Cayston 75 mg powder and solvent for nebuliser solution

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).

For a full list of excipients, see section 6.1.

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 (see section 5.1). Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Posology

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 (see section 5.1). 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.

Paediatric population

Cayston is not recommended for use in children below the age of 18 years due to insufficient data on safety and efficacy (see section 5.1).

Elderly population

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.

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. For instructions on reconstitution of the medicinal product before administration, see section 6.6.

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.

Pregnancy

There are no data from the use of aztreonam in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Systemic concentration of aztreonam following inhaled administration of Cayston is low compared to a standard dose of aztreonam for injection (approximately 1% of the concentration resulting from a dose of 500 mg aztreonam for injection).

Cayston should not be used during pregnancy unless the clinical condition of the woman requires treatment with aztreonam.

Breast-feeding

Following administration of aztreonam for injection, aztreonam is excreted in human milk at very low concentrations. Systemic concentration of aztreonam following inhaled administration of Cayston is approximately 1% of the concentration resulting from a standard dose of aztreonam for injection. Therefore, and because of low oral absorption, aztreonam exposure in breast-fed infants due to mothers receiving Cayston is likely to be extremely low.

Cayston can be used during breast-feeding.

Fertility

Non-clinical data for aztreonam for injection about fertility do not indicate any adverse effects.

No studies on the effects on the ability to drive and use machines have been performed. However, based on the safety profile and mechanism of action, Cayston is not expected to adversely affect the ability to drive or use machines.

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 (see section 4.4).

Allergic reactions

Rash has been reported with the use of Cayston and may be indicative of an allergic reaction to Cayston (see section 4.4).

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.

Adverse reactions specifically associated with overdose of Cayston have not been identified. Since the plasma concentration of aztreonam following administration of Cayston (75 mg) is approximately 0.6 µg/ml, compared to serum levels of 54 µg/ml following administration of aztreonam for injection (500 mg), no safety issues associated with Cayston overdose are anticipated.

Pharmacotherapeutic group: Antibacterials for systemic use, other beta-lactam antibacterials, ATC code: J01DF01

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, followed by filamentation and cell lysis.

Mechanisms of resistance

Loss of susceptibility to aztreonam in CF patients with P. aeruginosa occurs either through selection of strains with mutations located on the chromosome or rarely through acquisition of plasmid/integrin mediated genes.

Known mechanisms of resistance to aztreonam mediated by mutation of chromosomal genes include: hyperexpression of the Class C beta-lactamase AmpC and up-regulation of the efflux pump MexAB-OprM. The known mechanism of resistance to aztreonam mediated by acquisition of genes involves acquisition of extended spectrum beta-lactam enzymes (ESBLs) that hydrolyse the four-member, nitrogen-containing ring of aztreonam.

ESBLs from Class A, B and D beta-lactamases generally have little or no activity against aztreonam. Class A beta-lactamases reported to hydrolyse aztreonam include the VEB type (primarily Southeast Asia), PER type (Turkey), and GES and IBC types (France, Greece, and S. Africa). There are rare reports of organisms with metallo-beta-lactamases (MBLs), Class B, that are resistant to aztreonam, VIM-5 (K. pneumoniae and P. aeruginosa - Turkey), VIM-6 (P. putida - Singapore) and VIM-7 (P. aeruginosa - United States), however, it is possible that these organisms were expressing multiple resistance mechanisms and thus a MBL was not responsible for the observed resistance to aztreonam. There are rare reports of Class D beta-lactamases from clinical isolates of P. aeruginosa, OXA-11 (Turkey) and OXA-45 (United States) that hydrolyse aztreonam.

Microbiology

A single sputum sample from a CF patient may contain multiple isolates of P. aeruginosa and each isolate may have a different level of in vitro susceptibility to aztreonam. The in vitro antimicrobial susceptibility test methods used for parenteral aztreonam therapy can be used to monitor the susceptibility of P. aeruginosa isolated from CF patients.

In the Phase 3 placebo-controlled studies of Cayston, local aztreonam concentrations generally exceeded aztreonam MIC values for P. aeruginosa, regardless of the level of P. aeruginosa susceptibility.

Treatment with a 28-day course of 75 mg 3 times a day Cayston therapy resulted in clinically important improvements in respiratory symptoms, pulmonary function, and sputum P. aeruginosa CFU density, regardless of whether the highest aztreonam MIC for P. aeruginosa was above or below the established susceptibility breakpoint for intravenous aztreonam administration (8 µg/ml). Based on categorical analyses of the relationship between MIC and treatment response, a susceptibility breakpoint for Cayston cannot be established. Over 6 courses of Cayston therapy, P. aeruginosa MIC₅₀ and MIC₉₀ did not change (± 2 dilution change), however there is a theoretical risk that patients treated with Cayston may develop P. aeruginosa isolates resistant to aztreonam or other beta-lactam antibiotics.

In studies of up to six 28-day courses of Cayston therapy, no increases of clinical significance have been observed in the treatment-emergent isolation of other bacterial respiratory pathogens (Stenotrophomonas maltophilia, Alcaligenes xylosoxidans, and Staphylococcus aureus).

Clinical efficacy and safety

Cayston was evaluated over a period of 28-days of treatment (one course) in two randomised, double-blind, placebo-controlled, multicentre studies (CP-AI-005 and CP-AI-007). Patients participating in these studies could subsequently receive multiple courses of Cayston in an open-label follow-on study (CP-AI-006). Entry criteria included CF baseline FEV₁ % predicted between 25% and 75% and chronic P. aeruginosa lung infection. Overall, 344 predominantly adult patients (77%) were treated in these studies. Studies were conducted using the Altera Nebuliser System.

CP-AI-007

CP-AI-007 enrolled 164 adult (predominantly) and paediatric patients randomised in a 1:1 ratio comparing inhaled Cayston 75 mg (80 patients) or placebo (84 patients) administered 3 times a day for 28 days (one course). Patients were required to have been off antipseudomonal antibiotics for at least 28 days before treatment with study drug.

Pulmonary function and respiratory symptoms significantly improved from baseline to Day 28 in patients treated with one course of Cayston.

CP-AI-005

CP-AI-005 enrolled 246 adult (predominantly) and paediatric patients. All patients were treated with Tobramycin Nebuliser Solution (TNS) 300 mg, 2 times a day in the four weeks immediately prior to receiving Cayston or placebo either 2 or 3 times a day for 28 days. Patients continued on their baseline medications, including macrolide antibiotics. Patients were randomised in a 2:2:1:1 ratio to be treated with Cayston 75 mg 2 or 3 times a day or volume-matched placebo 2 or 3 times a day for 28 days immediately following the 28-day lead-in course of open-label TNS.

Cayston therapy resulted in significant improvements in pulmonary function and respiratory symptoms at Day 28 in the 66 patients treated with one course Cayston 75 mg 3 times a day.

CP-AI-006

CP-AI-006 was an open-label follow-on study to CP-AI-005 and CP-AI-007 evaluating the safety of repeated exposure to Cayston and the effect on disease-related endpoints over multiple 28-day courses. Patients received Cayston at the same frequency (2 or 3 times a day) as they took Cayston or placebo in the randomised studies. Patients continued on their baseline medications and whenever indicated additional antibiotics were used in the majority of patients to treat exacerbations. Each 28-day course of Cayston was followed by a 28-day off drug period. Over six 28-day courses of therapy, measures of pulmonary function (FEV₁), CFQ-R respiratory symptoms scores, and log₁₀ P. aeruginosa CFUs showed a trend to improvement while the patients were on treatment compared with off treatment. However, due to the uncontrolled nature of the study and concomitant medications no conclusion can be drawn on the sustainability of the observed short term benefit over subsequent courses of treatment.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Cayston in one or more subsets of the paediatric population in cystic fibrosis patients with Pseudomonas aeruginosa pulmonary infection/colonisation (see section 4.2 for information on paediatric use).

Absorption

Sputum concentrations

Individual patients' sputum aztreonam concentrations exhibited considerable variability. For the combined Phase 3 placebo-controlled studies, ten minutes following a single dose of 75 mg Cayston on Days 0, 14, and 28, the mean sputum concentrations in 195 patients with CF were 726 µg/g, 711 µg/g, and 715 µg/g, respectively, indicating no increased accumulation of aztreonam following repeated dosing.

Plasma concentrations

Individual patients' plasma aztreonam concentrations exhibited considerable variability. One hour following a single dose of 75 mg Cayston (at approximately peak plasma concentration), the mean plasma level in patients with CF was 0.59 µg/ml. Mean peak plasma levels at Days 0, 14, and 28 of a course with 75 mg Cayston 3 times a day were 0.55 µg/ml, 0.67 µg/ml, and 0.65 µg/ml, respectively, indicating no systemic accumulation of aztreonam following 3 times a day dosing. In contrast, the serum concentration of aztreonam following administration of aztreonam for injection (500 mg) is approximately 54 µg/ml.

Elimination

The elimination half-life of aztreonam from serum is approximately 2.1 hours following inhalation administration, similar to what has been reported for aztreonam for injection. Systemically absorbed aztreonam is eliminated by both active tubular secretion and glomerular filtration.

Pharmacokinetics in special populations

Age and gender

There was no clinically relevant effect of age or sex on the pharmacokinetics of Cayston.

Renal and hepatic impairment

Pharmacokinetic studies have not been performed in patients with renal or hepatic impairment.

Pharmacokinetic properties for aztreonam for injection

Peak levels of aztreonam are achieved at about one hour after i.m. administration. After identical single i.m. or i.v. doses, the serum concentrations are comparable at 1 hour (1.5 hours from the start of i.v. infusion), with similar slopes of serum concentrations thereafter. The serum half-life of aztreonam averaged 1.7 hours in subjects with normal renal function, independent of the dose and route. In healthy subjects 60-70% of a single i.m. or i.v. dose was recovered in the urine by 8 hours, and urinary excretion was essentially complete by 12 hours.

A 104-week rat inhalation toxicology study to assess the carcinogenic potential of ascending doses of Cayston demonstrated no drug-related increase in malignant tumours.

Genotoxicity (Chromosomal aberration and mouse lymphoma mutation assay) studies with aztreonam were negative.

Fertility, teratology, perinatal and postnatal studies were conducted with aztreonam for injection in rats at daily doses up to 750 mg/kg without adverse effects. The survival rate during the lactation period was slightly reduced in the offspring of rats that received the highest dose.

Powder vial

L-Lysine

Solvent ampoule

Sodium chloride

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Powder vial: 4 years.

Solvent: 4 years.

After reconstitution, immediate use of Cayston is recommended. If not used immediately, the reconstituted solution must be stored at 2°C - 8°C and used within 8 hours. In-use storage times and conditions prior to use are the responsibility of the user.

Powder vial and solvent ampoule: Store in a refrigerator (2°C - 8°C). May be stored outside a refrigerator but below 25°C for up to 28 days.

For storage conditions of the reconstitued medicinal product, see section 6.3.

Powder vial: Type I amber glass vial with siliconised grey rubber stopper and aluminium tear off overseal.

Solvent: 1 ml low density polyethylene ampoule.

Each 28-day pack of Cayston contains 84 vials of lyophilised Cayston and 88 solvent ampoules. The four additional solvent ampoules are provided in case of spillage.

The following pack sizes are available:

• 28-day pack of Cayston

• Pack containing one 28-day pack of Cayston plus one Altera Nebuliser Handset

Not all pack sizes may be marketed.

Reconstitution

Cayston should only be reconstituted with the solvent provided. Following reconstitution, Cayston is a clear, colourless to slightly coloured solution.

It is recommended that Cayston be administered immediately after reconstitution with solvent. Cayston should not be reconstituted until a dose is ready to be administered. One glass vial containing Cayston is opened by flipping up the metal tab, the metal ring is removed by carefully pulling the tab (tweezers or small pliers may be used to remove the metal ring if necessary) and the grey rubber stopper removed. The liquid is squeezed out of one solvent ampoule into the glass vial. The vial is then gently swirled until contents have completely dissolved. The reconstituted Cayston is then poured into the Altera Nebuliser Handset and the dose administered.

Cayston is administered by inhalation over a 2 to 3 minute period, using an Altera Nebuliser System (consisting of a Cayston specific Altera Nebuliser Handset and Altera Control Unit). 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 should not be used with any other type of handset or aerosol head. Cayston should not be mixed with any other medicinal products in the Altera Nebuliser Handset. Do not put other medicinal products in the Altera Nebuliser Handset.

Do not reconstitute or mix Cayston with any other solvent or medicinal product. Do not reconstitute more than one dose at a time. Any unused product or waste material should be disposed of in accordance with local requirements.

Gilead Sciences International Limited

Granta Park

Abington

Cambridge

CB21 6GT

United Kingdom

EU/1/09/543/001

EU/1/09/543/002

Date of first authorisation: 21 September 2009

Date of latest renewal: 21 September 2010

03/2012

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu