- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Excipients with known effect:Each capsule contains lactose anhydrous, and sulfur dioxide.For the full list of excipients, see section 6.1.
Posology:Zithromax capsules should be given as a single daily dose.In common with many other antibiotics Zithromax 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: Zithromax 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) (see section 4.4 and section 5.2).
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 (see section 4.4). Method of administration: Zithromax Capsules are for oral administration only.
HypersensitivityAs with erythromycin and other macrolides, serious allergic reactions including angioneurotic oedema and anaphylaxis (rarely fatal), 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.
HepatotoxicitySince 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 (see section 4.8). 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 derivativesIn 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 intervalProlonged 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 (see section 4.8); 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.
SuperinfectionAs with any antibiotic preparation, observation for signs of superinfection with non-susceptible organisms including fungi is recommended. Clostridium difficile associated diarrhoeaClostridium 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 infectionsPenicillin 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 (see section 5.2).
Myasthenia gravisExacerbations of the symptoms of myasthenia gravis and new onset of myasthenia syndrome have been reported in patients receiving azithromycin therapy (see section 4.8).
DiabetesPatients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.This medicinal product contains sulphur dioxide which may rarely cause severe hypersensitivity reactions and bronchospasm.Zithromax capsules are for oral administration only.
PregnancyAnimal reproduction studies have been performed at doses up to moderately maternally toxic dose concentrations. In these studies, no evidence of harm to the foetus due to azithromycin was found. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed.
Breast-feedingThere are no data on secretion in breast milk. As many drugs are excreted in human milk, azithromycin should not be used in the treatment of a lactating woman unless the physician feels that the potential benefits justify the potential risks to the infant.
Adverse reactions possibly or probably related to azithromycin based on clinical trial experience and post-marketing surveillance:
Infections and InfestationsUncommon (≥1/1,000 to <1/100)Candidiasis, oral candidiasis, vaginal infectionNot known (cannot be estimated from available data)Pseudomembranous colitis (see section 4.4)
Blood and Lymphatic System DisordersUncommon (≥ 1/1,000 to < 1/100) Leukopenia, neutropeniaNot known (cannot be estimated from available data)Thrombocytopenia, haemolytic anaemia
Immune System DisordersUncommon (≥1/1,000 to <1/100)Angioedema, hypersensitivityNot known (cannot be estimated from available data)Anaphylactic reaction (see section 4.4)
Metabolism and Nutrition DisordersCommon (> 1/100, < 1/10) Anorexia
Psychiatric DisordersUncommon (≥1/1,000 to <1/100)NervousnessRare (> 1/10000, < 1/1000)AgitationNot known (cannot be estimated from available data)Aggression, anxiety
Nervous System DisordersCommon (> 1/100, < 1/10) Dizziness, headache, paraesthesia, dysgeusiaUncommon (≥1/1,000 to <1/100)Hypoaesethesia, somnolence, insomniaNot known (cannot be estimated from available data)Syncope, convulsion, psychomotor hyperactivity, anosmia, ageusia, parosmia, Myasthenia gravis (see section 4.4).
Eye DisordersCommon (> 1/100, < 1/10) Visual impairment
Ear and Labyrinth DisordersCommon (> 1/100, < 1/10) DeafnessUncommon (≥1/1,000 to <1/100)Hearing impaired, tinnitusRare (> 1/10000, < 1/1000) Vertigo
Cardiac DisordersUncommon (≥1/1,000 to <1/100)PalpitationsNot known (cannot be estimated from available data)Torsades de pointes (see section 4.4), arrhythmia (see section 4.4) including ventricular tachycardia
Vascular DisordersNot known (cannot be estimated from available data)Hypotension
Gastrointestinal DisordersVery common (≥1/10)Diarrhoea, abdominal pain, nausea, flatulenceCommon (> 1/100, < 1/10) Vomiting, dyspepsia Uncommon (> 1/1000, < 1/100) Gastritis, constipationNot known (cannot be estimated from available data)Pancreatitis, tongue discolouration
Hepatobiliary DisordersUncommon (> 1/1000, < 1/100)HepatitisRare (> 1/10000, < 1/1000) Hepatic function abnormalNot known (cannot be estimated from available data)Hepatic failure (see section 4.4), which has rarely resulted in death, hepatitis fulminant, hepatic necrosis, jaundice cholestatic
Skin and Subcutaneous Tissue DisordersCommon (> 1/100, < 1/10) Pruritus and rash Uncommon (> 1/1000, < 1/100)SJS, photosensitivity reaction, urticarialVery Rare (< 1/10,000)DRESSNot known (cannot be estimated from available data)TEN, erythema multiforme
Musculoskeletal, Connective Tissue DisordersCommon (> 1/100, < 1/10) Arthralgia
Renal and Urinary DisordersNot known (cannot be estimated from available data)Renal failure acute, nephritis interstitial
General disorders and Administration Site ConditionsCommon (> 1/100, < 1/10) FatigueUncommon (> 1/1000, < 1/100)Chest pain, oedema, malaise, asthenia
InvestigationsCommon (> 1/100, < 1/10) Lymphocyte count decreased, eosinophil count increased, blood bicarbonate decreasedUncommon (> 1/1000, < 1/100)Aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, blood urea increased, blood creatinine increased, blood potassium abnormalNot known (cannot be estimated from available data)Electrocardiogram QT prolonged (see section 4.4)
Reporting of suspected adverse reactionsReporting 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.
General propertiesPharmacotherapeutic group: Antibacterials for systemic use. ATC code: J01FA10
Mode of action:Zithromax 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.
BreakpointsAzithromycin susceptibility breakpoints for typical bacterial pathogens, as published by EUCAST are:
|Organism||MIC breakpoints (mg/L)|
|Susceptible (S≤)||Resistant (R>)|
|Streptococcus groups A, B, C and G||0.25||0.5|
SusceptibilityThe 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|
|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|
|Staphylococci MRSA, MRSE*|
|Bacteroides fragilis group|
AbsorptionBioavailability after oral administration is approximately 37%. Peak plasma concentrations are attained 2 to 3 hours after taking the medicinal product.
DistributionOrally 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.
EliminationThe 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.
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.
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