Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. The typical symptoms of an overdose with macrolide antibiotics include reversible loss of hearing, severe nausea, vomiting and diarrhoea. In the event of overdose, the administration of medicinal charcoal and general symptomatic treatment and supportive measures are indicated as required.
Not applicable.
Azitromicina Farmoz is well tolerated with a low incidence of side effects.
The section below lists the adverse reactions identified through clinical trial experience and postmarketing surveillance by system organ class and frequency. Adverse reactions identified from post-marketing experience are included in italics. 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 azithromycin based on clinical trial experience and post-marketing surveillance:
Infections and Infestations
Uncommon (>1/1,000 to <1/100)
Candidiasis, oral candidiasis, vaginal infection
Not known (cannot be estimated from available data)
Pseudomembranous colitis
Blood and Lymphatic System Disorders
Uncommon (> 1/1,000 to < 1/100)
Leukopenia, neutropenia
Not known (cannot be estimated from available data)
Thrombocytopenia, haemolytic anaemia
Immune System Disorders
Uncommon (>1/1,000 to <1/100)
Angioedema, hypersensitivity
Not known (cannot be estimated from available data)
Anaphylactic reaction
Metabolism and Nutrition Disorders
Common (> 1/100, < 1/10)
Anorexia
Psychiatric Disorders
Uncommon (>1/1,000 to <1/100)
Nervousness
Rare (> 1/10000, < 1/1000)
Agitation
Not known (cannot be estimated from available data)
Aggression, anxiety
Nervous System Disorders
Common (> 1/100, < 1/10)
Dizziness, headache, paraesthesia, dysgeusia
Uncommon (>1/1,000 to <1/100)
Hypoaesethesia, somnolence, insomnia
Not known (cannot be estimated from available data)
Syncope, convulsion, psychomotor hyperactivity, anosmia, ageusia, parosmia, Myasthenia gravis.
Eye Disorders
Common (> 1/100, < 1/10)
Visual impairment
Ear and Labyrinth Disorders
Common (> 1/100, < 1/10)
Deafness
Uncommon (>1/1,000 to <1/100)
Hearing impaired, tinnitus
Rare (> 1/10000, < 1/1000)
Vertigo
Cardiac Disorders
Uncommon (>1/1,000 to <1/100)
Palpitations
Not known (cannot be estimated from available data)
Torsades de pointes , arrhythmia including ventricular tachycardia
Vascular Disorders
Not known (cannot be estimated from available data)
Hypotension
Gastrointestinal Disorders
Very common (>1/10)
Diarrhoea, abdominal pain, nausea, flatulence
Common (> 1/100, < 1/10)
Vomiting, dyspepsia
Uncommon (> 1/1000, < 1/100)
Gastritis, constipation
Not known (cannot be estimated from available data)
Pancreatitis, tongue discolouration
Hepatobiliary Disorders
Uncommon (> 1/1000, < 1/100)
Hepatitis
Rare (> 1/10000, < 1/1000)
Hepatic function abnormal
Not known (cannot be estimated from available data)
Hepatic failure , which has rarely resulted in death, hepatitis fulminant, hepatic necrosis, jaundice cholestatic
Skin and Subcutaneous Tissue Disorders
Common (> 1/100, < 1/10)
Pruritus and rash
Uncommon (> 1/1000, < 1/100)
SJS, photosensitivity reaction, urticarial
Rare (>1/10,000 to <1/1,000)
Acute Generalized Exanthematous Pustulosis (AGEP)*§
Very Rare (< 1/10,000)
DRESS
Not known (cannot be estimated from available data)
TEN, erythema multiforme
Musculoskeletal, Connective Tissue Disorders
Common (> 1/100, < 1/10)
Arthralgia
Renal and Urinary Disorders
Not known (cannot be estimated from available data)
Renal failure acute, nephritis interstitial
General disorders and Administration Site Conditions
Common (> 1/100, < 1/10)
Fatigue
Uncommon (> 1/1000, < 1/100)
Chest pain, oedema, malaise, asthenia
Investigations
Common (> 1/100, < 1/10)
Lymphocyte count decreased, eosinophil count increased, blood bicarbonate decreased
Uncommon (> 1/1000, < 1/100)
Aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, blood urea increased, blood creatinine increased, blood potassium abnormal
Not known (cannot be estimated from available data)
Electrocardiogram QT prolonged
*ADR identified post-marketing
§ADR frequency represented by the estimated upper limit of the 95% confidence interval calculated using the “Rule of 3â€.
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.
Phospholipidosis (intracellular phospholipid accumulation) has been observed in several tissues (e.g. eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and/or pancreas) of mice, rats, and dogs given multiple doses of azithromycin. Phospholipidosis has been observed to a similar extent in the tissues of neonatal rats and dogs. The effect has been shown to be reversible after cessation of azithromycin treatment. The significance of the finding for animals and humans 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 for embryotoxic effects of the substance, no teratogenic effect was observed in mice and rats. In rats, azithromycin doses of 100 and 200 mg/kg bodyweight/day led to mild retardation of foetal ossification and in maternal weight gain. In peri- and postnatal studies in rats, mild retardation following treatment with 50 mg/kg/day azithromycin and above was observed.
Azithromycin is indicated for the treatment of the following infections when known or likely to be due to one or more susceptible microorganisms :
- bronchitis
- community-acquired pneumonia
- sinusitis
)- otitis media
- skin and soft tissue infections
- uncomplicated genital infections due to Chlamydia trachomatis and Neisseria gonorrhoeae.
Considerations should be given to official guidance regarding the appropriate use of antibacterial agents.
General properties
Pharmacotherapeutic group: Antibacterials for systemic use. ATC code: J01FA10
Mode of action:
Azitromicina Farmoz is a macrolide antibiotic belonging to the azalide group. The molecule is constructed by adding a nitrogen atom to the lactone ring of erythromycin A. The chemical name of azithromycin is 9-deoxy-9a-aza-9a-methyl-9a-homoerythromycin A. The molecular weight is 749.0. The mechanism of action of azithromycin is based upon the suppression of bacterial protein synthesis by means of binding to the ribosomal 50S sub-unit and inhibition of peptide translocation.
Mechanism of resistance:
Resistance to azithromycin may be inherent or acquired. There are three main mechanisms of resistance in bacteria: target site alteration, alteration in antibiotic transport and modification of the antibiotic.
Azithromycin demonstrates cross resistance with erythromycin resistant gram positive isolates. A decrease in macrolide susceptibility over time has been noted particularly in Streptococcus pneumoniae and Staphylococcus aureus. Similarly, decreased susceptibility has been observed among Streptococcus viridans and Streptococcus agalactiae (Group B) streptococcus against other macrolides and lincosamides.
Breakpoints
Azithromycin susceptibility breakpoints for typical bacterial pathogens, as published by EUCAST are:
| Organism | MIC breakpoints (mg/L) | |
| Susceptible (S≤) | Resistant (R>) | |
| Staphylococcus spp. | 1 | 2 |
| Streptococcus groups A, B, C and G | 0.25 | 0.5 |
| Streptococcus pneumoniae | 0.25 | 0.5 |
| Haemophilus influenzae | 0.12 | 4 |
| Moraxella catarrhalis | 0.25 | 0.5 |
| Neisseria gonorrhoeae | 0.25 | 0.5 |
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.
Table: Antibacterial spectrum of Azithromycin
| Commonly susceptible species |
| Aerobic Gram-positive microorganisms |
| Staphylococcus aureus Methycillin-susceptible |
| Streptococcus pneumoniae Penicillin-susceptible |
| Streptococcus pyogenes (Group A) |
| Aerobic Gram-negative microorganisms |
| Haemophilus influenzae Haemophilus parainfluenzae |
| Legionella pneumophila |
| Moraxella catarrhalis |
| Neisseria gonorrhoeae |
| Pasteurella multocida |
| Anaerobic microorganisms |
| Clostridium perfringens |
| Fusobacterium spp. |
| Prevotella spp. |
| Porphyromonas spp. |
| Other microorganisms |
| Chlamydia trachomatis |
| Species for which acquired resistance may be a problem |
| Aerobic Gram-positive microorganisms |
| Streptococcus pneumoniae Penicillin-intermediate Penicillin-resistant |
| Inherently resistant organisms |
| Aerobic Gram-positive microorganisms |
| Enterococcus faecalis |
| Staphylococci MRSA, MRSE* |
| Anaerobic microorganisms |
| Bacteroides fragilis group |
* Methycillin-resistant staphylococci have a very high prevalence of acquired resistance to macrolides and have been placed here because they are rarely susceptible to azithromycin.
Absorption
Bioavailability after oral administration is approximately 37%. Peak plasma concentrations are attained 2 to 3 hours after taking the medicinal product.
Distribution
Orally administered azithromycin is widely distributed throughout the body. In pharmacokinetic studies it has been demonstrated that the concentrations of azithromycin measured in tissues are noticeably higher (as much as 50 times) than those measured in plasma, which indicates that the agent strongly binds to tissues.
Binding to serum proteins varies according to plasma concentration and ranges from 12% at 0.5 microgram/ml up to 52% at 0.05 microgram azithromycin/ml serum. The mean volume of distribution at steady state (VVss) has been calculated to be 31.1 l/kg.
Elimination
The 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 azithromycin is excreted unchanged in urine within the following three days. Particularly high concentrations of unchanged azithromycin have been found in human bile. Also in bile, ten metabolites were detected, which were formed through N- and O- demethylation, hydroxylation of desosamine and aglycone rings and cleavage of cladinose conjugate. Comparison of the results of liquid chromatography and microbiological analyses has shown that the metabolites of azithromycin are not microbiologically active.
In animal tests, high concentrations of azithromycin have been found in phagocytes. It has also been established that during active phagocytosis higher concentrations of azithromycin are released from inactive phagocytes. In animal models this results in high concentrations of azithromycin being delivered to the site of infection.
Hypersensitivity
As with erythromycin and other macrolides, serious allergic reactions including angioneurotic oedema and anaphylaxis (rarely fatal), Acute Generalized Exanthematous Pustulosis (AGEP) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been reported. Some of these reactions with azithromycin have resulted in recurrent symptoms and required a longer period of observation and treatment.
Hepatotoxicity
Since the liver is the principal route of elimination for azithromycin, the use of azithromycin 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 azithromycin. 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. Azithromycin administration should be stopped if liver dysfunction has emerged.
Ergot derivatives
In patients receiving ergot derivatives, ergotism has been precipitated by co-administration of some macrolide antibiotics. There are no data concerning the possibility of an interaction between ergot and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administrated.
Prolongation of the QT interval
Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with other macrolides. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarisation ; therefore caution is required when treating patients:
- With congenital or documented QT prolongation
- Currently receiving treatment with other active substance known to prolong QT interval such as antiarrhythmics of Classes Ia and III, cisapride and terfenadine
- With electrolyte disturbance, particularly in case of hypokalaemia and hypomagnesemia
- With clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.
Superinfection
As with any antibiotic preparation, observation for signs of superinfection with non-susceptible organisms including fungi is recommended.
Clostridium difficile associated diarrhoea
Clostridium difficile associated diarrhoea (CDAD) has been reported with the use of nearly all antibacterial agents, including azithromycin, and may range in severity from mild diarrhoea to fatal colitis. Strains of C. difficile producing hypertoxin A and B 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. Therefore, CDAD must be considered in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. Discontinuation of therapy with azithromycin and the administration of specific treatment for C. difficile should be considered.
Streptococcal infections
Penicillin is usually the first choice for treatment of pharyngitis/tonsillitis due to Streptococcus pyogenes and also for prophylaxis of acute rheumatic fever. Azithromycin is in general effective against streptococcus in the oropharynx, but no data are available that demonstrate the efficacy of azithromycin in preventing acute rheumatic fever.
Renal impairment:
In patients with severe renal impairment (GFR <10 ml/min) a 33% increase in systemic exposure to azithromycin was observed.
Myasthenia gravis
Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia syndrome have been reported in patients receiving azithromycin therapy.
Diabetes
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
This medicinal product contains sulfur dioxide which may rarely cause severe hypersensitivity reactions and bronchospasm.
Azitromicina Farmoz capsules are for oral administration only.
There is no evidence to suggest that Azitromicina Farmoz may have an effect on a patient's ability to drive or operate machinery.
Posology:
Azitromicina Farmoz capsules should be given as a single daily dose.
In common with many other antibiotics Azitromicina Farmoz Capsules should be taken at least 1 hour before or 2 hours after food.
Children over 45 kg body weight and adults, including elderly patients:
The total dose of azithromycin is 1500 mg which should be given over three days (500 mg once daily).
In uncomplicated genital infections due to Chlamydia trachomatis, the dose is 1000 mg as a single oral dose. For susceptible Neisseria gonorrhoeae the recommended dose is 1000 mg or 2000 mg of azithromycin in combination with 250 mg or 500 mg ceftriaxone according to local clinical treatment guidelines. For patients who are allergic to penicillin and/or cephalosporins, prescribers should consult local treatment guidelines.
Paediatric population:
In children under 45 kg body weight: Azitromicina Farmoz Capsules are not suitable for children under 45 kg.
Renal impairment:
No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10 - 80 ml/min). Caution should be exercised when azithromycin is administered to patients with severe renal impairment (GFR < 10 ml/min).
Hepatic impairment:
Since azithromycin is metabolised in the liver and excreted in the bile, the drug should not be given to patients suffering from severe liver disease. No studies have been conducted regarding treatment of such patients with azithromycin.
Method of administration:
Azitromicina Farmoz Capsules are for oral administration only.
No special requirements
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
