aztreonam: prescribing information – dosing, contraindications, interactions, side effects

Cayston is indicated for the suppressive therapy of chronic pulmonary infections due to Pseudomonas aeruginosa in patients with cystic fibrosis (CF) aged 6 years and older.

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 taking multiple inhaled therapies, the recommended order of administration is as follows:

1.
bronchodilator
2.
mucolytics
3.
and lastly, Cayston.

Adults and children 6 years and older

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.

Cayston may be taken in repeated cycles of 28 days on therapy followed by 28 days off Cayston therapy.

The dosing in children aged 6 years and older is the same as for adults.

Elderly

Clinical studies of Cayston did not include Cayston-treated patients aged 65 years and older to determine whether they respond 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.

Paediatric population

The safety and efficacy of Cayston in children younger than 6 years of age have not been established.
Currently available data are described in section 5.1 but no recommendation on posology can be given.

Method of administration

For inhalation use.

Cayston should only be used with the Altera Nebuliser Handset and Altera Aerosol Head connected to an eBase Controller or an eTrack Controller. 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 listed in section 6.1.

Summary of the safety profile

Assessment of adverse reactions is based on experience in four Phase 3 clinical studies involving CF patients with chronic P. aeruginosa infection and post-marketing spontaneous reporting.

In the two Phase 3 placebo-controlled clinical studies where patients received Cayston for 28 days, the most frequently occurring adverse reactions to Cayston were cough (58%), nasal congestion (18%), wheezing (15%), pharyngolaryngeal pain (13.0%), pyrexia (12%) and dyspnoea (10%).

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

Tabulated summary of adverse reactions

The adverse reactions considered at least possibly related to treatment from clinical study and post- marketing experience are listed below by body system organ class and frequency.

Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1000 to < 1/100).

Respiratory, thoracic and mediastinal disorders:
Very common:
cough, nasal congestion, wheezing, pharyngolaryngeal pain, dyspnoea
Common:
bronchospasm1, chest discomfort, rhinorrhoea, haemoptysis1
Skin and subcutaneous tissue disorders:
Common:
rash1
Musculoskeletal and connective tissue disorders:
Common:
arthralgia
Uncommon:
joint swelling
General disorders and administration site conditions:
Very common:
pyrexia
Investigations:
Common:
lung function test decreased1
1 See section Description of selected adverse reactions

Description of selected adverse reactions

Bronchospasm

Nebulised therapies, including Cayston, may be associated with bronchospasm (an acute reduction of ≥ 15% in FEV1). Refer to section 4.4.

Haemoptysis

Inhalation of nebulised solutions may induce a cough reflex which could aggravate underlying conditions (see section 4.4).

Allergic reactions

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

Lung function test decreased

Lung function test decreased has been reported with use of Cayston, but was not associated with a sustained decrease in FEV1 (see section 5.1).

The following rare and severe adverse reactions have been reported after parenteral use of other aztreonam containing products: toxic epidermal necrolysis, anaphylaxis, purpura, erythema multiforme, exfoliative dermatitis, urticaria, petechiae, pruritus, diaphoresis.

Paediatric population

A total of 137 paediatric patients aged 6 to 17 years with chronic P. aeruginosa infection and FEV1 ≤ 75% predicted have received Cayston in Phase 2 and Phase 3 clinical studies (6-12 years, n = 35;
13-17 years, n = 102).

Pyrexia was observed at a higher incidence rate in paediatric patients aged 6 to 17 years compared to adults.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Allergic reactions

If an allergic reaction to aztreonam 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 aztreonam.

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 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 (an acute reduction of ≥ 15% in FEV1) is a complication associated with nebulised therapies. Bronchospasm has been reported after Cayston administration (see section 4.8). 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).

Haemoptysis

Inhalation of nebulised solutions may induce a cough reflex. The use of Cayston in paediatric CF patients has been associated with haemoptysis during treatment cycles and could have aggravated underlying conditions. Administration of Cayston in CF patients with active haemoptysis should be undertaken only if the benefits of treatment are considered to outweigh the risks of inducing further haemorrhage.

Other precautions

Efficacy has not been established in patients with FEV1 > 75% predicted. 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.

Resistance to aztreonam, other antibiotics and treatment-emergent microorganisms

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. A decrease in P. aeruginosa susceptibility to aztreonam and other beta-lactam antibiotics was observed in clinical studies of Cayston. In a 24-week active-controlled clinical study of Cayston therapy, increases were observed in the MIC90 for all P. aeruginosa isolates as well as in the percentages of patients with P. aeruginosa resistant (MIC above the parenteral breakpoint) to aztreonam, to at least 1 beta-lactam antibiotic, and to all 6 beta-lactam antibiotics tested (see section 5.1). However, decreased P. aeruginosa susceptibility was not predictive of clinical efficacy of Cayston during the study.
Among patients with multidrug-resistant P. aeruginosa, improvements in respiratory symptoms and pulmonary function were observed following treatment with Cayston. The emergence of parenteral P. aeruginosa resistance to aztreonam or other beta-lactam antibiotics may have potential consequences for the treatment of acute pulmonary exacerbations with systemic antibiotics.

An increased prevalence of methicillin-resistant Staphylococcus aureus (MRSA), methicillin-sensitive S. aureus (MSSA), Aspergillus and Candida species was observed over time in patients treated with several Cayston treatment courses. An association between persistent isolation of MRSA and worse clinical outcome has been reported in the literature. During clinical studies of Cayston, isolation of MRSA did not result in worsening of lung function.

No interaction studies have been performed. However, no evidence of any drug interactions with aztreonam 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.

Cayston has no or negligible influence on the ability to drive or use machines.

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 aztreonam overdose are anticipated.

5.
PHARMACOLOGICAL PROPERTIES

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/integron 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 may have 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 up to nine 28-day courses 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; no increases in P. aeruginosa MIC50 (± 2 dilution change) were observed,

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 inhaled aztreonamon 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 inhaled aztreonam (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 inhaled aztreonam 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.

Plasma aztreonam concentrations in paediatric patients aged 3 months to < 6 years are comparable to those observed for children > 6 years, adolescents and adults.

Distribution

The protein binding of aztreonam in plasma is approximately 77% at clinically relevant plasma concentrations.

Metabolism

Aztreonam is not extensively metabolised. The principal metabolite (SQ26,992) is inactive and is formed by opening of the beta-lactam ring due to hydrolysis. Recovery data indicate that about 10% of the dose is excreted as this metabolite.

Elimination