- 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
Excipient with known effect:Soya lecithin (see section 4.4)For the full list of excipients, see section 6.1.
AdultsIn uncomplicated Chlamydia trachomatis urethritis and cervicitis the dosage is 1000 mg as a single oral dose.For all other indications the dose is 1500 mg, to be administered as 500 mg per day for three consecutive days. As an alternative the same total dose (1500 mg) can also be administered over a period of five days with 500 mg on the first day and 250 mg on the second to the fifth day.
Older peopleThe same dosage as in adult patients is used for older people. Since older people can be patients with ongoing proarrhythmic conditions a particular caution is recommended due to the risk of developing cardiac arrhythmia and torsades de pointes (see section 4.4).
Paediatric populationAzithromycin 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 azithromycine, e.g. suspensions, may be used.In patients with renal impairment: No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10-80 ml/min) (see section 4.4).In patients with hepatic impairment: A dose adjustment is not necessary for patients with mild to moderately impaired liver function (see section 4.4).
Method of administrationAzithromycin Tablets should be given as a single daily dose. The tablets may be taken with food.
The following should be considered before prescribing azithromycin:Azithromycin tablets are not suitable for treatment of severe infections where a high concentration of the antibiotic in the blood is rapidly needed.Azithromycin is not the first choice for the empiric treatment of infections in areas where the prevalence of resistant isolates is 10% or more (see section 5.1).In areas with a high incidence of erythromycin A resistance, it is especially important to take into consideration the evolution of the pattern of susceptibility to azithromycin and other antibiotics. As for other macrolides, high resistance rates of Streptococcus pneumoniae (> 30 %) have been reported for azithromycin in some European countries (see section 5.1). This should be taken into account when treating infections caused by Streptococcus pneumoniae.
Pharyngitis/ tonsilitisAzithromycin is not the substance of first choice for the treatment of pharyngitis and tonsillitis caused by Streptococcus pyogenes. For this and for the prophylaxis of acute rheumatic fever penicillin is the treatment of first choice.
SinusitisOften, azithromycin is not the substance of first choice for the treatment of sinusitis.
Acute otitis mediaOften, azithromycin is not the substance of first choice for the treatment of acute otitis media.
Skin and soft tissue infectionsThe main causative agent of soft tissue infections, Staphylococcus aureus, is frequently resistant to azithromycin. Therefore, susceptibility testing is considered a precondition for treatment of soft tissue infections with azithromycin.
Infected burn woundsAzithromycin is not indicated for the treatment of infected burn wounds.
Sexually transmitted diseaseIn case of sexually transmitted diseases a concomitant infection by T. palladium should be excluded.
Neurological or psychiatric diseasesAzithromycin should be used with caution in patients with neurological or psychiatric disorders.As with any antibiotic preparation, observation for signs of superinfection with non-susceptible organisms, including fungi is recommended.In patients with severe renal impairment (GFR < 10 ml/min) a 33% increase in systemic exposure to azithromycin was observed (see section 5.2).Azithromycin Tablets contains soya lecithin which might be a source of soya protein and should therefore not be taken in patients allergic to soya or peanut due to the risk of hypersensitivity reactions.
Effects of other medicinal products on azithromycin:
AntacidsIn a pharmacokinetic study investigating the effects of simultaneous administration of antacids and azithromycin, no effect on overall bioavailability was seen, although the peak serum concentrations were reduced by approximately 25%. In patients receiving both azithromycin and antacids, the drugs should not be taken simultaneously. Azithromycin must be taken at least 1 hour before or 2 hours after the antacids.Co-administration of azithromycin prolonged-release granules for oral suspension with a single 20 ml dose of co-magaldrox (aluminium hydroxide and magnesium hydroxide) did not affect the rate and extent of azithromycin absorption.
FluconazoleCoadministration of a single dose of 1200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. Total exposure and half-life of azithromycin were unchanged by the coadministration of fluconazole, however, a clinically insignificant decrease in Cmax (18%) of azithromycin was observed.
NelfinavirCoadministration of azithromycin (1200 mg) and nelfinavir at steady state (750 mg three times daily) resulted in increased azithromycin concentrations. No clinically significant adverse effects were observed and no dose adjustment is required.
RifabutinCoadministration of azithromycin and rifabutin did not affect the serum concentrations of either drug.Neutropenia was observed in subjects receiving concomitant treatment of azithromycin and rifabutin. Although neutropenia has been associated with the use of rifabutin, a causal relationship to combination with azithromycin has not been established (see section 4.8).
TerfenadinePharmacokinetic studies have reported no evidence of an interaction between azithromycin and terfenadine. There have been rare cases reported where the possibility of such an interaction could not be entirely excluded; however there was no specific evidence that such an interaction had occurred.
CimetidineIn a pharmacokinetic study investigating the effects of a single dose of cimetidine, given 2 hours before azithromycin, on the pharmacokinetics of azithromycin, no alteration of azithromycin pharmacokinetics was seen.
Effect of azithromycin on other medicinal products:
Ergotamine derivativesDue to the theoretical possibility of ergotism, the concurrent use of azithromycin with ergot derivatives is not recommended (see section 4.4).
Digoxin (P-gp substrates)Concomitant administration of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin, has been reported to result in increased serum levels of the P-glycoprotein substrate. Therefore, if azithromycin and P-gp substrates such as digoxin are administered concomitantly, the possibility of elevated serum concentrations of the substrate should be considered.
Coumarin-Type Oral AnticoagulantsIn a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15-mg dose of warfarin administered to healthy volunteers. There have been reports received in the post-marketing period of potentiated anticoagulation subsequent to coadministration of azithromycin and coumarin-type oral anticoagulants. Although a causal relationship has not been established, consideration should be given to the frequency of monitoring prothrombin time when azithromycin is used in patients receiving coumarin-type oral anticoagulants.
CyclosporinIn a pharmacokinetic study with healthy volunteers that were administered a 500 mg/day oral dose of azithromycin for 3 days and were then administered a single 10 mg/kg oral dose of cyclosporin, the resulting cyclosporin Cmax and AUC0-5 were found to be significantly elevated. Consequently, caution should be exercised before considering concurrent administration of these drugs. If coadministration of these drugs is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.
TheophyllineThere is no evidence of a clinically significant pharmacokinetic interaction when azithromycin and theophylline are co-administered to healthy volunteers. As interactions of other macrolides with theophylline have been reported, alertness to signs that indicate a rise in theophylline levels is advised.
Trimethoprim/sulfamethoxazoleCoadministration of trimethoprim/sulfamethoxazole DS (160 mg/800 mg) for 7 days with azithromycin 1200 mg on Day 7 had no significant effect on peak concentrations total exposure or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were similar to those seen in other studies.
ZidovudineSingle 1000 mg doses and multiple 1200 mg or 600 mg doses of azithromycin had little effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of azithromycin increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of this finding is unclear, but it may be of benefit to patients.Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not believed to undergo the pharmacokinetic drug interactions as seen with erythromycin and other macrolides. Hepatic cytochrome P450 induction or inactivation via cytochrome-metabolite complex does not occur with azithromycin.
Astemizole, alfentanilThere are no known data on interactions with astemizole or alfentanil. Caution is advised in the co-administration of these medicines with azithromycin because of the known enhancing effect of these medicines when used concurrently with the macrolid antibiotic erythromycin.
AtorvastatinCoadministration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter the plasma concentrations of atorvastatin (based on a HMG CoA-reductase inhibition assay).However, post-marketing cases of rhabdomyolysis in patients receiving azithromycin with statins have been reported.
CarbamazepineIn a pharmacokinetic interaction study in healthy volunteers, no significant effect was observed on the plasma levels of carbamazepine or its active metabolite in patients receiving concomitant azithromycin.
CisaprideCisapride is metabolized in the liver by the enzyme CYP 3A4. Because macrolides inhibit this enzyme, concomitant administration of cisapride may cause the increase of QT interval prolongation, ventricular arrhythmias and torsades de pointes.
CetirizineIn healthy volunteers, coadministration of a 5-day regimen of azithromycin with cetirizine 20 mg at steady-state resulted in no pharmacokinetic interaction and no significant changes in the QT interval.
Didanosins (Dideoxyinosine)Coadministration of 1200 mg/day azithromycin with 400 mg/day didanosine in 6 HIV-positive subjects did not appear to affect the steady-state pharmacokinetics of didanosine as compared with placebo.
EfavirenzCoadministration of a 600 mg single dose of azithromycin and 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interactions.
IndinavirCoadministration of a single dose of 1200 mg azithromycin had no statistically significant effect on the pharmacokinetics of indinavir administered as 800 mg three times daily for 5 days.
MethylprednisoloneIn a pharmacokinetic interaction study in healthy volunteers, azithromycin had no significant effect on the pharmacokinetics of methylprednisolone.
MidazolamIn healthy volunteers, coadministration of azithromycin 500 mg/day for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single 15 mg dose of midazolam.
SildenafilIn normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC and Cmax of sildenafil or its major circulating metabolite.
TriazolamIn 14 healthy volunteers, coadministration of azithromycin 500 mg on Day 1 and 250 mg on Day 2 with 0.125 mg triazolam on Day 2 had no significant effect on any of the pharmacokinetic variables for triazolam compared to triazolam and placebo.
PregnancyThere are no adequate data from the use of azithromycin in pregnant women. In reproduction toxicity studies in animals azithromycin was shown to pass the placenta, but no teratogenic effects were observed (see section 5.3). The safety of azithromycin has not been confirmed with regard to the use of the active substance during pregnancy. Therefore azithromycin should only be used during pregnancy if the benefit outweighs the risk.
Breast-feedingAzithromycin has been reported to be secreted into human breast milk, but there are no adequate and well-controlled clinical studies in nursing women that have characterized the pharmacokinetics of azithromycin excretion into human breast milk. Because it is not known whether azithromycin may have adverse effects on the breast-fed infant, nursing should be discontinued during treatment with azithromycin. Among other things diarrhoea, fungus infection of the mucous membrane as well as sensitisation is possible in the nursed infant. It is recommended to discard the milk during treatment and up until 2 days after discontinuation of treatment. Nursing may be resumed thereafter.
FertilityIn fertility studies conducted in rat, reduced pregnancy rates were noted following administration of azithromycin. The relevance of this finding to humans is unknown.
Adverse reactions possibly or probably related to azithromycin based on clinical trial experience and post-marketing surveillance:
|System Organ Class||Frequency||Adverse reaction|
|Infections and infestations||Uncommon||Candidiasis Vaginal infection Pneumonia Fungal infection Bacterial infection Pharyngitis Gastroenteritis Respiratory disorder Rhinitis Oral candidiasis|
|Not known||Pseudomembranous colitis (see section 4.4)|
|Blood and lymphatic system disorders||Uncommon||Leukopenia Neutropenia Eosinophilia|
|Not known||Thrombocytopenia Haemolytic anaemia|
|Immune system disorders||Uncommon||Angioedema Hypersensitivity|
|Not known||Anaphylactic reaction (see section 4.4)|
|Metabolism and nutrition disorders||Uncommon||Anorexia|
|Psychiatric disorders||Uncommon||Nervousness Insomnia|
|Not known||AggressionAnxietyDelirium Hallucination|
|Nervous system disorders||Common||Headache|
|Uncommon||Dizziness Somnolence Dysgeusia Paraesthesia|
|Not known||Syncope, convulsionHypoaesthesia Psychomotor hyperactivityAnosmiaAgeusiaParosmiaMyasthenia gravis (see section 4.4).|
|Eye disorders||Uncommon||Visual impairment|
|Ear and labyrinth disorders||Uncommon||Ear disorder Vertigo|
|Not known||Hearing impairment including deafness and/or tinnitus|
|Not known||Torsades de pointes (see section 4.4) Arrhythmia (see section 4.4) including ventricular tachycardiaElectrocardiogram QT prolonged (see section 4.4)|
|Vascular disorders||Uncommon||Hot flush|
|Respiratory, thoracic and mediastinal disorders||Uncommon||Dyspnoea Epistaxis|
|Gastrointestinal disorders||Very common||Diarrhoea|
|Common||Vomiting Abdominal pain Nausea|
|Uncommon||Constipation Flatulence Dyspepsia Gastritis Dysphagia Abdominal distension Dry mouth Eructation Mouth ulceration Salivary hypersecretion|
|Not known||PancreatitisTongue discolouration|
|Rare||Hepatic function abnormalJaundice cholestatic|
|Not known||Hepatic failure (which has rarely resulted in death) (see section 4.4)* Hepatitis fulminantHepatic necrosis|
|Skin and subcutaneous tissue disorders||Uncommon||Rash Pruritus Urticaria Dermatitis Dry skin Hyperhidrosis|
|Not known||Steven-Johnson syndrome Toxic epidermal necrolysisErythema multiforme|
|Musculoskeletal and connective tissue disorders||Uncommon||Osteoarthritis Myalgia Back pain Neck pain|
|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 oedema Chest pain Pyrexia Pain Peripheral oedema|
|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 bilirubine 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|
|System Organ Class||Frequency||Adverse reaction|
|Metabolism and nutrition disorders||Common||Anorexia|
|Nervous system disorders||Common||Dizziness Headache Paraesthesia Dysgeusia|
|Eye disorders||Common||Visual impairment|
|Ear and labyrinth disorders||Common||Deafness|
|Uncommon||Hearing impaired Tinnitus|
|Gastrointestinal disorders||Very common||Diarrhoea Abdominal pain Nausea Flatulence Abdominal discomfort Loose stools|
|Skin and subcutaneous tissue disorders||Common||Rash Pruritus|
|Uncommon||Steven-Johnson syndrome Photosensitivity reaction|
|Musculoskeletal and connective tissue disorders||Common||Arthralgia|
|General disorders and administration site conditions||Common||Fatigue|
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 (www.mhra.gov.uk/yellowcard).
General propertiesPharmacotherapeutic group: antibacterials for systemic use; macrolids; azithromycin, ATC code: J01FA10
Mode of action:Azithromycin is an azalide, a sub-class of the macrolid antibiotics. By binding to the 50S-ribosomal sub-unit, azithromycin avoids the translocation of peptide chains from one side of the ribosome to the other. As a consequence of this, RNA-dependent protein synthesis in sensitive organisms is prevented.
PK/PD relationshipFor azithromycin the AUC/MIC is the major PK/PD parameter correlating best with the efficacy of azithromycin.
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. Complete cross resistance exists among Streptococcus pneumoniae, betahaemolytic streptococcus of group A, Enterococcus faecalis and Staphylococcus aureus, including methicillin resistant S. aureus (MRSA) to erythromycin, azithromycin, other macrolides and lincosamides.
BreakpointsEUCAST (European Committee on Antimicrobial Susceptibility Testing)
|Pathogens||susceptible (mg/l)||resistant (mg/l)|
|Staphylococcus spp.||≤ 1||> 2|
|Streptococcus spp. (Group A, B, C, G)||≤ 0.25||> 0.5|
|Streptococcus pneumoniae||≤ 0.25||> 0.5|
|Haemophilus influenzae||≤ 0.12||> 4|
|Moraxella catarrhalis||≤ 0.5||> 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.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|
|Species for which acquired resistance may be a problem|
|Aerobic Gram-positive microorganisms|
|Inherently resistant organisms|
|Aerobic Gram-positive microorganisms|
|Staphylococcus aureus methicillin resistant and erythromycin resistant strains|
|Streptococcus pneumoniae penicillin resistant strains|
|Aerobic Gram-negative microorganisms|
|Anaerobic Gram-negative microorganisms|
|Bacteroides fragilis group|
AbsorptionAfter oral administration the bioavailability of azithromycin is approximately 37%. Peak plasma levels are reached after 2-3 hours (Cmax after a single dose of 500 mg orally was approximately 0.4 mg/l).
DistributionKinetic studies have shown markedly higher azithromycin levels in tissue than in plasma (up to 50 times the maximum observed concentration in plasma) indicating that the active substance is heavily tissue bound (steady state distribution volume of approximately 31 l/kg). Concentrations in target tissues such as lung, tonsil, and prostate exceed the MIC90 for likely pathogens after a single dose of 500 mg.In experimental in vitro and in vivo studies azithromycin accumulates in the phagocytes, freeing is stimulated by active phagocytosis. In animal studies this process appeared to contribute to the accumulation of azithromycin in the tissue.In serum the protein binding of azithromycin is variable and depending on the serum concentration varies from 50% in 0.05 mg/l to 12% in 0.5 mg/l.
ExcretionPlasma terminal elimination half-life closely reflects the tissue depletion half-life of 2 to 4 days. About 12% of an intravenously administered dose is excreted in the urine unchanged over a period of 3 days; the majority in the first 24 hours. Biliary excretion of azithromycin, predominantly in unchangedform, is a major route of elimination.The identified metabolites (formed by N- and O- demethylising, by hydroxylising of the desosamine and aglycone rings, and by the splitting of the cladinose conjugate) are microbiologically inactive.After a 5 day treatment slightly higher (29%) AUC values were seen in the elderly volunteers (>65 years of age) compared to the younger volunteers (< 45 years of age). However these differences are not regarded as clinically relevant; therefore a dose adjustment is not recommended.
Pharmacokinetics in special populations
Renal insufficiencyFollowing a single oral dose of azithromycin 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 insufficiencyIn patients with mild to moderate hepatic impairment, there is no evidence of a marked change in serum pharmacokinetics of azithromycin compared to normal hepatic function. In these patients, urinary recovery of azithromycin appears to increase perhaps to compensate for reduced hepatic clearance.
ElderlyThe pharmacokinetics of azithromycin 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 adolescentsPharmacokinetics 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.
Carcinogenic potential:Long-term studies in animals have not been performed to evaluate carcinogenic potential.
Mutagenic potential:Azithromycin has shown no mutagenic potential in standard laboratory tests: mouse lymphoma assay, human lymphocyte clastogenic assay, and mouse bone marrow clastogenic assay.
Reproductive toxicity:No teratogenic effects were observed in animal studies of embryotoxicity in mice and rats. In rats, azithromycin dosages of 100 and 200 mg/kg bodyweight/day led to mild retardations in foetal ossification and in maternal weight gain. In peri-/postnatal studies in rats, mild retardations following treatment with 50 mg/kg/day azithromycin and above were observed.
Core:Microcrystalline cellulosePregelatinised maize starchSodium starch glycolate Type AColloidal anhydrous silicaSodium laurilsulfateMagnesium stearate
Coating:Polyvinyl alcoholTitanium dioxide (E 171)TalcSoya LecithinXanthan Gum.
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