Aztreonam with L-arginine

The treatment of the following infections caused by susceptible aerobic Gram-negative micro-organisms:

Urinary tract infections: including pyelonephritis and cystitis (initial and recurrent) and asymptomatic bacteriuria, including those due to pathogens resistant to the aminoglycosides, cephalosporins or penicillins.

Gonorrhoea: acute uncomplicated urogenital or anorectal infections due to beta-lactamase producing or non-producing strains of N. gonorrhoeae.

Lower respiratory tract infections: including pneumonia, bronchitis and lung infections in patients with cystic fibrosis.

Bacteraemia/septicaemia.

Meningitis caused by Haemophilus influenzae or Neisseria meningitidis. Since Aztreonam with L-arginine provides only Gram negative cover, it should not be given alone as initial blind therapy, but may be used with an antibiotic active against Gram positive organisms until the results of sensitivity tests are known.

Bone and joint infections.

Skin and soft tissue infections: including those associated with postoperative wounds, ulcers and burns.

Intra-abdominal infections: peritonitis.

Gynaecological infections: pelvic inflammatory disease, endometritis and pelvic cellulitis.

Aztreonam with L-arginine is indicated for adjunctive therapy to surgery in the management of infections caused by susceptible organisms, including abscesses, infections complicating hollow viscus perforations, cutaneous infections and infections of serous surfaces.

Bacteriological studies to determine the causative organism(s) and their sensitivity to aztreonam should be performed. Therapy may be instituted prior to receiving the results of sensitivity tests.

In patients at risk of infections due to non-susceptible pathogens, additional antibiotic therapy should be initiated concurrently with Aztreonam with L-arginine to provide broad-spectrum coverage before identification and susceptibility testing results of the causative organism(s) are known. Based on these results, appropriate antibiotic therapy should be continued.

Patients with serious Pseudomonas infections may benefit from concurrent use of Aztreonam with L-arginine and an aminoglycoside because of their synergistic action. If such concurrent therapy is considered in these patients, susceptibility tests should be performed in vitro to determine the activity in combination. The usual monitoring of serum levels and renal function during aminoglycoside therapy applies.

Aztreonam with L-arginine 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.

Intramuscular or intravenous injection, or intravenous infusion.

Aztreonam with L-arginine is given by deep injection into a large muscle mass, such as the upper quadrant of the gluteus maximus or the lateral part of the thigh.

Adults:

The dose range of Aztreonam with L-arginine is 1 to 8 g daily in equally divided doses. The usual dose is 3 to 4 g daily. The maximum recommended dose is 8 g daily. The dosage and route of administration should be determined by the susceptibility of the causative organisms, severity of infection and the condition of the patient.

Dosage Guide: Adults (see table below)

The intravenous route is recommended for patients requiring single doses greater than 1 g, or those with bacterial septicaemia, localised parenchymal abscess (e.g. intra-abdominal abscess), peritonitis, meningitis or other severe systemic or life-threatening infections.

Elderly:

Renal status is a major determinant of dosage in the elderly; these patients in particular may have diminished renal function. Serum creatinine may not be an accurate determinant of renal status. Therefore, as with all antibiotics eliminated by the kidneys, estimates of creatinine clearance should be obtained, and appropriate dosage modifications made if necessary.

Elderly patients normally have a creatinine clearance in excess of 30 mL/min and therefore would receive the normal recommended dose. If renal function is below this level, the dosage schedule should be adjusted (see Renal Impairment).

Renal Impairment:

Prolonged serum levels of aztreonam may occur in patients with transient or persistent renal insufficiency. Therefore, after an initial usual dose, the dosage of aztreonam should be halved in patients with estimated creatinine clearances between 10 and 30 mL/min/1.73 m².

In patients with severe renal failure (creatinine clearance less than 10 mL/min/1.73 m²), such as those supported by hemodialysis, the usual dose should be given initially. The maintenance dose should be one-fourth of the usual initial dose given at the usual fixed interval of 6, 8 or 12 hours. For serious or life-threatening infections, in addition to the maintenance doses, one-eighth of the initial dose should be given after each hemodialysis session.

Hepatic impairment:

A dose reduction of 20-25% is recommended for long-term treatment of patients with chronic liver disease with cirrhosis, especially in cases of alcoholic cirrhosis and when renal function is also impaired.

Paediatric:

The usual dosage for patients older than one week is 30 mg/kg/dose every 6 or 8 hours. For severe infections in patients 2 years of age or older, 50 mg/kg/dose every 6 or 8 hours is recommended. The recommended dose for all patients in the treatment of infections due to P. aeruginosa is 50 mg/kg every six to eight hours.

The maximum daily paediatric dose should not exceed the maximum recommended dose for adults.

Dosage information is not yet available for new-borns less than 1 week old.

Posology

Patients should use a bronchodilator before each dose of Aztreonam with L-arginine. 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 Aztreonam with L-arginine.

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

1. bronchodilator

2. mucolytics

3. and lastly, Aztreonam with L-arginine.

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.

Aztreonam with L-arginine may be taken in repeated cycles of 28 days on therapy followed by 28 days off Aztreonam with L-arginine therapy.

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

Elderly

Clinical studies of Aztreonam with L-arginine did not include Aztreonam with L-arginine-treated patients aged 65 years and older to determine whether they respond differently from younger patients. If Aztreonam with L-arginine 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 Aztreonam with L-arginine 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 Aztreonam with L-arginine 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 Aztreonam with L-arginine 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 Aztreonam with L-arginine in children younger than 6 years of age have not been established.

Method of administration

For inhalation use.

Aztreonam with L-arginine should only be used with the Altera Nebuliser Handset and Altera Aerosol Head connected to an eBase Controller or an eFlow rapid Control Unit.

Allergic reactions

Antibiotics, like other drugs, should be given with caution to any patients with a history of allergic reaction to structurally related compounds. If an allergic reaction occurs, discontinue the drug and institute supportive treatments as appropriate. Serious hypersensitivity reactions may require epinephrine and other emergency measures. Specific studies have not shown significant cross-reactivity between Aztreonam with L-arginine and antibodies to penicillins or cephalosporins. The incidence of hypersensitivity to Aztreonam with L-arginine in clinical trials has been low but caution should be exercised in patients with a history of hypersensitivity to beta-lactam antibiotics until further experience is gained.

Renal/hepatic impairment

In patients with impaired hepatic or renal function, appropriate monitoring is recommended during therapy.

Serious blood/skin disorders

Serious blood disorders (incl. pancytopenia) and skin disorders (incl. toxic epidermal necrolysis) have been reported with the use of aztreonam. In case of serious hemogram and skin changes, it is recommended to stop aztreonam.

Convulsions

Convulsions have rarely been reported during treatment with beta-lactams, including aztreonam.

Clostridium difficile associated diarrhoea

Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including Aztreonam with L-arginine, and may range in severity from mild diarrhoea to fatal colitis. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Medication that inhibits intestinal peristalsis should not be given.

Concurrent therapy with other antimicrobial agents and Aztreonam with L-arginine is recommended as initial therapy in patients who are at risk of having an infection due to pathogens that are not susceptible to aztreonam.

As with other antibiotics, in the treatment of acute pulmonary exacerbations in patients with cystic fibrosis, while clinical improvement is usually noted, lasting bacterial eradications may not be achieved.

Overgrowth of non-susceptible organisms

Therapy with Aztreonam with L-arginine may result in overgrowth of non-susceptible organisms, including gram-positive organisms and fungi. Should superinfection occur during therapy, appropriate measures should be taken. In comparative studies, the number of patients treated for superinfections was similar to that of the control drugs used.

Prolongation of prothrombin time / increased activity of oral anticoagulants

Prolongation of prothrombin time has been reported rarely in patients receiving aztreonam. Additionally, numerous cases of increased activity of oral anticoagulants have been reported in patients receiving antibiotics, including beta-lactams. Severe infection or inflammation, and the age and general condition of the patient appear to be risk factors. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.

Concomitant use with aminoglycosides

If an aminoglycoside is used concurrently with aztreonam, especially if high dosages of the former are used or if therapy is prolonged, renal function should be monitored because of the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics.

Paediatric population

Data on safety and effectiveness in neonates younger than one week are limited; use in this population needs to be carefully assessed.

Arginine

Aztreonam for injection contains arginine. Studies in low birth weight infants have demonstrated that arginine administered in the aztreonam formulation may result in increases in serum arginine, insulin, and indirect bilirubin. The consequences of exposure to this amino acid during treatment of neonates have not been fully ascertained.

Interference with serological testing

A positive direct or indirect Coombs test may develop during treatment with 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 Aztreonam with L-arginine 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 Aztreonam with L-arginine administration. Patients should use a bronchodilator before each dose of Aztreonam with L-arginine. 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 Aztreonam with L-arginine in paediatric CF patients has been associated with haemoptysis during treatment cycles and could have aggravated underlying conditions. Administration of Aztreonam with L-arginine 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 Aztreonam with L-arginine. In a 24-week active-controlled clinical study of Aztreonam with L-arginine 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. However, decreased P. aeruginosa susceptibility was not predictive of clinical efficacy of Aztreonam with L-arginine during the study. Among patients with multidrug-resistant P. aeruginosa, improvements in respiratory symptoms and pulmonary function were observed following treatment with Aztreonam with L-arginine. 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 Aztreonam with L-arginine treatment courses. An association between persistent isolation of MRSA and worse clinical outcome has been reported in the literature. During clinical studies of Aztreonam with L-arginine, isolation of MRSA did not result in worsening of lung function.

No studies on the effects on the ability to drive and use machines have been performed.

Aztreonam with L-arginine has no or negligible influence on the ability to drive or use machines.

The list of undesirable effects shown below is presented by system organ class, MedDRA preferred term, and frequency. Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1000 to <1/100); rare (>1/10,000 to <1/1000); very rare (>1/10,000); Not known (cannot be estimated from the available data).

*Usually reversing during therapy and without overt signs or symptoms of hepatobiliary dysfunction.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

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 Aztreonam with L-arginine for 28 days, the most frequently occurring adverse reactions to Aztreonam with L-arginine 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 Aztreonam with L-arginine.

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 c. Description of selected adverse reactions

Description of selected adverse reactions

Bronchospasm

Nebulised therapies, including Aztreonam with L-arginine, may be associated with bronchospasm (an acute reduction of > 15% in FEV₁).

Haemoptysis

Inhalation of nebulised solutions may induce a cough reflex which could aggravate underlying conditions.

Allergic reactions

Rash has been reported with the use of Aztreonam with L-arginine and may be indicative of an allergic reaction to aztreonam.

Lung function test decreased

Lung function test decreased has been reported with use of Aztreonam with L-arginine, but was not associated with a sustained decrease in FEV₁.

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 Aztreonam with L-arginine 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:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

or search for MHRA Yellow Card in the Google Play or Apple App Store

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

There have been no reported cases of overdosage. If necessary, aztreonam may be cleared from the serum by hemodialysis and/or peritoneal dialysis. Aztreonam has been shown to be cleared from the serum by continuous arteriovenous hemofiltration.

Adverse reactions specifically associated with overdose of Aztreonam with L-arginine have not been identified. Since the plasma concentration of aztreonam following administration of Aztreonam with L-arginine (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.

Pharmacotherapeutic group: Anti-infectives for systemic use, ATC code: J01DF01

Aztreonam is a monocyclic beta-lactam antibiotic with potent bactericidal activity against a wide spectrum of Gram-negative aerobic pathogens.

Unlike the majority of beta-lactam antibiotics, it is not an inducer in vitro of beta-lactamase activity. Aztreonam is usually active in vitro against those resistant aerobic organisms whose beta-lactamases hydrolyse other antibiotics.

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 Aztreonam with L-arginine, 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 Aztreonam with L-arginine 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, whereas MIC₉₀ increased intermittently to 4 times the initial MIC. In a 24-week active-controlled study of Aztreonam with L-arginine therapy, no increases in P. aeruginosa MIC₅₀ (± 2 dilution change) were observed, whereas MIC₉₀ increased to 4 times the initial MIC. At the end of the study, the percentage of patients with aztreonam MIC for P. aeruginosa above the parenteral breakpoint (> 8 µg/ml) increased from 34% at baseline to 49%, the percentage of patients with P. aeruginosa resistant to at least 1 beta-lactam antibiotic increased from 56% at baseline to 67%, and the percentage of patients with P. aeruginosa resistant to all 6 beta-lactam antibiotics tested increased from 13% at baseline to 18%. There is a risk that P. aeruginosa isolates may develop resistance to aztreonam or other beta-lactam antibiotics in patients treated with Aztreonam with L-arginine. The emergence of parenteral P. aeruginosa resistance to aztreonam and other beta-lactam antibiotics may have potential consequences for the treatment of acute pulmonary exacerbations with systemic antibiotics. However, similar improvements in lung function were seen after treatment with Aztreonam with L-arginine among patients with aztreonam susceptible or resistant P. aeruginosa isolates.

In studies of up to nine 28-day courses of Aztreonam with L-arginine therapy, no increases of clinical significance were observed in the treatment-emergent isolation of other gram-negative bacterial respiratory pathogens (Burkholderia species, Stenotrophomonas maltophilia and Alcaligenes species). During the 6-month randomised phase of study GS-US-205-0110, treatment-emergent isolation of MSSA and MRSA was observed more commonly among aztreonam-treated patients than Tobramycin Nebuliser Solution (TNS)-treated patients. The majority of the treatment-emergent isolations were intermittent. Treatment-emergent persistent isolation (defined as absent at screening/baseline then present at 3 or more subsequent consecutive visits) of MSSA occurred in 6% of aztreonam-treated patients compared to 3% of TNS-treated patients. Treatment-emergent intermittent isolation of MRSA occurred in 7% of aztreonam-treated patients compared to 1% of TNS-treated patients and treatment-emergent persistent isolation of MRSA occurred in 3% of aztreonam-treated patients compared to no TNS-treated patients. An association between persistent isolation of MRSA and more severe disease and increased mortality has been reported in the literature. During clinical studies of Aztreonam with L-arginine, isolation of MRSA did not result in worsening of lung function.

Clinical efficacy and safety

Aztreonam with L-arginine was compared to TNS over three 28-day courses of treatment in a randomised, active-controlled, multicenter study (GS-US-205-0110). Patients participating in this study in Europe who completed at least 1 course of Aztreonam with L-arginine or TNS during the randomised phase could subsequently receive up to three 28-day courses of Aztreonam with L-arginine in an open-label extension phase. Entry criteria included CF, FEV₁ ≤ 75% predicted, stable pulmonary disease, a recent positive sputum culture for P. aeruginosa, and previous treatment with aerosolised antibiotics without demonstration of drug intolerance.

Aztreonam with L-arginine 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 Aztreonam with L-arginine in an open-label follow-on study (CP-AI-006). Entry criteria included CF, baseline FEV₁ between 25% and 75% predicted, and chronic P. aeruginosa lung infection.

Overall, 539 patients (78% adults) were treated in these studies. Studies were conducted using the Altera Nebuliser System to administer Aztreonam with L-arginine.

GS-US-205-0110

In GS-US-205-0110, 268 patients with CF and chronic P. aeruginosa lung infection were randomised and received Aztreonam with L-arginine (n = 136) or TNS (n = 132). Fifty-nine paediatric patients aged 6 to 17 years were included in the study. Patients were randomised in a 1:1 ratio to receive either aztreonam (75 mg) administered by inhalation 3 times a day or TNS (300 mg) administered 2 times a day. Treatments were administered for three cycles of 28 days on therapy followed by 28 days off therapy. The co-primary endpoints were non-inferiority of Aztreonam with L-arginine to TNS in relative change from baseline to Day 28 in FEV₁ % predicted and superiority of Aztreonam with L-arginine to TNS in actual change from baseline in FEV₁ % predicted across 3 treatment courses (the average of the actual change in FEV₁ % predicted observed at the end of each treatment course).

The adjusted mean percent change from baseline to Day 28 in FEV₁ % predicted was 8.35 and 0.55 in the Aztreonam with L-arginine and TNS groups, respectively (treatment difference: 7.80; p = 0.0001; 95% CI: 3.86, 11.73). The adjusted mean actual change from baseline in FEV₁ % predicted across 3 treatment courses was 2.05 and -0.66 in the Aztreonam with L-arginine and TNS groups, respectively (treatment difference: 2.70; p = 0.0023; 95% CI: 0.98, 4.43). Patients treated with aztreonamexperienced a longer time to need for i.v. antipseudomonal antibiotics related to respiratory events compared to TNS-treated patients (p = 0.0025). The Kaplan-Meier estimates for this event rate at week 24 were 36% in aztreonam-treated patients and 54% in TNS-treated patients. Additionally, aztreonam-treated patients had fewer hospitalisations due to respiratory events (40 versus 58, p = 0.044) and fewer respiratory events requiring the use of i.v. or inhaled antipseudomonal antibiotics (84 versus 121, p = 0.004) than TNS-treated patients. Aztreonam-treated patients also demonstrated larger mean improvements in CFQ-R respiratory symptoms scores compared to TNS-treated patients across 3 treatment courses (6.30 versus 2.17, p = 0.019).

In the limited subgroup of patients who received inhaled tobramycin for less than 84 days in the previous 12 months (n = 40), lung function improvements at Day 28 and across three 28-day treatment courses were numerically smaller among aztreonam-treated patients than TNS-treated patients.

CP-AI-007

CP-AI-007 enrolled 164 adult (predominantly) and paediatric patients randomised in a 1:1 ratio comparing Aztreonam with L-arginine 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 Aztreonam with L-arginine.

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 Aztreonam with L-arginine 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 aztreonam 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.

Aztreonamtherapy resulted in significant improvements in pulmonary function and respiratory symptoms at Day 28 in the 66 patients treated with one course Aztreonam with L-arginine 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 aztreonamand the effect on disease-related endpoints over multiple 28-day courses. Patients received Aztreonam with L-arginine at the same frequency (2 or 3 times a day) as they took Aztreonam with L-arginine 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 Aztreonam with L-arginine was followed by a 28-day off drug period. Over nine 28-day courses of therapy, measures of pulmonary function (FEV₁), CFQ-R respiratory symptoms scores, and P. aeruginosa sputum density 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

A total of 137 paediatric patients aged 6 to 17 years with chronic P. aeruginosa infection and FEV₁ ≤ 75% predicted have received Aztreonam with L-arginine in Phase 2 and Phase 3 clinical studies. Paediatric patients had clinical improvements with aztreonamas determined by an increase in FEV₁, improvement in CFQ-R respiratory symptoms scores and decline in P. aeruginosa sputum density. Aztreonam with L-arginine is indicated for use in paediatric patients aged 6 years and older with repeated cycles of 28 days on therapy followed by 28 days off Aztreonam with L-arginine therapy based on the above clinical experience.

In a Phase 2 open-label study (GS-US-205-0162), 105 paediatric patients aged 3 months to < 18 years (24 patients aged 3 months to < 2 years; 25 patients aged 2 to < 6 years; 56 patients aged 6 to < 18 years) with CF and documented initial/new onset P. aeruginosa infection/colonisation received Aztreonam with L-arginine 3 times a day for a single course of 28 days.

Of the 101 patients, all having a positive cultures for P. aeruginosa within 30 days of study enrolment, of whom 56 (55.4%) were free of P. aeruginosa at baseline who completed a 28-day treatment course 89.1% (n = 90) were free of P. aeruginosa at the end of treatment (Day 28) and 75.2% (n = 76) were free of P. aeruginosa 1 month after the end of treatment (Day 56). A total of 79 patients who completed a 28-day treatment course and who did not receive an additional antipseudomonal antibiotic during the treatment period were evaluable 6 months after the end of treatment; of these, 58.2% (n = 46) remained free of P. aeruginosa throughout this time period.

The European Medicines Agency has deferred the obligation to submit the results of studies with Aztreonam with L-arginine 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).

Single 30-minute i.v. infusions of 0.5 g, 1.0 g and 2.0 g in healthy volunteers produced peak serum levels of 54, 90 and 204 mg/L, and single 3-minute i.v. injections of the same doses produced peak levels of 58, 125 and 242 mg/L. 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.

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

The elimination half-life of aztreonam from serum is approximately 2.1 hours for inhalation administration, similar to what has been reported for aztreonam for injection. Approximately 10% of the total inhaled aztreonamdose is excreted in the urine as unchanged drug, as compared to 60-65% following intravenous administration of aztreonam for injection. Systemically absorbed aztreonam is eliminated about equally by 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 aztreonam.

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.

Paediatric population

The Phase 2 and 3 placebo-controlled, registrational studies permitted comparison of plasma concentrations 1 hour post dose of Aztreonam with L-arginine by age (6 to 12 years, 13 to 17 years, and > 18 years). Data from these studies revealed minimal differences in mean plasma aztreonam concentrations between age groups in patients receiving Aztreonam with L-arginine 3 times a day.

Pooled sputum concentration data from the Phase 2 and 3 registrational studies revealed some evidence of lower mean sputum concentrations in patients aged 13 to 17 years following one dose of Aztreonam with L-arginine 3 times a day. However, all mean sputum concentration values were associated with relatively large standard deviations.

Aztreonam was well tolerated in a comprehensive series of preclinical toxicity and safety studies.

A 104-week rat inhalation toxicology study to assess the carcinogenic potential of ascending doses of aztreonamdemonstrated 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 i.v. 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.

Aztreonam with L-arginine should not be physically mixed with any other drug, antibiotic or diluent, except those listed in the Posology and Method of Administration section under Reconstitution for Intravenous infusion.

With intermittent infusion of Aztreonam with L-arginine and another drug via a common delivery tube, the tube should be flushed before and after delivery of Aztreonam with L-arginine with any appropriate infusion solution compatible with both drug solutions. The drugs should not be delivered simultaneously.

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

Reconstitution

Aztreonam with L-arginine for Injection 1 g or 2 g Vial are supplied in 15 mL vials.

Upon the addition of the diluent the contents should be shaken immediately and vigorously. Vials of reconstituted Aztreonam with L-arginine are not intended for multi-dose use, and any unused solution from a single dose must be discarded. Depending on the type and amount of diluent, the pH ranges from 4.5 to 7.5, and the colour may vary from colourless to light straw-yellow, which may develop a slight pink tint on standing; however this does not affect the potency.

For intramuscular injection: For each gram of aztreonam add at least 3 mL Water for Injections Ph. Eur. or 0.9% Sodium Chloride Injection B.P. and shake well.

For intravenous injection: To the contents of the vial add 6 to 10 mL of Water for Injections Ph. Eur. and shake well. Slowly inject directly into the vein over a period of 3 to 5 minutes.

For intravenous infusion:

Vials: For each gram of aztreonam add at least 3 mL of Water for Injections Ph. Eur. and shake well.

Dilute this initial solution with an appropriate infusion solution to a final concentration less than 2% w/v (at least 50 mL solution per gram of aztreonam). The infusion should be administered over 20-60 minutes.

Appropriate infusion solutions include:

0.9% Sodium Chloride Injection B.P.

5% Glucose Intravenous Infusion B.P.

5% or 10% Mannitol Intravenous Infusion B.P.

Sodium Lactate Intravenous Infusion B.P.

0.9%, 0.45% or 0.2% Sodium Chloride and 5% Glucose Intravenous Infusion B.P.

Compound Sodium Chloride Injection B.P.C. 1959 (Ringer's Solution for Injection)

Compound Sodium Lactate Intravenous Infusion B.P. (Hartmann's Solution for Injection).

A volume control administration set may be used to deliver the initial solution of Aztreonam with L-arginine into a compatible infusion solution being administered. With use of a Y-tube administration set, careful attention should be given to the calculated volume of Aztreonam with L-arginine solution required so that the entire dose will be infused.

Reconstitution:

Intravenous infusion solutions of Aztreonam with L-arginine for Injection prepared with 0.9% Sodium Chloride Injection B.P. or 5% Glucose Intravenous B.P., in PVC or glass containers, to which clindamycin phosphate, gentamicin sulphate, tobramycin sulphate, or cephazolin sodium have been added at concentrations usually used clinically, are stable for up to 24 hours in a refrigerator (2-8°C). Ampicillin sodium admixtures with aztreonam in 0.9% Sodium Chloride Injection B.P. are stable for 24 hours in a refrigerator (2-8°C); stability in 5% Glucose Intravenous Infusion B.P. is eight hours under refrigeration.

If aztreonam and metronidazole are to be used together, they should be administered separately as a cherry red colour has been observed after storage of solutions containing combinations of the two products.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Reconstitution

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

It is recommended that Aztreonam with L-arginine be administered immediately after reconstitution with solvent. Aztreonam with L-arginine should not be reconstituted until a dose is ready to be administered. One glass vial containing Aztreonam with L-arginine is opened by tearing and flipping up the blue cap or lifting up the metal flap, the metal ring is removed by carefully pulling the flap (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 Aztreonam with L-arginine is then poured into the Altera Nebuliser Handset and the dose administered.

Aztreonam with L-arginine is administered by inhalation over a 2 to 3 minute period, using a Aztreonam with L-arginine specific Altera Nebuliser Handset and Altera Aerosol Head connected to an eBase Controller or an eFlow rapid Control Unit. Aztreonam with L-arginine should not be used with any other type of handset or aerosol head. Aztreonam with L-arginine 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 Aztreonam with L-arginine 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.