CAYSTON Powder and solvent for nebuliser solution Ref.[6351] Active ingredients: Aztreonam

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.

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).

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.

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