AZACTAM Powder for solution for injection or infusion Ref.[8665] Active ingredients: Aztreonam

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 Azactam and antibodies to penicillins or cephalosporins. The incidence of hypersensitivity to Azactam 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

As with some other beta-lactams there have been reports of encephalopathy with aztreonam (e.g. confusion, impairment of consciousness, epilepsy, movement disorders); particularly in patients with renal impairment and in association with beta-lactam overdose.

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 (see section 4.8).

Clostridium difficile associated diarrhoea

Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including Azactam, 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 Azactam 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 Azactam 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 (see section 4.5 and 4.8).

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.

Concomitant administration of probenecid or furosemide and aztreonam cause clinically insignificant increases in the serum levels of aztreonam.

Due to the induction of beta-lactamases, certain antibiotics (eg, cefoxitin, imipenem) have been found to cause antagonism with many beta-lactams, including aztreonam, for certain gram-negative aerobes, such as Enterobacter species and Pseudomonas species.

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 (see section 4.4 and 4.8).

Single-dose pharmacokinetic studies have not shown any significant interaction between aztreonam and gentamicin, cephradine, clindamycin or metronidazole.

Unlike broad spectrum antibiotics, aztreonam produces no effects on the normal anaerobic intestinal flora. No disulfiram-like reactions with alcohol ingestion have been reported.

Pregnancy

Aztreonam is contraindicated in pregnancy. Aztreonam crosses the placenta and enters the foetal circulation.

There are no adequate and well-controlled studies in pregnant women. Studies in pregnant rats and rabbits, with daily doses up to 15 and 5 times the maximum recommended human dose respectively, revealed no evidence of embryo- or fetotoxicity or teratogenicity. Because animal reproduction studies are not always predictive of human response, aztreonam should be used during pregnancy only if clearly needed.

Breastfeeding

Aztreonam is excreted in breast milk in concentrations that are less than 1% of those in simultaneously obtained maternal serum. Lactating mothers should refrain from breast feeding during the course of therapy.

This medicine can have an important impact on the ability to drive and use of machines should encephalopathy occur (see 4.4 Special warnings and special precautions for use and 4.9 Overdose).

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).

Blood and lymphatic system disorders

Rare: Pancytopenia^a, thrombocytopenia, thrombocythaemias, leukocytosis, neutropenia, eosinophilia, anaemia, prothrombin time prolonged, activated partial thromboplastin time prolonged, Coombs test positive^a

Ear and labyrinth disorders

Rare: Vertigo, tinnitus

Eye disorders

Rare: Diplopia

Gastrointestinal disorders

Rare: Gastro intestinal haemorrhage, pseudomembranous colitisa, breath odour

Not known: Abdominal pains, mouth ulceration, nausea, vomiting, diarrhoea, altered taste

General disorders and administration site conditions

Rare: Chest pain, pyrexia, asthenia, malaise

Not known: Injection site discomfort, weakness, sweating, muscle aches, fever, transient increases in serum creatinine

Hepato-biliary disorders

Rare: Hepatitis, jaundice

Not known: Transaminases increased*, blood alkaline phosphatase increased*

Infections and infestations

Rare: Vaginitis, vaginal candidiasis

Immune system disorders

Not known: Anaphylactic reaction

Investigations

Rare: Electrocardiogram change

Musculoskeletal, connective tissue and bone disorders

Rare: Myalgia

Nervous system disorders

Rare: Convulsions^a, paraesthesia, dizziness, headache

Not known: Dysgeusia, Encephalopathy (confusional state, altered state of consciousness, epilepsy, movement disorder)

Psychiatric disorders

Rare: Confusional state, insomnia

Renal and urinary disorders

Uncommon: Blood creatinine increased

Reproductive system and breast disorders

Rare: Breast tenderness

Respiratory, thoracic and mediastinal disorders

Rare: Wheezing, dyspnoea, sneezing, nasal congestion

Not known: Bronchospasm

Skin and subcutaneous tissue disorders

Not known: Toxic epidermal necrolysis^a, angioedema, erythema multiforme, dermatitis exfoliative, hyperhidrosis, petechiae, purpura, urticaria, rash, pruritus

Vascular disorders

__Rare:__RareHypotension, haemorrhage

Not known: Phlebitis, thrombophlebitis, flushing

* Usually reversing during therapy and without overt signs or symptoms of hepatobiliary dysfunction.
^a See section 4.4.

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

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