Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. In the event of overdosage, general symptomatic and supportive measures are indicated as required.
Not applicable
The table below lists the adverse reactions identified through clinical trial experience and postmarketing surveillance by system organ class and frequency.
The frequency grouping is defined using the following convention:
Very common (>1/10); Common (>1/100 to <1/10); Uncommon (>1/1,000 to <1/100); Rare (>1/10,000 to <1/1,000); Very rare (<1/10,000) and Not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Adverse reactions possibly or probably related to Azitral based on clinical trial experience and post-marketing surveillance:
| Infections and infestations | |
| Uncommon: | Candidiasis, vaginal infection, pneumonia, fungal infections, bacterial infection, pharyngitis, gastroenteritis, respiratory disorder, rhinitis, oral candidiasis |
| Not known: | Pseudomembraneous colitis |
| Blood and lymphatic system disorders | |
| Uncommon: | Leukopenia, neutropenia, eosinophilia |
| Not known: | Thrombocytopenia, haemolytic anaemia |
| Immune system disorders | |
| Uncommon: | Angioedema, hypersensitivity |
| Not known: | Anaphylactic reaction |
| Metabolism and nutrition disorders | |
| Uncommon: | Anorexia |
| Psychiatric disorders | |
| Uncommon: | Nervousness, insomnia |
| Rare: | Agitation |
| Not known: | Aggression, anxiety, delirium, hallucination |
| Nervous system disorders | |
| Common: | Headache |
| Uncommon: | Dizziness, somnolence, dysgeusia, paraesthesia |
| Not known: | Syncope, convulsion, hypoaesthesia, psychomotor hyperactivity, anosmia, ageusia, parosmia, myasthenia gravis |
| Eye disorders | |
| Uncommon: | Visual impairment |
| Ear and labyrinth disorders | |
| Uncommon: | Ear disorder, vertigo |
| Not known: | Hearing impairment including deafness and/or tinnitus |
| Cardiac disorders | |
| Uncommon: | Palpitations |
| Not known: | Torsades de pointes , arrhythmia including ventricular tachycardia, electrocardiogram QT prolonged |
| Vascular disorders | |
| Uncommon: | Hot flush |
| Not known: | Hypotension |
| Respiratory, thoracic and mediastinal disorders | |
| Uncommon: | Dyspnoea, epistaxis |
| Gastrointestinal disorders | |
| Very common: | Diarrhea |
| Common: | Vomiting, abdominal pain, nausea |
| Uncommon: | Constipation, flatulence, dyspepsia, gastritis, dysphagia, abdominal distension, dry mouth, eructation, mouth ulceration, salivary hypersecretion |
| Not known: | Pancreatitis, tongue discoloration |
| Hepatobiliary disorders | |
| Rare: | Hepatic function abnormal, jaundice cholestatic |
| Not known: | Hepatic failure (which has rarely resulted in death) , hepatitis fulminant, hepatic necrosis |
| Skin and subcutaneous tissue disorders | |
| Uncommon: | Rash, pruritus, urticaria, dermatitis, dry skin, hyperhidrosis |
| Rare: | Photosensitivity reaction, acute generalised exanthematous pustulosis (AGEP) |
| Not known: | Stevens-Johnson syndrome, Toxic epidermal necrolysis, erythema multiforme |
| Musculoskeletal and connective tissue disorders | |
| Uncommon: | Osteoarthritis, myalgia, back pain, neck pain |
| Not known: | Arthralgia |
| Renal and urinary disorders | |
| Uncommon: | Dysuria, renal pain |
| Not known: | Renal failure acute, nephritis interstitial |
| Reproductive system and breast disorders | |
| Uncommon: | Metrorrhagia, testicular disorder |
| General disorders and administration site conditions | |
| Uncommon: | Oedema, asthenia, malaise, fatigue, face edema, chest pain, pyrexia, pain, peripheral edema |
| Investigations | |
| Common: | Lymphocyte count decreased, eosinophil count increased, blood bicarbonate decreased, basophils increased, monocytes increased, neutrophils increased |
| Uncommon: | Aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, blood urea increased, blood bilirubin increased, blood urea increased, blood creatinine increased, blood potassium abnormal, blood alkaline phosphatase increased, chloride increased, glucose increased, platelets increased, hematocrit decreased, bicarbonate increased, abnormal sodium |
| Injury and poisoning | |
| Uncommon: | post procedural complication |
Adverse reactions possibly or probably related to Mycobacterium Avium Complex prophylaxis and treatment based on clinical trial experience and post-marketing surveillance. These adverse reactions differ from those reported with immediate release or the prolonged release formulations, either in kind or in frequency:
| Metabolism and nutrition disorders | |
| Common: | Anorexia |
| Nervous system disorders | |
| Common: | Dizziness, headache, paraesthesia, dysgeusia |
| Uncommon: | Hypoaesthesia |
| Eye disorders | |
| Common: | Visual impairment |
| Ear and labyrinth disorders | |
| Common: | Deafness |
| Uncommon: | Hearing impaired, tinnitus |
| Cardiac disorders | |
| Uncommon: | Palpitations |
| Gastrointestinal disorders | |
| Very common: | Diarrhea, abdominal pain, nausea, flatulence, abdominal discomfort, loose stools |
| Hepatobiliary disorders | |
| Uncommon: | Hepatitis |
| Skin and subcutaneous tissue disorders | |
| Common: | Rash, pruritus |
| Uncommon: | Stevens-Johnson syndrome, photosensitivity reaction |
| Musculoskeletal and connective tissue disorders | |
| Common: | Arthralgia |
| General disorders and administration site conditions | |
| Common: | Fatigue |
| Uncommon: | Asthenia, malaise |
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 (www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in the Google Play or Apple App Store.
In animal tests in which the dosages used amounted to 40 times the clinical therapeutic dosages, Azitral was found to have caused reversible phospholipidosis, but as a rule, no true toxicological consequences were observed which were associated with this. The relevance of this finding to humans receiving Azitral in accordance with the recommendations is unknown.
Carcinogenic potential:
Long-term studies in animals have not been performed to evaluate carcinogenic potential as the drug is indicated for short-term treatment only, and there were no signs indicative of carcinogenic activity.
Mutagenic potential:
There was no evidence of a potential for genetic and chromosome mutations in in-vivo and in-vitro test models.
Reproductive toxicity:
In animal studies of the embryotoxic effects of the substance, no teratogenic effect was observed in mice and rats. In rats, Azitral dosages of 100 and 200 mg/kg bodyweight/day led to mild retardations in foetal ossification and in maternal weight gain. In peri- and postnatal studies in rats, mild retardation in physical development and delay in reflex development following treatment with 50 mg/kg/day Azitral and above were observed.
Azitral is indicated for the treatment of the following infections, when caused by microorganisms sensitive to Azitral :
- acute bacterial sinusitis (adequately diagnosed)
- acute bacterial otitis media (adequately diagnosed)
- pharyngitis/tonsillitis
- acute exacerbation of chronic bronchitis (adequately diagnosed)
- mild to moderately severe community-acquired pneumonia
- skin and soft tissue infections
- uncomplicated Chlamydia trachomatis urethritis and cervicitis
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
General properties
Pharmacotherapeutic group: antibacterials for systemic use, macrolides, Azitral,
ATC code: J01FA10
Mode of action
The mechanism of action of Azitral is based on the suppression of bacterial protein synthesis, that is to say that it binds to the ribosomal 50s sub-unit and inhibits the translocation of peptides. Azitral acts bacteriostatic.
PK/PD Relationship
The efficacy of Azitral is best described by the relationship AUC/MIC, where AUC describes the area under the curve and MIC represents the mean inhibitory concentration of the microbe concerned.
Mechanism of resistance
Resistance to Azitral may be natural or acquired. There are 3 main mechanisms of resistance affecting Azitral:
- Efflux: resistance may be due to an increase in the number of efflux pumps on the cell membrane. In particular, 14- and 15-link macrolides are affected. (M-phenotype)
- Alterations of the cell structure: methylisation of the 23s rRNS may reduce the affinity of the ribosomal binding sites, which can result in microbial resistance to macrolides, lincosamides and group B streptogramins (SB) (MLSB-phenotype).
- Enzymatic deactivation of macrolides is only of limited clinical significance.
In the presence of the M-phenotype, complete cross resistance exists between Azitral and clarithomycin, erythromycin and roxithromycin. With the MLSB-phenotype, additional cross resistance exists with clindamycin and streptogramin B. A partial cross resistance exists with spiramycin.
Breakpoints
According to EUCAST (European Committee on Antimicrobial Susceptibility Testing) the following breakpoints have been defined for Azitral (2009-06-01):
| Species | Susceptible | Resistant |
| Staphylococcus spp. | ≤ 1 mg/l | > 2 mg/l |
| Streptococcus (Group A,B,C,G) | ≤ 0,25 mg/l | > 0,5 mg/l |
| Streptococcus pneumoniae | ≤ 0,25 mg/l | > 0,5 mg/l |
| Haemophilus influenzae | ≤ 0,12 mg/l | > 4 mg/l |
| Moraxella catarrhalis | ≤ 0,5 mg/l | > 0,5 mg/l |
| Neisseria gonorrhoeae | ≤ 0,25 mg/l | > 0,5 mg/l |
Susceptibility
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Pathogens for which resistance may be a problem: prevalence of resistance is equal to or greater than 10% in at least one country in the European Union.
Table of Susceptibility
| Commonly susceptible species |
| Aerobic Gram-negative microorganisms |
| Haemophilus influenzae * |
| Moraxella catarrhalis * |
| Neisseria gonorrhoeae |
| Other microorganisms |
| Chlamydophila pneumoniae |
| Chlamydia trachomatis |
| Legionella pneumophila |
| Mycobacterium avium |
| Mycoplasma pneumonia * |
| Species for which acquired resistance may be a problem |
| Aerobic Gram-positive microorganisms |
| Staphylococcus aureus * |
| Streptococcus agalactiae |
| Streptococcus pneumoniae * |
| Streptococcus pyogenes * |
| Other microorganisms |
| Ureaplasma urealyticum |
| Inherently resistant organisms |
| Staphylococcus aureus - methicillin resistant and erythromycin resistant strains |
| Streptococcus pneumoniae - penicillin resistant strains |
| Escherichia coli |
| Pseudomonas aeruginosa |
| Klebsiella spp. |
* Clinical effectiveness is demonstrated by sensitive isolated organisms for approved clinical indication.
Absorption
Bioavailability after oral administration is approximately 37%. Peak concentrations in the plasma are attained 2-3 hours after taking the medicinal product.
Distribution
Orally administered Azitral is widely distributed throughout the body.
In pharmacokinetic studies it has been demonstrated that the concentrations of Azitral measured in tissues are noticeably higher (as much as 50 times) than those measured in plasma.
Concentrations in the infected tissues, such as lungs, tonsil and prostate are higher than the MRC90 of the most frequently occurring pathogens after a single dose of 500 mg.
Binding to serum proteins varies in dependence on exposure in concentration range from 12% in 0.5 microgram/ml up to 52% in 0.05 microgram Azitral/ml serum. The mean volume of distribution at steady state (VVss) has been calculated to be 31.1 l/kg.
Elimination
Terminal plasma elimination half-life closely reflects the elimination half-life from tissues of 2-4 days.
Approximately 12% of an intravenously administered dose of Azitral is excreted unchanged in urine within the following three days. Particularly high concentrations of unchanged Azitral have been found in human bile. In the same source, 10 metabolites were also detected, which were formed through N- and O-demethylation, hydroxylation of desosamine- and aglycone rings and degradation of cladinose conjugate. Comparison of the results of liquid chromatography and microbiological analyses has shown that the metabolites of Azitral are not microbiologically active.
In animal tests, high concentrations of Azitral have been found in phagocytes. It has also been established that during active phagocytosis higher concentrations of Azitral are released than are released from inactive phagocytes. In animal models the Azitral concentrations measured in inflammation foci were high.
Pharmacokinetics in Special Populations
Renal insufficiency
Following a single oral dose of Azitral 1 g, mean Cmax and AUC0-120 increased by 5.1% and 4.2% respectively, in subjects with mild to moderate renal impairment (glomerular filtration rate of 10-80 ml/min) compared with normal renal function (GFR > 80 ml/min). In subjects with severe renal impairment, the mean Cmax and AUC0-120 increased 61% and 33% respectively compared to normal.
Hepatic insufficiency
In patients with mild to moderate hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of Azitral compared to normal hepatic function. In these patients, urinary recovery of Azitral appears to increase perhaps to compensate for reduced hepatic clearance.
Elderly
The pharmacokinetics of Azitral in elderly men was similar to that of young adults; however, in elderly women, although higher peak concentrations (increased by 30-50%) were observed, no significant accumulation occurred.
Infants, toddlers, children and adolescents
Pharmacokinetics have been studied in children aged 4 months - 15 years taking capsules, granules or suspension. At 10 mg/kg on day 1 followed by 5 mg/kg on days 2-5, the Cmax achieved is slightly lower than adults with 224 ug/l in children aged 0.6-5 years and after 3 days dosing and 383 ug/l in those aged 6-15 years. The t1/2 of 36 h in the older children was within the expected range for adults.
Hypersensitivity
As with erythromycin and other macrolides, rare serious allergic reactions, including angioneurotic oedema and anaphylaxis (rarely fatal), dermatologic reactions including acute generalised exanthematous pustulosis (AGEP), Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (rarely fatal) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. Some of these reactions with Azitral have resulted in recurrent symptoms and required a longer period of observation and treatment.
If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.
Since liver is the principal route of elimination for Azitral, the use of Azitral should be undertaken with caution in patients with significant hepatic disease. Cases of fulminant hepatitis potentially leading to life-threatening liver failure have been reported with Azitral. Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products.
In case of signs and symptoms of liver dysfunction, such as rapid developing asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy, liver function tests/investigations should be performed immediately. Azitral administration should be stopped if liver dysfunction has emerged.
In patients receiving ergot derivatives, ergotism has been precipitated by coadministration of some macrolide antibiotics. There are no data concerning the possibility of an interaction between ergot and Azitral. However, because of the theoretical possibility of ergotism, Azitral and ergot derivatives should not be co-administered.
As with any antibiotic preparation, observation for signs of superinfection with non-susceptible organisms, including fungi is recommended.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Azitral, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
In patients with severe renal impairment (GFR <10 ml/min) a 33% increase in systemic exposure to Azitral was observed.
Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with macrolides including Azitral. Therefore as the following situations may lead to an increased risk for ventricular arrhythmias (including torsade de pointes) which can lead to cardiac arrest, Azitral should be used with caution in patients with ongoing proarrhythmic conditions (especially women and elderly patients) such as patients:
- With congenital or documented QT prolongation
- Currently receiving treatment with other active substances known to prolong QT interval such as antiarrhythmics of class IA (quinidine and procainamide ) and class III (dofetilide, amiodarone and sotalol), cisapride and terfenadine; antipsychotic agents such as pimozide; antidepressants such as citalopram; and fluoroquinolones such as moxifloxacin and levofloxacin
- With electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesaemia
- With clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency
Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia syndrome have been reported in patients receiving Azitral therapy.
Safety and efficacy for the prevention or treatment of Mycobacterium Avium Complex in children have not been established.
Azitral film-coated tablets contain Lactose.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Azitral film-coated tablets contains 0.025 mmol (0.57 mg) sodium per dose which is less than 1 mmol sodium (23 mg), that is to say essentially 'sodium-free'.
There is no evidence to suggest that Azitral may have an effect on a patient's ability to drive or operate machinery.
Posology
Adults
In uncomplicated Chlamydia trachomatis urethritis and cervicitis the dosage is 1,000 mg as a single oral dose.
For all other indications the dose is 1,500 mg, to be administered as 500 mg per day for three consecutive days.
Older people
The same dose range as in younger patients may be used in the elderly.
Children
Azitral film-coated tablets should only be administered to children weighing more than 45 kg when normal adult dose should be used. For children under 45 kg other pharmaceutical forms of Azitral, e.g. suspensions, may be used.
Patients with renal impairment:
No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10-80 ml/min).
Patients with hepatic impairment:
A dose adjustment is not necessary for patients with mild to moderately impaired liver function.
In the Elderly:
The same dosage as in adult patients is used in the elderly. Since elderly patients can be patients with ongoing proarrhythmic conditions a particular caution is recommended due to the risk of developing cardiac arrhythmia and torsades de pointes..
Method of administration
Azitral 250 mg film-coated tablet should be administered as a daily single dose. Azitral 250mg film-coated tablet may be taken with food.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
