- Approval Id
- e9285212898ed830
- Drug Approval Emc Name
- Azithromycin 500mg film-coated tablets
- Drug Name
- Azithromycin 500mg film-coated tablets
- Company Name
- Aurobindo Pharma - Milpharm Ltd.
- Company Address
- Odyssey Business Park, Ares Block, West End Road, South Ruislip, Middlesex, HA4 6QD
- Company Website
- http://www.aurobindo.com
- Company Telephone
- + 44 (0)208 845 8811
- Company Medical Info Email
- medinfo@aurobindo.com
- Company Customer Care Direct Line
- +44 (0)208 845 8811
- Company Medical Info Fax
- +44 (0)208 845 8795
- Atc Code
- J01FA10
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Milpharm Limited
Ares Block
Odyssey Business Park, West End Road
Ruislip
HA4 6QD
United Kingdom
- Authorisation Number
- PL 16363/0462
- Authorisation Date
- 01/08/2016 & 12/05/2021
- Instruction Authorisation Holder
- Milpharm Limited
Ares Block
Odyssey Business Park, West End Road
Ruislip
HA4 6QD
United Kingdom
- Instruction Authorisation Number
- PL 16363/0462
- Instruction Authorisation Date
- 01/08/2016 & 12/05/2021
- Instruction Composition
- Each film-coated tablet contains 500 mg of azithromycin (as dihydrate).
\*\*Excipient with known effect\*\*: Each film-coated tablet contains 10.26 mg of lactose.
For the full list of excipients, see section 6.1.
- Instruction Dosage Form
- Film-coated tablet.
\*\*\*Azithromycin 500 mg film-coated tablets:\*\*\*
White to off-white, oval shaped, film coated biconvex tablets debossed with “6” and “7” on either side of the score-line on one side and “D” on other side. The tablet can be divided into equal doses. The size is 17.1 mm x 8.5 mm.
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
Azithromycin is indicated for the following bacterial infections induced by microorganisms susceptible to azithromycin (see sections 4.4 and 5.1):
• 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
• Infections of the skin and soft tissues of mild to moderate severity e.g. folliculitis, cellulitis, erysipelas
• Uncomplicated genital infections due to Chlamydia trachomatis \*and\* Neisseria gonorrhoeae.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.4.2 Posology and method of administration
\*\*Posology\*\*
Azithromycin should be given as a single daily dose. Duration of the treatment for the different infection diseases is given below.
\*\*Children over 45 kg body weight and adults, including elderly patients:\*\*
The total dose is 1500 mg, administered as 500 mg once daily for 3 days. Alternatively, the same total dose (1500 mg) can be administered in a period of 5 days, 500 mg on the first day and 250 mg on day 2 to 5.
In the case of 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 with250 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:\*\*
\*\*Children and adolescents with a body weight below 45 kg\*\*
Azithromycin tablets are not suitable for patients under 45 kg body weight. Other dosage forms are available for this group of patients.
\*\*Elderly patients\*\*
For elderly patients the same dose as for adults can be applied. 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. (see section 4.4).
\*\*Patients with renal impairment\*\*
Dose adjustment is not required 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).
\*\*Patients with hepatic impairment\*\*
Dose adjustment is not required for patients with mild to moderate hepatic dysfunction (see section 4.4). 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
Azithromycin should be given as a single daily dose. The tablets can be taken with or without food. The tablets should be taken with ½ glass of water.4.3 Contraindications
Hypersensitivity to the active substance, erythromycin, any macrolide, ketolide antibiotic, or to any of the excipient listed in section 6.1.4.4 Special warnings and precautions for use
H\*ypersensitivity\*
As with erythromycin and other macrolides, rare serious allergic reactions, including angioneurotic oedema and anaphylaxis (rarely fatal), dermatologic reactions including acute generalized 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 azithromycin have resulted in recurrent symptoms and required a longer period of observation and treatment.
If an allergic reaction occurs, the medicinal product 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.
\*\*\*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 (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.
\*Infantile hypertrophic pyloric stenosis (IHPS)\*
Following the use of azithromycin in neonates (treatment up to 42 days of life), infantile hypertrophic pyloric stenosis (IHPS) has been reported. Parents and caregivers should be informed to contact their physician if vomiting or irritability with feeding occurs
\*Ergot alkaloids and azithromycin\*
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 ergotamine derivatives and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administered (see section 4.5).
\*Superinfections:\*
As with any antibiotic preparation, it is recommended to pay attention to signs of superinfection with nonsusceptible microorganisms like fungi. A superinfection may require an interruption of the azithromycin treatment and initiation of adequate measures.
\*Clostridium difficile\* associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including azithromycin, and may range in severity from mild diarrhoea 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 diarrhoea 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 case of CDAD anti-peristaltics are contraindicated. Discontinuation of therapy with azithromycin and the administration of specific treatment for C. difficile should be considered.
\*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).
\*Cardiovascular events\*
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, including azithromycin (see section 4.8). Therefore as the following situations may lead to an increased risk for ventricular arrhythmias (including torsade de pointes) which can lead to cardiac arrest, azithromycin should be used with caution in patients with ongoing proarrhythmic conditions (especially women and elderly patients) such as patients:
- With congenital or documented acquired 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.
Epidemiological studies investigating the risk of adverse cardiovascular outcomes with macrolides have shown variable results. Some observational studies have identified a rare short term risk of arrhythmia, myocardial infarction and cardiovascular mortality associated with macrolides including azithromycin. Consideration of these findings should be balanced with treatment benefits when prescribing azithromycin.
\*Myasthenia gravis\*
Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia syndrome have been reported in patients receiving azithromycin therapy (see section 4.8).
\*\*\*Hydroxychloroquine or chloroquine\*\*\*
Carefully consider the balance of benefits and risks before prescribing azithromycin for any patients taking hydroxychloroquine or chloroquine, because of the potential for an increased risk of cardiovascular events and cardiovascular mortality (see section 4.5).
\*\*Paediatric population\*\*
Safety and efficacy for the prevention or treatment of \*Mycobacterium avium\* complex in children have not been established.
\*\*The following should be considered before prescribing azithromycin:\*\*
Azithromycin is not suitable for treatment of severe infections where a high concentration of the antibiotic in the blood is rapidly needed.
The selection of azithromycin to treat an individual patient should take into account the appropriateness of using a macrolide antibacterial agent based on adequate diagnosis to ascertain the bacterial etiology of the infection in the approved indications and the prevalence of resistance to azithromycin or other macrolides.
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/ tonsillitis\*
Azithromycin 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. 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.
\*Sinusitis\*
Often, azithromycin is not the substance of first choice for the treatment of sinusitis.
\*Acute otitis media\*
Often, azithromycin is not the substance of first choice for the treatment of acute otitis media.
\*Skin and soft tissue infections\*
The 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 wounds:\*
Azithromycin is not indicated for the treatment of infected burn wounds.
\*Sexually transmitted disease:\*
In case of sexually transmitted diseases a concomitant infection by \*T. pallidium\* should be excluded.
\*Neurological or psychiatric diseases:\*
Azithromycin should be used with caution in patients with neurological or psychiatric disorders.
Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
\*\*\*Lactose\*\*\*
Patients with rare hereditary problems of galactose intolerance, total lactose deficiency or glucose-galactose malabsorption should not take this medicine.
\*\*\*Sodium\*\*\*
Azithromycin contains less than 1 mmol (23 mg) of sodium per tablet, that is to say it is essentially 'sodium-free.'4.5 Interaction with other medicinal products and other forms of interaction
\*Antacids:\*
In a pharmacokinetic study investigating the effects of simultaneous administration of antacids with azithromycin, no effect on overall bioavailability was seen, although peak serum levels were reduced by approximately 25%. In patients receiving both azithromycin and antacids, the medicinal products should not be taken simultaneously. Azithromycin must be taken at least 1 hour before or 2 hours after 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.
Co-administration 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.
\*Cetirizine:\*
In 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.
\*Digoxin (P-gp substrates) and colchicine:\*
Concomitant administration of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine, 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\*.\* Clinical monitoring, and possibly serum digoxin levels, during treatment with azithromycin and after its discontinuation are necessary\*.\*
\*Zidovudine:\*
Single 1000 mg doses and multiple doses of 600 mg or 1200 mg 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.
\*Ergotamine derivatives:\*
Due 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.
Astemizole, alfentanil
There are no known data on interactions with astemizole or alfentanil. Caution is advised in the coadministration of these medicines with Azithromycin because of the known enhancing effect of these medicines when used concurrently with the macrolide antibiotic erythromycin.
\*Atorvastatin:\*
Coadministration 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, postmarketing cases of rhabdomyolysis in patients receiving azithromycin with statins have been reported.
\*Carbamazepine:\*
In 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.
\*Cimetidine:\* In 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 Anticoagulants:\*
In 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 postmarketing 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 thefrequency of monitoring prothrombin time when azithromycin is used in patients receiving coumarintypeoral anticoagulants.
\*Cyclosporin:\*
In 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.
\*Efavirenz:\*
Coadministration 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.
\*Fluconazole:\*
Coadministration of a single dose of 1200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. Total exposure and halflife of azithromycin were unchanged by the coadministration of fluconazole, however, a clinically insignificant decrease in Cmax (18%) of azithromycin was observed.
\*Indinavir:\*
Coadministration 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.
\*Methylprednisolone:\*
In a pharmacokinetic interaction study in healthy volunteers, azithromycin had no significant effect on the pharmacokinetics of methylprednisolone.
\*Midazolam:\*
In 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.
\*Nelfinavir:\*
Coadministration 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.
\*Rifabutin:\*
Coadministration of azithromycin and rifabutin did not affect the serum concentrations of either medicinal product. 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).
\*Sildenafil:\*
In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3days) on the AUC and Cmax of sildenafil or its major circulating metabolite.
\*Terfenadine:\*
Pharmacokinetic 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.
\*Theophylline:\* There 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.
\*Triazolam:\*
In 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/sulfamethoxazole:\*
Coadministration 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.
\*\*Hydroxychloroquine or chloroquine:\*\* Observational data have shown that co-administration of azithromycin with hydroxychloroquine in patients with rheumatoid arthritis is associated with an increased risk of cardiovascular events and cardiovascular mortality. Carefully consider the balance of benefits and risks before prescribing azithromycin for any patients taking hydroxychloroquine. Similar careful consideration of the balance of benefits and risk should also be undertaken before prescribing azithromycin for any patients taking chloroquine, because of the potential for a similar risk with chloroquine.
\*\*Medicinal products known to prolong the QT interval\*\*
Azithromycin should be used with caution in patients receiving medicines known to prolong the QT interval with potential to induce cardiac arrhythmia, e.g. hydroxychloroquine.
\*Cisapride\*
Cisapride 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.4.6 Fertility, pregnancy and lactation
\*\*Pregnancy\*\*
Animal 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.
There is a large amount of data from observational studies performed in several countries on exposure to azithromycin during pregnancy, compared to no antibiotic use or use of another antibiotic during the same period (> 7,300 first trimester exposures). While most studies do not suggest an association with adverse foetal effects such as major congenital malformations or cardiovascular malformations, there is limited epidemiological evidence of an increased risk of miscarriage following azithromycin exposure in early pregnancy. Therefore, azithromycin should only be used during pregnancy if clinically needed and the benefit of treatment is expected to outweigh any small increased risks which may exist.
\*\*Breastfeeding\*\*
Azithromycin has been reported to be secreted into human breast milk, The limited information available from published literature indicates azithromycin is present in human milk at an estimated highest median daily dose of 0.1 to 0.7 mg / kg / day. No serious side effects have been observed by azithromycin in breast-fed infants.
A decision should be taken whether breastfeeding is discontinued or that treatment with azithromycin is discontinued/initiated or not, taking into account the benefit of breastfeeding for the child and the benefit of treatment for the woman.
\*\*Fertility\*\*
In fertility studies conducted in rat, reduced pregnancy rates were noted following administration of azithromycin. The relevance of this finding to humans is unknown.4.7 Effects on ability to drive and use machines
No data are available regarding the influence of azithromycin on a patient's ability to drive or operate machinery. However, the possibility of undesirable effects like dizziness and convulsions should be taken into account when performing these activities. Visual impairment and vision blurred may have an effect on a patient's ability to drive or operate machinery (section 4.8).4.8 Undesirable effects
Azithromycin is well tolerated with a low incidence of side effects.
The table below lists the adverse reactions identified through clinical trial experience and post-marketing 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:\*\*
| | | | | | |
| --- | --- | --- | --- | --- | --- |
| \*\*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 | \*\*Not known\*\* frequency cannot be estimated from available data |
| \*\*Infections and infestations\*\* | | | | | |
| | | Candidiasis, Oral candidiasis Vaginal infection Pneumonia Fungal infection Bacterial infection Pharyngitis Gastroenteritis Respiratory disorder, Rhinitis. | | | Pseudo-membranous 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 Dysgeusia Paraesthesia | Hypoaesthesia Somnolence | | | Syncope Convulsion Psychomotor hyperactivity Anosmia Ageusia Parosmia Myasthenia gravis (see section 4.4) |
| \*\*Eye disorders\*\* | | | | | |
| | Visual impairment | | | | Blurred vision |
| \*\*Ear and labyrinth disorders\*\* | | | | | |
| | Deafness | Ear disorder Hearing Impaired, tinnitus | Vertigo | | |
| \*\*Cardiac disorders\*\* | | | | | |
| | | Palpitations | | | Torsades de pointes (see section 4.4) Arrhythmia (see section 4.4) including ventricular tachycardia Electro-cardiogram QT prolonged (see section 4.4) |
| \*\*Vascular disorders\*\* | | | | | |
| | | Hot flush | | | Hypotension |
| \*\*Respiratory, thoracic and mediastinal disorders\*\* | | | | | |
| | | Dyspnoea Epistaxis | | | |
| \*\*Gastrointestinal disorders\*\* | | | | | |
| Diarrhoea Abdominal pain, Nausea, flatulence | Vomiting dyspepsia | Constipation Dysphagia Gastritis dysphagia Abdominal distension Dry mouth Eructation Mouth ulceration Salivary Hypersecretion | | | Pancreatitis, Tongue and teeth discoloration |
| \*\*Hepatobiliary disorders\*\* | | | | | |
| | | Hepatitis | Hepatic function abnormal | | Hepatic failure (which has rarely resulted in death) (see section 4.4) Hepatitis fulminant Hepatic necrosis Jaundice, cholestatic |
| \*\*Skin and subcutaneous tissue disorders\*\* | | | | | |
| | Pruritus Rash | Stevens-Johnson syndrome Photosensitivity reaction Urticaria Dermatitis Dry skin Hyperhidrosis | Allergic reactions including Angioneurotic oedema Acute generalised exanthematous pustulosis (AGEP) \\*§ DRESS (Drug reaction with eosinophilia and systemic symptoms) \\*§ | | Toxic epidermal necrolysis Erythema Multiforme |
| \*\*Musculoskeletal and connective tissue disorders\*\* | | | | | |
| | Arthralgia | Osteoarthritis Myalgia Back pain Neck pain | | | |
| \*\*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\*\* | | | | | |
| | Fatigue | Oedema Asthenia Malaise Face edema Chest pain Pyrexia Peripheral pain | | | |
| \*\*Investigations\*\* | | | | | |
| | Lymphocyte count decreased Eosinophil count increased Blood bicarbonate decreased Basophils increased Monocytes increased, Neutrophils increased | Aspartate 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 | | | Electrocardiogram QT prolonged (see \*\*section 4.4)\*\* |
| \*\*Injury and poisoning\*\* | | | | | |
| | | Post procedural complications | | | |
\\*ADR identified post-marketing
§ ADR frequency represented by the estimated upper limit of the 95% confidence interval calculated using the “ Rule of3” .
\*\*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:\*\*
| | | |
| --- | --- | --- |
| \*\*System Organ Class\*\* | \*\*Adverse reaction\*\* | \*\*Frequency\*\* |
| \*\*Metabolism and Nutrition Disorders\*\* | Anorexia | Common |
| \*\*Nervous System Disorders\*\* | Dizziness Headache Paraesthesia Dysgeusia | Common |
| Hypoesthesia | Uncommon |
| \*\*Eye Disorders\*\* | Visual impairment | Common |
| \*\*Ear and Labyrinth Disorders\*\* | Deafness | Common |
| Hearing impaired Tinnitus | Uncommon |
| \*\*Cardiac Disorders\*\* | Palpitations | Uncommon |
| \*\*Gastrointestinal Disorders\*\* | Diarrhoea Abdominal pain Nausea Flatulence Abdominal discomfort Loose stools | Very common |
| \*\*Hepatobiliary Disorders\*\* | Hepatitis | Uncommon |
| \*\*Skin and Subcutaneous Tissue Disorders\*\* | Rash Pruritus | Common |
| Steven-Johnson syndrome Photosensitivity reaction | Uncommon |
| \*\*Musculoskeletal and Connective Tissue Disorders\*\* | Arthralgia | Common |
| \*\*General Disorders and Administration Site Conditions\*\* | Fatigue | Common |
| Asthenia Malaise | Uncommon |
\*\*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 or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose
Adverse events experienced in higher than recommended doses were similar to those seen at normal doses.
\*Symptoms\*
The typical symptoms of an overdose with macrolide antibiotics include reversible loss of hearing, severe nausea, vomiting and diarrhoea.
\*Treatment\*
In the event of overdose, general symptomatic and supportive measures are indicated as required.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antibacterials for systemic use, macrolides. ATC code: J01FA10.
Azithromycin 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.
\*\*Mechanism of action\*\*
Azithromycin 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.
\*\*\*Cardiac electrophysiology:\*\*\*
QTc interval prolongation was studied in a randomised, placebo-controlled parallel trial in 116 healthy subjects, who received chloroquine (1000 mg), either alone or in combination with azithromycin (500 mg, 1000 mg and 1500 mg once daily). Concomitant administration of azithromycin increased the QTc interval in a dose and concentration-dependent manner. Compared to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were 5 (10) ms, 7 (12) ms and 9 (14) ms with concomitant administration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively.
\*\*\*PK/PD relationship:\*\*\*
For azithromycin the AUC/MIC is the major PK/PD parameter correlating best with the efficacy of azithromycin.
\*Mechanism of resistance:\*
The two most frequently occurring mechanisms of resistance to macrolides, such as azithromycin, its target modification (most often due to methylation of 23S rRNA) and active efflux. The occurrence of these mechanisms of resistance varies by species and within a species varies the frequency of the resistance of each geographical location.
The most important ribosomal modification that determines reduced binding of macrolides is post-transcriptional (N6)-dimethylation of adenine at nucleotide A2058 (Escherichia coli numbering system) of the 23S rRNA by methylases encoded by erm (erythromycin ribosome methylase) genes.
Ribosomal modifications often determine cross resistance (MLSB phenotype) to other classes of antibiotics whose ribosomal binding sites overlap those of the macrolides: the lincosamides (including clindamycin), and the streptogramin B (which include, for example, the quinupristin component of quinupristin/dalfopristin). Different erm genes are present in different bacterial species, in particular Streptococci and Staphylococci. Susceptibility to macrolides can also be affected by less frequently encountered mutational changes in nucleotides A2058 and A2059, and at some other positions of 23S rRNA, or in the large subunit ribosomal proteins L4 and L22.
Efflux pumps occur in a number of species, including Gram-negatives, such as Haemophilus influenzae (where they may determine intrinsically higher MICs) and Staphylococci. In Streptococci and Enterococci, an efflux pump that recognises 14- and 15-membered macrolides (which include, respectively, erythromycin and azithromycin) is encoded by mef (A) genes.
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.
Azithromycin demonstrates cross resistance with erythromycin-resistant gram-positive isolates. As discussed above, some ribosomal modifications determine cross resistance with other classes of antibiotics whose ribosomal binding sites overlap those of the macrolides: the lincosamides (including clindamycin), and the streptogramins B (which include, for example, the quinupristin component of quinupristin/dalfopristin).
A decrease in macrolide susceptibility over time has been noted particularly in Streptococcus pneumoniae and Staphylococcus aureus and is also observed in Streptococcus viridans and in Streptococcus agalactiae.
\*\*Breakpoints\*\*
EUCAST (European Committee on Antimicrobial Susceptibility Testing)
| | | |
| --- | --- | --- |
| | \*\*MIC breakpoint (mg/L)\*\* | |
| \*\*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\* | Note1 | Note1 |
| \*Moraxella catarrhalis\* | ≤ 0.25 | > 0.5 |
| \*Neisseria gonorrhoeae\* | ≤ 0.25 | > 0.5 |
\*\*Note1:\*\* Clinical evidence for the efficacy of macrolides in H. influenzae respiratory infections is conflicting due to high spontaneous cure rates. Should there be a need to test any macrolide against this species, the epidemiological cut-offs (ECOFFs) should be used to detect strains with acquired
\*\*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\\*\* 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\* |
\\* Clinical effectiveness is demonstrated by sensitive isolated organisms for approved clinical indications.
Susceptibility testing breakpoints
MIC (minimum inhibitory concentration) interpretive criteria for susceptibility testing have been established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for Azithromycin and are listed here:
\*\*Paediatric population\*\*
Following the assessment of studies conducted in children, the use of azithromycin is not recommended for the treatment of malaria, neither as monotherapy nor combined with chloroquine or artemisinin based drugs, as non-inferiority to anti-malarial drugs recommended in the treatment of uncomplicated malaria was not established.5.2 Pharmacokinetic properties
\*\*Absorption:\*\*
Bioavailability of azithromycin after oral administration is approximately 37%. Peak plasma concentrations are attained after 2-3 hours. The mean maximum concentration observed (Cmax) after a single dose of 500 mg is approximately 0.4 μg/ml.
\*\*Distribution:\*\*
Orally administered azithromycin is widely distributed throughout the body.
Pharmacokinetic studies have demonstrated that the concentrations of azithromycin measured in tissues are noticeably higher (up to 50 times the maximum observed concentration in plasma) than those measured in plasma. This indicates that the agent strongly binds to tissues (steady-state distribution volume approx. 31 l/kg).
At the recommended dose no accumulation appears in the serum. Accumulation appears in tissues where levels are much higher than in serum. Three days after administration of 500 mg as a single dose or in partial doses concentrations of 1,3-4,8 μg/g, 0,6-2,3 μg/g, 2,0-2,8 μg/g and 0-0,3 μg/ml have been measured in resp. lung, prostate, tonsil and serum. These concentrations are higher than the MIC90 of the most common pathogens.
In experimental \*in vitro\* and \*in vivo\* studies azithromycin accumulates in phagocytes. Release is stimulated by active phagocytosis. In animal models this process contributes to the accumulation of azithromycin in tissue.
Binding of azithromycin to serum proteins is variable and varies from 50% at 0,05 mg/l to 18% at 0,5 mg/l, depending on the serum concentration.
\*\*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 is excreted in unchanged form with the urine over a period of 3 days; the major proportion in the first 24 hours. Concentrations of up to 237 μg/ml azithromycin, 2 days after a 5-day course of treatment, have been found in human bile. Ten metabolites have been identified (formed by N and O demethylation, by hydroxylation of the desosamine and aglycone rings, and by splitting of the cladinose conjugate). Investigations suggest that the metabolites do not play a role in the microbiological activity of azithromycin.
\*\*Pharmacokinetics in Special populations:\*\*
\*Renal Insufficiency:\*
Following 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 > 80ml/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 azithromycin compared to normal hepatic function. In these patients, urinary recovery of azithromycin appears to increase perhaps to compensate for reduced hepatic clearance.
\*Elderly:\*
The 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.
In elderly volunteers (> 65 years) higher (29%) AUC values have been measured after a 5 day treatment than in younger volunteers (< 45 years). These differences are not regarded as clinically relevant; dose adjustment is therefore not recommended.
\*Infants, toddlers, children and adolescents:\*
Pharmacokinetics has 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 25, the Cmax achieved is slightly lower than in adults, with 224μg/l in children aged 0.6-5 years and after 3 days dosing, and 383 μg/l in those aged 6-15 years. The half-life of 36 h in the older children was within the expected range for adults.5.3 Preclinical safety data
Phospholipidosis (intracellular phospholipid accumulation) has been observed in several tissues (e.g. eye, dorsal rootganglia, 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 beenshown to be reversible after cessation of azithromycin treatment. The significance of the finding for animals and humans is unknown.
Electrophysiological investigations have shown that azithromycin prolongs the QT interval.
\*Carcinogenic potential:\*
Long-term studies in animals have not been performed to evaluate carcinogenic potential.
\*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 body weight/ day led to mild retardation in foetal ossification and in maternal weight gain. In peri- and postnatal studies in rats mild retardations in physical and reflex development were noted following treatment with 50 mg/kg/day azithromycin and above.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
\*Tablet core\*:
Calcium hydrogen phosphate, anhydrous
Starch, pregelatinized (maize starch)
Croscarmellose sodium
Sodium lauryl sulfate
Magnesium stearate
\*Tablet coating\*:
Lactose monohydrate
Hypromellose
Titanium dioxide (E 171)
Triacetin6.2 Incompatibilities
Not applicable.6.3 Shelf life
3 years.6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.6.5 Nature and contents of container
Azithromycin film-coated tablets are available in clear PVC- Aluminium blister packs.
\*\*Blister packs:\*\* 2, 3, 4, 6 and 12 film-coated tablets
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements
- Instruction Content
- ## Composition
Each film-coated tablet contains 500 mg of azithromycin (as dihydrate).
\*\*Excipient with known effect\*\*: Each film-coated tablet contains 10.26 mg of lactose.
For the full list of excipients, see section 6.1.
## Pharmaceutical Form
Film-coated tablet.
\*\*\*Azithromycin 500 mg film-coated tablets:\*\*\*
White to off-white, oval shaped, film coated biconvex tablets debossed with “6” and “7” on either side of the score-line on one side and “D” on other side. The tablet can be divided into equal doses. The size is 17.1 mm x 8.5 mm.
## Clinical Particulars
4.1 Therapeutic indications
Azithromycin is indicated for the following bacterial infections induced by microorganisms susceptible to azithromycin (see sections 4.4 and 5.1):
• 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
• Infections of the skin and soft tissues of mild to moderate severity e.g. folliculitis, cellulitis, erysipelas
• Uncomplicated genital infections due to Chlamydia trachomatis \*and\* Neisseria gonorrhoeae.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.4.2 Posology and method of administration
\*\*Posology\*\*
Azithromycin should be given as a single daily dose. Duration of the treatment for the different infection diseases is given below.
\*\*Children over 45 kg body weight and adults, including elderly patients:\*\*
The total dose is 1500 mg, administered as 500 mg once daily for 3 days. Alternatively, the same total dose (1500 mg) can be administered in a period of 5 days, 500 mg on the first day and 250 mg on day 2 to 5.
In the case of 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 with250 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:\*\*
\*\*Children and adolescents with a body weight below 45 kg\*\*
Azithromycin tablets are not suitable for patients under 45 kg body weight. Other dosage forms are available for this group of patients.
\*\*Elderly patients\*\*
For elderly patients the same dose as for adults can be applied. 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. (see section 4.4).
\*\*Patients with renal impairment\*\*
Dose adjustment is not required 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).
\*\*Patients with hepatic impairment\*\*
Dose adjustment is not required for patients with mild to moderate hepatic dysfunction (see section 4.4). 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
Azithromycin should be given as a single daily dose. The tablets can be taken with or without food. The tablets should be taken with ½ glass of water.4.3 Contraindications
Hypersensitivity to the active substance, erythromycin, any macrolide, ketolide antibiotic, or to any of the excipient listed in section 6.1.4.4 Special warnings and precautions for use
H\*ypersensitivity\*
As with erythromycin and other macrolides, rare serious allergic reactions, including angioneurotic oedema and anaphylaxis (rarely fatal), dermatologic reactions including acute generalized 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 azithromycin have resulted in recurrent symptoms and required a longer period of observation and treatment.
If an allergic reaction occurs, the medicinal product 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.
\*\*\*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 (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.
\*Infantile hypertrophic pyloric stenosis (IHPS)\*
Following the use of azithromycin in neonates (treatment up to 42 days of life), infantile hypertrophic pyloric stenosis (IHPS) has been reported. Parents and caregivers should be informed to contact their physician if vomiting or irritability with feeding occurs
\*Ergot alkaloids and azithromycin\*
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 ergotamine derivatives and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administered (see section 4.5).
\*Superinfections:\*
As with any antibiotic preparation, it is recommended to pay attention to signs of superinfection with nonsusceptible microorganisms like fungi. A superinfection may require an interruption of the azithromycin treatment and initiation of adequate measures.
\*Clostridium difficile\* associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including azithromycin, and may range in severity from mild diarrhoea 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 diarrhoea 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 case of CDAD anti-peristaltics are contraindicated. Discontinuation of therapy with azithromycin and the administration of specific treatment for C. difficile should be considered.
\*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).
\*Cardiovascular events\*
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, including azithromycin (see section 4.8). Therefore as the following situations may lead to an increased risk for ventricular arrhythmias (including torsade de pointes) which can lead to cardiac arrest, azithromycin should be used with caution in patients with ongoing proarrhythmic conditions (especially women and elderly patients) such as patients:
- With congenital or documented acquired 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.
Epidemiological studies investigating the risk of adverse cardiovascular outcomes with macrolides have shown variable results. Some observational studies have identified a rare short term risk of arrhythmia, myocardial infarction and cardiovascular mortality associated with macrolides including azithromycin. Consideration of these findings should be balanced with treatment benefits when prescribing azithromycin.
\*Myasthenia gravis\*
Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia syndrome have been reported in patients receiving azithromycin therapy (see section 4.8).
\*\*\*Hydroxychloroquine or chloroquine\*\*\*
Carefully consider the balance of benefits and risks before prescribing azithromycin for any patients taking hydroxychloroquine or chloroquine, because of the potential for an increased risk of cardiovascular events and cardiovascular mortality (see section 4.5).
\*\*Paediatric population\*\*
Safety and efficacy for the prevention or treatment of \*Mycobacterium avium\* complex in children have not been established.
\*\*The following should be considered before prescribing azithromycin:\*\*
Azithromycin is not suitable for treatment of severe infections where a high concentration of the antibiotic in the blood is rapidly needed.
The selection of azithromycin to treat an individual patient should take into account the appropriateness of using a macrolide antibacterial agent based on adequate diagnosis to ascertain the bacterial etiology of the infection in the approved indications and the prevalence of resistance to azithromycin or other macrolides.
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/ tonsillitis\*
Azithromycin 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. 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.
\*Sinusitis\*
Often, azithromycin is not the substance of first choice for the treatment of sinusitis.
\*Acute otitis media\*
Often, azithromycin is not the substance of first choice for the treatment of acute otitis media.
\*Skin and soft tissue infections\*
The 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 wounds:\*
Azithromycin is not indicated for the treatment of infected burn wounds.
\*Sexually transmitted disease:\*
In case of sexually transmitted diseases a concomitant infection by \*T. pallidium\* should be excluded.
\*Neurological or psychiatric diseases:\*
Azithromycin should be used with caution in patients with neurological or psychiatric disorders.
Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
\*\*\*Lactose\*\*\*
Patients with rare hereditary problems of galactose intolerance, total lactose deficiency or glucose-galactose malabsorption should not take this medicine.
\*\*\*Sodium\*\*\*
Azithromycin contains less than 1 mmol (23 mg) of sodium per tablet, that is to say it is essentially 'sodium-free.'4.5 Interaction with other medicinal products and other forms of interaction
\*Antacids:\*
In a pharmacokinetic study investigating the effects of simultaneous administration of antacids with azithromycin, no effect on overall bioavailability was seen, although peak serum levels were reduced by approximately 25%. In patients receiving both azithromycin and antacids, the medicinal products should not be taken simultaneously. Azithromycin must be taken at least 1 hour before or 2 hours after 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.
Co-administration 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.
\*Cetirizine:\*
In 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.
\*Digoxin (P-gp substrates) and colchicine:\*
Concomitant administration of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine, 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\*.\* Clinical monitoring, and possibly serum digoxin levels, during treatment with azithromycin and after its discontinuation are necessary\*.\*
\*Zidovudine:\*
Single 1000 mg doses and multiple doses of 600 mg or 1200 mg 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.
\*Ergotamine derivatives:\*
Due 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.
Astemizole, alfentanil
There are no known data on interactions with astemizole or alfentanil. Caution is advised in the coadministration of these medicines with Azithromycin because of the known enhancing effect of these medicines when used concurrently with the macrolide antibiotic erythromycin.
\*Atorvastatin:\*
Coadministration 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, postmarketing cases of rhabdomyolysis in patients receiving azithromycin with statins have been reported.
\*Carbamazepine:\*
In 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.
\*Cimetidine:\* In 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 Anticoagulants:\*
In 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 postmarketing 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 thefrequency of monitoring prothrombin time when azithromycin is used in patients receiving coumarintypeoral anticoagulants.
\*Cyclosporin:\*
In 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.
\*Efavirenz:\*
Coadministration 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.
\*Fluconazole:\*
Coadministration of a single dose of 1200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. Total exposure and halflife of azithromycin were unchanged by the coadministration of fluconazole, however, a clinically insignificant decrease in Cmax (18%) of azithromycin was observed.
\*Indinavir:\*
Coadministration 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.
\*Methylprednisolone:\*
In a pharmacokinetic interaction study in healthy volunteers, azithromycin had no significant effect on the pharmacokinetics of methylprednisolone.
\*Midazolam:\*
In 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.
\*Nelfinavir:\*
Coadministration 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.
\*Rifabutin:\*
Coadministration of azithromycin and rifabutin did not affect the serum concentrations of either medicinal product. 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).
\*Sildenafil:\*
In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3days) on the AUC and Cmax of sildenafil or its major circulating metabolite.
\*Terfenadine:\*
Pharmacokinetic 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.
\*Theophylline:\* There 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.
\*Triazolam:\*
In 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/sulfamethoxazole:\*
Coadministration 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.
\*\*Hydroxychloroquine or chloroquine:\*\* Observational data have shown that co-administration of azithromycin with hydroxychloroquine in patients with rheumatoid arthritis is associated with an increased risk of cardiovascular events and cardiovascular mortality. Carefully consider the balance of benefits and risks before prescribing azithromycin for any patients taking hydroxychloroquine. Similar careful consideration of the balance of benefits and risk should also be undertaken before prescribing azithromycin for any patients taking chloroquine, because of the potential for a similar risk with chloroquine.
\*\*Medicinal products known to prolong the QT interval\*\*
Azithromycin should be used with caution in patients receiving medicines known to prolong the QT interval with potential to induce cardiac arrhythmia, e.g. hydroxychloroquine.
\*Cisapride\*
Cisapride 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.4.6 Fertility, pregnancy and lactation
\*\*Pregnancy\*\*
Animal 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.
There is a large amount of data from observational studies performed in several countries on exposure to azithromycin during pregnancy, compared to no antibiotic use or use of another antibiotic during the same period (> 7,300 first trimester exposures). While most studies do not suggest an association with adverse foetal effects such as major congenital malformations or cardiovascular malformations, there is limited epidemiological evidence of an increased risk of miscarriage following azithromycin exposure in early pregnancy. Therefore, azithromycin should only be used during pregnancy if clinically needed and the benefit of treatment is expected to outweigh any small increased risks which may exist.
\*\*Breastfeeding\*\*
Azithromycin has been reported to be secreted into human breast milk, The limited information available from published literature indicates azithromycin is present in human milk at an estimated highest median daily dose of 0.1 to 0.7 mg / kg / day. No serious side effects have been observed by azithromycin in breast-fed infants.
A decision should be taken whether breastfeeding is discontinued or that treatment with azithromycin is discontinued/initiated or not, taking into account the benefit of breastfeeding for the child and the benefit of treatment for the woman.
\*\*Fertility\*\*
In fertility studies conducted in rat, reduced pregnancy rates were noted following administration of azithromycin. The relevance of this finding to humans is unknown.4.7 Effects on ability to drive and use machines
No data are available regarding the influence of azithromycin on a patient's ability to drive or operate machinery. However, the possibility of undesirable effects like dizziness and convulsions should be taken into account when performing these activities. Visual impairment and vision blurred may have an effect on a patient's ability to drive or operate machinery (section 4.8).4.8 Undesirable effects
Azithromycin is well tolerated with a low incidence of side effects.
The table below lists the adverse reactions identified through clinical trial experience and post-marketing 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:\*\*
| | | | | | |
| --- | --- | --- | --- | --- | --- |
| \*\*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 | \*\*Not known\*\* frequency cannot be estimated from available data |
| \*\*Infections and infestations\*\* | | | | | |
| | | Candidiasis, Oral candidiasis Vaginal infection Pneumonia Fungal infection Bacterial infection Pharyngitis Gastroenteritis Respiratory disorder, Rhinitis. | | | Pseudo-membranous 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 Dysgeusia Paraesthesia | Hypoaesthesia Somnolence | | | Syncope Convulsion Psychomotor hyperactivity Anosmia Ageusia Parosmia Myasthenia gravis (see section 4.4) |
| \*\*Eye disorders\*\* | | | | | |
| | Visual impairment | | | | Blurred vision |
| \*\*Ear and labyrinth disorders\*\* | | | | | |
| | Deafness | Ear disorder Hearing Impaired, tinnitus | Vertigo | | |
| \*\*Cardiac disorders\*\* | | | | | |
| | | Palpitations | | | Torsades de pointes (see section 4.4) Arrhythmia (see section 4.4) including ventricular tachycardia Electro-cardiogram QT prolonged (see section 4.4) |
| \*\*Vascular disorders\*\* | | | | | |
| | | Hot flush | | | Hypotension |
| \*\*Respiratory, thoracic and mediastinal disorders\*\* | | | | | |
| | | Dyspnoea Epistaxis | | | |
| \*\*Gastrointestinal disorders\*\* | | | | | |
| Diarrhoea Abdominal pain, Nausea, flatulence | Vomiting dyspepsia | Constipation Dysphagia Gastritis dysphagia Abdominal distension Dry mouth Eructation Mouth ulceration Salivary Hypersecretion | | | Pancreatitis, Tongue and teeth discoloration |
| \*\*Hepatobiliary disorders\*\* | | | | | |
| | | Hepatitis | Hepatic function abnormal | | Hepatic failure (which has rarely resulted in death) (see section 4.4) Hepatitis fulminant Hepatic necrosis Jaundice, cholestatic |
| \*\*Skin and subcutaneous tissue disorders\*\* | | | | | |
| | Pruritus Rash | Stevens-Johnson syndrome Photosensitivity reaction Urticaria Dermatitis Dry skin Hyperhidrosis | Allergic reactions including Angioneurotic oedema Acute generalised exanthematous pustulosis (AGEP) \\*§ DRESS (Drug reaction with eosinophilia and systemic symptoms) \\*§ | | Toxic epidermal necrolysis Erythema Multiforme |
| \*\*Musculoskeletal and connective tissue disorders\*\* | | | | | |
| | Arthralgia | Osteoarthritis Myalgia Back pain Neck pain | | | |
| \*\*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\*\* | | | | | |
| | Fatigue | Oedema Asthenia Malaise Face edema Chest pain Pyrexia Peripheral pain | | | |
| \*\*Investigations\*\* | | | | | |
| | Lymphocyte count decreased Eosinophil count increased Blood bicarbonate decreased Basophils increased Monocytes increased, Neutrophils increased | Aspartate 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 | | | Electrocardiogram QT prolonged (see \*\*section 4.4)\*\* |
| \*\*Injury and poisoning\*\* | | | | | |
| | | Post procedural complications | | | |
\\*ADR identified post-marketing
§ ADR frequency represented by the estimated upper limit of the 95% confidence interval calculated using the “ Rule of3” .
\*\*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:\*\*
| | | |
| --- | --- | --- |
| \*\*System Organ Class\*\* | \*\*Adverse reaction\*\* | \*\*Frequency\*\* |
| \*\*Metabolism and Nutrition Disorders\*\* | Anorexia | Common |
| \*\*Nervous System Disorders\*\* | Dizziness Headache Paraesthesia Dysgeusia | Common |
| Hypoesthesia | Uncommon |
| \*\*Eye Disorders\*\* | Visual impairment | Common |
| \*\*Ear and Labyrinth Disorders\*\* | Deafness | Common |
| Hearing impaired Tinnitus | Uncommon |
| \*\*Cardiac Disorders\*\* | Palpitations | Uncommon |
| \*\*Gastrointestinal Disorders\*\* | Diarrhoea Abdominal pain Nausea Flatulence Abdominal discomfort Loose stools | Very common |
| \*\*Hepatobiliary Disorders\*\* | Hepatitis | Uncommon |
| \*\*Skin and Subcutaneous Tissue Disorders\*\* | Rash Pruritus | Common |
| Steven-Johnson syndrome Photosensitivity reaction | Uncommon |
| \*\*Musculoskeletal and Connective Tissue Disorders\*\* | Arthralgia | Common |
| \*\*General Disorders and Administration Site Conditions\*\* | Fatigue | Common |
| Asthenia Malaise | Uncommon |
\*\*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 or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose
Adverse events experienced in higher than recommended doses were similar to those seen at normal doses.
\*Symptoms\*
The typical symptoms of an overdose with macrolide antibiotics include reversible loss of hearing, severe nausea, vomiting and diarrhoea.
\*Treatment\*
In the event of overdose, general symptomatic and supportive measures are indicated as required.
## Pharmacological Properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antibacterials for systemic use, macrolides. ATC code: J01FA10.
Azithromycin 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.
\*\*Mechanism of action\*\*
Azithromycin 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.
\*\*\*Cardiac electrophysiology:\*\*\*
QTc interval prolongation was studied in a randomised, placebo-controlled parallel trial in 116 healthy subjects, who received chloroquine (1000 mg), either alone or in combination with azithromycin (500 mg, 1000 mg and 1500 mg once daily). Concomitant administration of azithromycin increased the QTc interval in a dose and concentration-dependent manner. Compared to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were 5 (10) ms, 7 (12) ms and 9 (14) ms with concomitant administration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively.
\*\*\*PK/PD relationship:\*\*\*
For azithromycin the AUC/MIC is the major PK/PD parameter correlating best with the efficacy of azithromycin.
\*Mechanism of resistance:\*
The two most frequently occurring mechanisms of resistance to macrolides, such as azithromycin, its target modification (most often due to methylation of 23S rRNA) and active efflux. The occurrence of these mechanisms of resistance varies by species and within a species varies the frequency of the resistance of each geographical location.
The most important ribosomal modification that determines reduced binding of macrolides is post-transcriptional (N6)-dimethylation of adenine at nucleotide A2058 (Escherichia coli numbering system) of the 23S rRNA by methylases encoded by erm (erythromycin ribosome methylase) genes.
Ribosomal modifications often determine cross resistance (MLSB phenotype) to other classes of antibiotics whose ribosomal binding sites overlap those of the macrolides: the lincosamides (including clindamycin), and the streptogramin B (which include, for example, the quinupristin component of quinupristin/dalfopristin). Different erm genes are present in different bacterial species, in particular Streptococci and Staphylococci. Susceptibility to macrolides can also be affected by less frequently encountered mutational changes in nucleotides A2058 and A2059, and at some other positions of 23S rRNA, or in the large subunit ribosomal proteins L4 and L22.
Efflux pumps occur in a number of species, including Gram-negatives, such as Haemophilus influenzae (where they may determine intrinsically higher MICs) and Staphylococci. In Streptococci and Enterococci, an efflux pump that recognises 14- and 15-membered macrolides (which include, respectively, erythromycin and azithromycin) is encoded by mef (A) genes.
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.
Azithromycin demonstrates cross resistance with erythromycin-resistant gram-positive isolates. As discussed above, some ribosomal modifications determine cross resistance with other classes of antibiotics whose ribosomal binding sites overlap those of the macrolides: the lincosamides (including clindamycin), and the streptogramins B (which include, for example, the quinupristin component of quinupristin/dalfopristin).
A decrease in macrolide susceptibility over time has been noted particularly in Streptococcus pneumoniae and Staphylococcus aureus and is also observed in Streptococcus viridans and in Streptococcus agalactiae.
\*\*Breakpoints\*\*
EUCAST (European Committee on Antimicrobial Susceptibility Testing)
| | | |
| --- | --- | --- |
| | \*\*MIC breakpoint (mg/L)\*\* | |
| \*\*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\* | Note1 | Note1 |
| \*Moraxella catarrhalis\* | ≤ 0.25 | > 0.5 |
| \*Neisseria gonorrhoeae\* | ≤ 0.25 | > 0.5 |
\*\*Note1:\*\* Clinical evidence for the efficacy of macrolides in H. influenzae respiratory infections is conflicting due to high spontaneous cure rates. Should there be a need to test any macrolide against this species, the epidemiological cut-offs (ECOFFs) should be used to detect strains with acquired
\*\*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\\*\* 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\* |
\\* Clinical effectiveness is demonstrated by sensitive isolated organisms for approved clinical indications.
Susceptibility testing breakpoints
MIC (minimum inhibitory concentration) interpretive criteria for susceptibility testing have been established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for Azithromycin and are listed here:
\*\*Paediatric population\*\*
Following the assessment of studies conducted in children, the use of azithromycin is not recommended for the treatment of malaria, neither as monotherapy nor combined with chloroquine or artemisinin based drugs, as non-inferiority to anti-malarial drugs recommended in the treatment of uncomplicated malaria was not established.5.2 Pharmacokinetic properties
\*\*Absorption:\*\*
Bioavailability of azithromycin after oral administration is approximately 37%. Peak plasma concentrations are attained after 2-3 hours. The mean maximum concentration observed (Cmax) after a single dose of 500 mg is approximately 0.4 μg/ml.
\*\*Distribution:\*\*
Orally administered azithromycin is widely distributed throughout the body.
Pharmacokinetic studies have demonstrated that the concentrations of azithromycin measured in tissues are noticeably higher (up to 50 times the maximum observed concentration in plasma) than those measured in plasma. This indicates that the agent strongly binds to tissues (steady-state distribution volume approx. 31 l/kg).
At the recommended dose no accumulation appears in the serum. Accumulation appears in tissues where levels are much higher than in serum. Three days after administration of 500 mg as a single dose or in partial doses concentrations of 1,3-4,8 μg/g, 0,6-2,3 μg/g, 2,0-2,8 μg/g and 0-0,3 μg/ml have been measured in resp. lung, prostate, tonsil and serum. These concentrations are higher than the MIC90 of the most common pathogens.
In experimental \*in vitro\* and \*in vivo\* studies azithromycin accumulates in phagocytes. Release is stimulated by active phagocytosis. In animal models this process contributes to the accumulation of azithromycin in tissue.
Binding of azithromycin to serum proteins is variable and varies from 50% at 0,05 mg/l to 18% at 0,5 mg/l, depending on the serum concentration.
\*\*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 is excreted in unchanged form with the urine over a period of 3 days; the major proportion in the first 24 hours. Concentrations of up to 237 μg/ml azithromycin, 2 days after a 5-day course of treatment, have been found in human bile. Ten metabolites have been identified (formed by N and O demethylation, by hydroxylation of the desosamine and aglycone rings, and by splitting of the cladinose conjugate). Investigations suggest that the metabolites do not play a role in the microbiological activity of azithromycin.
\*\*Pharmacokinetics in Special populations:\*\*
\*Renal Insufficiency:\*
Following 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 > 80ml/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 azithromycin compared to normal hepatic function. In these patients, urinary recovery of azithromycin appears to increase perhaps to compensate for reduced hepatic clearance.
\*Elderly:\*
The 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.
In elderly volunteers (> 65 years) higher (29%) AUC values have been measured after a 5 day treatment than in younger volunteers (< 45 years). These differences are not regarded as clinically relevant; dose adjustment is therefore not recommended.
\*Infants, toddlers, children and adolescents:\*
Pharmacokinetics has 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 25, the Cmax achieved is slightly lower than in adults, with 224μg/l in children aged 0.6-5 years and after 3 days dosing, and 383 μg/l in those aged 6-15 years. The half-life of 36 h in the older children was within the expected range for adults.5.3 Preclinical safety data
Phospholipidosis (intracellular phospholipid accumulation) has been observed in several tissues (e.g. eye, dorsal rootganglia, 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 beenshown to be reversible after cessation of azithromycin treatment. The significance of the finding for animals and humans is unknown.
Electrophysiological investigations have shown that azithromycin prolongs the QT interval.
\*Carcinogenic potential:\*
Long-term studies in animals have not been performed to evaluate carcinogenic potential.
\*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 body weight/ day led to mild retardation in foetal ossification and in maternal weight gain. In peri- and postnatal studies in rats mild retardations in physical and reflex development were noted following treatment with 50 mg/kg/day azithromycin and above.
## Pharmaceutical Particulars
6.1 List of excipients
\*Tablet core\*:
Calcium hydrogen phosphate, anhydrous
Starch, pregelatinized (maize starch)
Croscarmellose sodium
Sodium lauryl sulfate
Magnesium stearate
\*Tablet coating\*:
Lactose monohydrate
Hypromellose
Titanium dioxide (E 171)
Triacetin6.2 Incompatibilities
Not applicable.6.3 Shelf life
3 years.6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.6.5 Nature and contents of container
Azithromycin film-coated tablets are available in clear PVC- Aluminium blister packs.
\*\*Blister packs:\*\* 2, 3, 4, 6 and 12 film-coated tablets
Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements
