cayston is only for inhalation use.

Cayston should only be used with the Altera Nebuliser Handset and Altera Aerosol Head connected to an Altera Control Unit or an eFlow rapid Control Unit.

Cayston is not recommended for use in children below the age of 18 years due to insufficient data on safety and efficacy.

Clinical studies with Cayston did not include sufficient numbers of patients aged 65 years and over to determine whether they responded differently from younger patients. If Cayston is to be prescribed to the elderly then the posology is the same as for adults.

Hypersensitivity to the active substance or to any of the excipients.

Allergic reactions

If an allergic reaction to Cayston does occur, stop administration of the medicinal product and initiate treatment as appropriate. The occurrence of rash may be indicative of an allergic reaction to Cayston.

Cross-reactivity may occur in patients with a history of allergy to beta-lactam antibiotics, such as penicillins, cephalosporins, and/or carbapenems. Animal and human data demonstrate low risk of cross-reactivity between aztreonam and beta-lactam antibiotics. Aztreonam, a monobactam, is only weakly immunogenic. Caution is advised when administering Cayston to patients if they have a history of beta-lactam allergy.

The following rare and severe adverse reactions, although these have not been observed to date with Cayston, have been reported after parenteral use of other aztreonam containing products: toxic epidermal necrolysis, anaphylaxis, purpura, erythema multiforme, exfoliative dermatitis, urticaria, petechiae, pruritus, diaphoresis.

Bronchospasm

Bronchospasm is a complication associated with nebulised therapies. Patients were pre-treated with a bronchodilator before dosing with study therapy. An acute reduction of  15% in forced expiratory volume in 1 second (FEV1) following administration of study therapy was observed in 3% of patients treated with Cayston and 4% of patients receiving placebo despite pre-treatment with a bronchodilator before dosing with study therapy. Patients should use a bronchodilator before each dose of Cayston. If a case of bronchospasm is suspected to be part of an allergic reaction appropriate measures should be taken (see “allergic reactions” paragraph above).

Other precautions

In clinical studies, the efficacy and safety of Cayston were not tested in patients with FEV1 % predicted < 25% or > 75%. Patients with Burkholderia cepacia isolated from sputum within the previous 2 years were excluded from the clinical studies.

Aztreonam for injection must not be used in the Altera or other nebulisers. Aztreonam for injection has not been formulated for inhalation, and contains arginine, a substance known to cause pulmonary inflammation.

The development of antibiotic-resistant P. aeruginosa and superinfection with other pathogens represent potential risks associated with antibiotic therapy. Development of resistance during inhaled aztreonam therapy could limit treatment options during acute exacerbations. In clinical studies of Cayston, no increases of clinical significance were observed in the prevalence of antibiotic-resistant P. aeruginosa or other bacterial respiratory pathogens among patients treated three times daily with Cayston. Among patients with multidrug-resistant P. aeruginosa, improvements in respiratory symptoms and pulmonary function were observed following treatment with Cayston. An increased prevalence of Aspergillus and Candida species were observed over time in patients treated with several Cayston treatment courses. The clinical significance of this finding is unknown.

No interaction studies have been performed. However, no evidence of any drug interactions with Cayston were identified from clinical studies in which Cayston was taken concomitantly with bronchodilators, dornase alfa, pancreatic enzymes, azithromycin, tobramycin, oral steroids (less than 10 mg daily/20 mg every other day) and inhaled steroids.

a. Summary of the safety profile

The safety of Cayston was evaluated in three Phase 3 studies in 344 predominantly adult patients (77%) with chronic P. aeruginosa. In two Phase 3 placebo-controlled studies patients received Cayston 75 mg 2 times (69 patients) or 3 times a day (146 patients) for 28 days. In one Phase 3 open-label follow-on study 274 CF patients received up to nine 28-day treatment courses of Cayston 75 mg 2 times or 3 times a day.

In the two Phase 3 placebo-controlled clinical studies, the most frequently occurring adverse reactions to Cayston were cough (58%), nasal congestion (18%), wheezing (15%), pharyngolaryngeal pain (13.0%), and pyrexia (12%).

An acute reduction of  15% in FEV1 is a complication associated with nebulised therapies, including Cayston (see section 4.4).

b. Tabulated summary of adverse reactions

The adverse reactions with suspected (at least possible) relationship to treatment in the placebo-controlled studies are listed below by body system organ class and frequency.

Frequencies are defined as follows: very common ( 1/10) and common ( 1/100 to < 1/10).

1 See section c. Description of selected adverse reactions

c. Description of selected adverse reactions

Bronchospasm

Nebulised therapies, including Cayston, may be associated with bronchospasm (an acute reduction of  15% in FEV1). In placebo-controlled studies, bronchospasm was observed in 3% of patients treated with Cayston versus 4% of patients treated with placebo, despite pre-treatment with a bronchodilator before dosing with study treatment.

Allergic reactions

Rash has been reported with the use of Cayston and may be indicative of an allergic reaction to Cayston.

The following rare and severe adverse reactions, although these have not been observed to date with Cayston, have been reported after parenteral use of other aztreonam containing products: toxic epidermal necrolysis, anaphylaxis, purpura, erythema multiforme, exfoliative dermatitis, urticaria, petechiae, pruritus, diaphoresis.

Gilead Sciences Ltd

(POM)

13 March 2012