- 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
AdultsIn uncomplicated Chlamydia trachomatis urethritis and cervicitis, the dosage is 1,000 mg in one single oral dose. For all other indications the dosage is 1,500 mg, to be administered as 500 mg per day for three consecutive days. Alternatively the same total dosage (1,500 mg) can also be given over a period of 5 days with 500 mg on the first day and then 250 mg on days 2 to 5.To treat these patients other pharmaceutical forms are also available.
Older peopleThe same dosage as in adult patients is used in the older people. Since older 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 (see section 4.4).
Children and adolescents (< 18 years)The total dosage in children aged 1 year and older is 30 mg/kg administered as 10 mg/kg once daily for three days, or over a period of five days starting with a single dose of 10 mg/kg on the first day, followed by doses of 5 mg/kg per day for the following 4 days, according to the tables shown below. There are limited data on use in children younger than 1 year.
|Weight (kg)||3-day therapy||5-day therapy||Contents of the bottle|
|Day 1-3 10 mg/kg/day||Day 1 10 mg/kg/day||Day 2-5 5 mg/kg/day|
|10 kg||2.5 ml||2.5 ml||1.25 ml||15 ml|
|12 kg||3 ml||3 ml||1.5 ml||15 ml|
|14 kg||3.5 ml||3.5 ml||1.75 ml||15 ml|
|16 kg||4 ml||4 ml||2 ml||15 ml|
|17 25 kg||5 ml||5 ml||2.5 ml||15 ml|
|26 35 kg||7.5 ml||7.5 ml||3.75 ml||22.5 ml|
|36 45 kg||10 ml||10 ml||5 ml||30 ml|
|> 45 kg||12.5 ml||12.5 ml||6.25 ml||22.5 ml + 15 ml|
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).
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 administrationBefore use the powder should be reconstituted with water into a white to off white, homogenous suspension, see section 6.6. After reconstitution the drug can be administered using a PE/PP syringe for oral use. After taking the suspension a bitter after-taste can be avoided by drinking fruit juice directly after swallowing. Azithromycin powder for oral suspension should be given in a single daily dosage. The suspension may be taken together with food.
The following should be considered before prescribing azithromycin:Azithromycin powder for oral solution is 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.Caution in diabetic patients: 5 ml of reconstituted suspension contain 3.70 g of sucrose.Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine since it contains sucrose.Azithromycin 200mg/5 ml contain aspartame which is a source of phenylalanine. It may be harmful for people with phenylketonuria.
AntacidsIn a pharmacokinetic study investigating the effects of simultaneous administration of antacid with azithromycin, no effect on overall bioavailability was seen although peak serum concentrations were reduced by approximately 25%. In patients receiving both azithromycin and antacids, the drugs should not be taken simultaneously.
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.
Didanosine (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.
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.
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.
ErgotDue to the theoretical possibility of ergotism, the concurrent use of azithromycin with ergot derivatives is not recommended (see Section 4.4).
Pharmacokinetic studies have been conducted between azithromycin and the following drugs known to undergo significant cytochrome P450 mediated metabolism.Ergotamine derivatives: Due to the theoretical possibility of ergotism, the concurrent use of azithromycin with ergot derivatives is not recommended (see section 4.4).Astemizole, alfentanil There 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.
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.
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.
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.
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.
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 did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single 15 mg dose of midazolam.
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).
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.
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.
TheophyllineThere is no evidence of a clinically significant pharmacokinetic interaction when azithromycin and theophylline are co-administered to healthy volunteers.
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.
Trimethoprim/sulfamethoxazoleCoadministration of trimethoprim/sulfamethoxazole (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.Substances that prolong the QT intervalAzithromycin should not be used concurrently with other active substances that prolong the QT interval (see section 4.4).
LactationAzithromycin 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.
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:*
|Very Common (≥1/10)||Common (≥1/100 to <1/10)||Uncommon (≥1/1000 to < 1/100)||Rare (≥ 1/10,000 to <1/1,000)||Frequency Not Known|
|Infections and Infestations||Candidiasis Vaginal infectionPneumonia Fungal infection Bacterial infectionPharyngitisGastroenteritis Respiratory disorder Rhinitis Oral candidiasis||Pseudomembranous colitis (see section 4.4)|
|Blood and Lymphatic System Disorders||Leukopenia Neutropenia Eosinophilia||Thrombocytopenia Haemolytic anaemia|
|Immune System Disorders||Angioedema Hypersensitivity||Anaphylactic reaction (see section 4.4)|
|Metabolism and Nutrition Disorders||Anorexia|
|Psychiatric Disorders||Nervousness Insomnia,||Agitation||Aggression Anxiety Delirium Hallucination|
|Nervous System Disorders||Headache||Dizziness Somnolence Dysgeusia Paraesthesia||Syncope, convulsion Hypoestheia Psychomotor hyperactivity Anosmia Ageusia Parosmia Myasthenia gravis (see Section 4.4)|
|Eye Disorders||Visual impairment|
|Ear and Labyrinth Disorders||Ear disorder Vertigo||Hearing impairment including deafness and/or tinnitus|
|Cardiac Disorders||Palpitations||Torsades de pointes (see section 4.4) Arrhythmia (see section 4.4) including ventricular tachycardia Electrocardiogram QT prolonged (see section 4.4)|
|Vascular Disorders||Hot flush||Hypotension|
|Respiratory, thoracic and mediastinal disorders||Dyspnoea, Epistaxis|
|Gastrointestinal Disorders||Diarrhea||Vomiting Abdominal pain Nausea||Constipation Flatulence Dyspepsia, Gastritis dysphagia Abdominal distension Dry mouth Eructation Mouth ulceration Salivary hypersecretion||Pancreatitis Tongue discolouration|
|Hepatobiliary Disorders||Hepatic function abnormal Jaundice cholestatic||Hepatic failure (which has rarely resulted in death) (see section 4.4) Hepatitis fulminant Hepatic necrosis|
|Skin and Subcutaneous Tissue Disorders||Rash Pruritus Urticaria, Dermatitis Dry skin Hyperhidrosis||Photosensitivity reaction||Stevens-Johnson syndrome Toxic epidermal necrolysis Erythema multiforme|
|Musculoskeletal and Connective Tissue Disorders||Osteoarthritis, Myalgia Back pain Neck pain||Arthralgia|
|Renal and Urinary Disorders||Dysuria Renal pain||Renal failure acute Nephritis interstitial|
|Reproductive system and breast disorders||Metrorrhagia, Testicular disorder|
|General Disorders and Administration Site Conditions||Injection site pain * Injection site inflammation||Oedema Asthenia Malaise Fatigue Face edema Chest pain Pyrexia Pain Peripheral edema|
|Investigations||Lymphocyte count decreased Eosinophil count increased Blood bicarbonate decreased Basophils increased Monocytes increased Neutrophils increased||Aspartate aminotransferase increased Alanine aminotransferase 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||Post procedural complication|
|Very Common (≥1/10)||Common (≥1/100 to <1/10)||Uncommon (≥1/1000 to < 1/100)|
|Metabolism and Nutrition Disorders||Anorexia|
|Nervous System Disorders||Dizziness Headache Paraesthesia Dysgeusia||Hypoesthesia|
|Eye Disorders||Visual impairment|
|Ear and Labyrinth Disorders||Deafness||Hearing impaired Tinnitus|
|Gastrointestinal Disorders||Diarrhea Abdominal pain Nausea Flatulence Abdominal discomfort Loose stools|
|Skin and Subcutaneous Tissue Disorders||Rash Pruritus||Stevens-Johnson syndrome Photosensitivity reaction|
|Musculoskeletal and Connective Tissue Disorders||Arthralgia|
|General Disorders and Administration Site Conditions||Fatigue||Asthenia Malaise|
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; macrolides; azithromycin, ATC code: J01FA10
Mode of actionAzithromycin is an azalide, a sub-class of the macrolide 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 resistanceResistance 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||≤ 0.125||> 4|
|Moraxella catarrhalis||≤ 0.5||> 0.5|
|Neisseria gonorrhoeae||≤ 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.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* 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|
|Aerobic Gram-positive microorganisms Staphylococcus aureus methicillin resistant and erythromycin resistant strains Streptococcus pneumoniae penicillin resistant strains Aerobic Gram-negative microorganisms Escherichia coli Pseudomonas aeruginosa Klebsiella spp. Anaerobic Gram-negative microorganisms Bacteroides fragilis-group|
AbsorptionThe biological availability of azithromycin after oral administration is approximately 37%. Peak plasma levels are achieved 2-3 hours after taking the medicinal product.
DistributionAfter oral administration, azithromycin is distributed throughout the entire body. Pharmacokinetic studies have shown clearly higher azithromycin levels in the tissues than in the plasma (up to 50 times the maximum observed concentration in plasma). This indicates that the substance is bound in the tissues in considerable quantities.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.The protein binding of azithromycin in serum is variable and varies, depending on the serum concentration, from 52% at 0.05 mg/l to 12% at 0.5 mg/l. The steady state distribution volume is 31.1 l/kg.
EliminationThe terminal plasma-elimination half-life closely follows the tissue depletion half-life from 2 to 4 days.Approximately 12% of an intravenously administered dose of azithromycin is, over a period of 3 days, excreted unchanged in the urine. High concentrations of unchanged azithromycin were found in human bile. In this, ten metabolites were also detected (formed by N- and O- desmethylation, by hydroxylation of the desosamin and aglycon rings and by splitting the cladinose conjugate). A comparison of fluid chromatography and microbiological assessment methods shows that the metabolites are microbiologically inactive.In animal models high concentrations of azithromycin were found in phagocytes. Also it has been shown that during active phagocytosis higher concentrations of azithromycin are released than during inactive phagocytosis. In animal models this process was shown to contribute to the accumulation of azithromycin in infectious tissue.
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.
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 embryotoxicity studies in mice and rats no teratogenic effects were observed. In rats, azithromycin dosages of 100 and 200 mg/kg bodyweight/day led to slight retardations in fetal ossification and in maternal weight gain. In peri-/postnatal studies in rats, slight retardations in physical development and delay in reflex development were observed following treatment with 50 mg/kg/day azithromycin and above.
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