4.1. Therapeutic indications

Azithromycin is indicated for the treatment of the following infections in adults and adolescents weighing at least 45 kg (see sections 4.4 and 5.1):

• Acute streptococcal tonsillitis and pharyngitis

• Acute bacterial sinusitis

• Acute bacterial otitis media

• Community-acquired pneumonia (CAP)

• Acute bacterial skin and skin structure infections (ABSSSI)

• Erythema migrans (early localised Lyme disease)

• Periodontal abscesses and periodontitis

• Urethritis and cervicitis caused by Chlamydia trachomatis

• Urethritis and cervicitis caused by Neisseria gonorrhoeae, in combination with another appropriate antibacterial agent (e.g. ceftriaxone)

• Chronic prostatitis caused by Chlamydia trachomatis

• Chancroid

• Disseminated Mycobacterium avium complex (DMAC) infection in people living with advanced HIV infection, in combination with ethambutol

Azithromycin is also indicated for the prophylaxis of Mycobacterium avium complex (MAC) infection in people living with HIV with inadequate immune restoration.

Azithromycin is indicated for the treatment of adult patients with acute exacerbation of chronic bronchitis or with pelvic inflammatory disease, the latter always in combination with other appropriate antibacterial agent(s) (e.g. metronidazole).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2. Posology and method of administration

Posology

Adults and adolescents weighing at least 45 kg

Azithromycin should be administered as a single daily dose.

Table 1: Dosing recommendations for adults and adolescents weighing at least 45 kg

Indication

Azithromycin dosing regimen

Acute streptococcal tonsillitis and pharyngitis

Acute bacterial sinusitis

Acute bacterial otitis media

Acute exacerbation of chronic bronchitis*

Community-acquired pneumonia#

Acute bacterial skin and skin structure infections

Periodontal abscesses and periodontitis

500 mg/day for 3 days

or

500 mg on day 1, followed by 250 mg/day on days 2-5

Erythema migrans (early localised Lyme disease)

1000 mg on day 1, followed by 500 mg/day on days 2-10

Urethritis and cervicitis caused by Chlamydia trachomatis

1000 mg as a single dose

Urethritis and cervicitis caused by Neisseria gonorrhoeae, in combination with another appropriate antibacterial agent (e.g. ceftriaxone)

1000 mg or 2000 mg* as a single dose

Pelvic inflammatory disease, in combination with other appropriate agent(s) (e.g. metronidazole)*+

Only as an oral switch after intravenous administration if clinically indicated:

250 mg once daily to complete a 7- day course of treatment

Chronic prostatitis caused by Chlamydia trachomatis

500 mg/day on 3 consecutive days per week for 3 weeks

(total dose: 4500 mg)

Chancroid

1000 mg as a single dose

Treatment of disseminated Mycobacterium avium complex (DMAC) infection in people living with advanced HIV infection (in combination with ethambutol)

<500 mg> or <600 mg> once daily

Prophylaxis of Mycobacterium avium complex (MAC) infections in people living with HIV with inadequate immune restoration

<1200 mg> or <1250 mg> once a week

* for treatment of adults only

# in adults, oral treatment may also follow intravenous treatment, if clinically indicated to complete a 7- to 10-day total course of treatment (for details refer to the Summary of Product Characteristics of azithromycin IV formulations).

+ oral azithromycin should not be used for the initial treatment of pelvic inflammatory disease (for details refer to the Summary of Product Characteristics of azithromycin IV formulations).

Consideration should be given to the treatment regimens, doses and duration of treatment as recommended in updated treatment guidelines for each indication.

Missed dose

If 12 hours or less have passed since the missed dose, the patient should be advised to take it as soon as possible and then take the next dose at the regularly scheduled time. If more than 12 hours have passed since the time the dose is usually taken, the patient should be advised to wait until the next scheduled dose.

Special populations

Renal impairment

No dose adjustment is required in patients with GFR ≥10 ml/min. In patients with GFR <10 ml/min azithromycin should be administered with caution (see section 5.2).

Hepatic impairment

No dose adjustment is required in patients with mild (Child-Pugh Class A) or moderate hepatic impairment (Child-Pugh Class B) (see section 5.2). No data are available in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, azithromycin should be administered with caution in these patients (see section 4.4).

Elderly

No dose adjustment is required in elderly patients (see section 5.2). Since the elderly are more likely to experience proarrhythmic conditions, particular caution is recommended due to the risk of developing cardiac arrhythmia and torsade de pointes (see section 4.4).

Paediatric population

The safety and efficacy of Azithromycin for the treatment of adolescent girls with pelvic inflammatory disease has not been established.

There is no relevant use of Azithromycin for the treatment of acute exacerbations of chronic bronchitis in paediatric patients.

The safety and efficacy of Azithromycin in prevention or treatment of Mycobacterium avium complex infections in paediatric patients < 12 years has not been established.

Other pharmaceutical forms are available that may be more appropriate to treat patients unable to swallow tablets as well as paediatric patients weighing less than 45 kg.

Method of administration

For oral use.

Tablets should be swallowed whole as a single daily dose and may be taken with or without a meal. Administration immediately before a meal may enhance the gastrointestinal tolerability.

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

Potential for resistance

Azithromycin could favour the development of resistance due to the associated long-lasting and decreasing levels in plasma and tissues after the end of treatment (see section 5.2). Treatment with azithromycin should only be initiated after a careful assessment of the benefit and the risks, considering the local prevalence of resistance, and when preferred treatment regimens are not indicated.

Severe skin and hypersensitivity reactions

Rare serious allergic reactions, including angioedema and anaphylaxis (rarely fatal), severe cutaneous adverse reactions (SCARs) including Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalised exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported in association with azithromycin treatment (see section 4.8). At the time of prescription, patients should be advised of the signs and symptoms and monitored closely for skin reactions. 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, azithromycin 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 liver is the principal route of elimination for azithromycin, the use of azithromycin should be undertaken with caution in patients with significant hepatic disease. Cases of fulminant hepatitis potentially leading to life-threatening liver failure have been reported with azithromycin, some of which have resulted in death (see section 4.8). Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products. Patients should be advised to stop azithromycin administration and to contact their physician if signs and symptoms of liver dysfunction, such as rapid developing asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy develop. In such cases liver function tests/investigations should be performed immediately.

Infantile hypertrophic pyloric stenosis

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 derivatives

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 ergot and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administered (see section 4.5).

Clostridium difficile associated diarrhoea (CDAD), pseudomembranous colitis

CDAD and pseudomembranous colitis have been reported with azithromycin and may range in severity from mild diarrhoea to fatal colitis (see section 4.8). CDAD and pseudomembranous colitis must be considered in patients who present with diarrhoea during or subsequent to the administration of azithromycin. Discontinuation of therapy with azithromycin and the use of supportive measures together with the administration of specific treatment for C. difficile should be considered. Medicinal products that inhibit peristalsis should not be given.

Sexually transmitted infections

Neisseria gonorrhoeae is very likely to be resistant to macrolides, including the azalide azithromycin (see section 5.1). Therefore, azithromycin is not recommended for the treatment of uncomplicated gonorrhoea and pelvic inflammatory disease unless laboratory results have confirmed susceptibility of the organism to azithromycin. If left untreated or treated sub-optimally, this condition may lead to late onset complications such as infertility and ectopic pregnancy.

In addition, if single dose azithromycin is considered for the treatment of urethritis and cervicitis due to N. gonorrhoeae or C. trachomatis (see section 4.2), concomitant urogenital infection by Mycoplasma genitalium should be excluded due to the high risk of emergence of resistance in this organism.

Furthermore, a concomitant infection caused by Treponema pallidum should be excluded as symptoms of incubating syphilis could be masked delaying diagnosis.

For all patients with sexually transmitted urogenital infections, appropriate antibacterial therapy and microbiological follow-up tests should be initiated.

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).

QT interval prolongation

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 (see section 4.5)

• With electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesaemia

• With clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency

• Elderly patients: Elderly patients may be more susceptible to drug-associated effects on the QT interval

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).

Non-susceptible organisms

The use of azithromycin may result in the overgrowth of non-susceptible organisms. If superinfection occurs, interruption of treatment or other appropriate measures may be required.

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

Although azithromycin is a weak CYP450 inhibitor and does not interact significantly with CYP450 substrates, CYP3A4 inhibition cannot be completely ruled out. Therefore, caution is recommended in case of co-administration with CYP3A4 substrates with narrow therapeutic index.

Azithromycin is an inhibitor of the transporter P-glycoprotein (P-gp). Co-administration of azithromycin with P-gp substrates, such as digoxin and colchicine, may increase their exposure. For narrow therapeutic index drugs, caution and clinical and/or therapeutic drug monitoring and dose adjustment as appropriate are advised. The relatively long half-life of azithromycin should be taken into account in this context (see section 5.2).

Medicinal products that are known to prolong the QT interval

Azithromycin should be used with caution in patients receiving medicinal products known to prolong the QT interval (see section 4.4), such as antiarrhythmics of Classes IA (e.g. quinidine and procainamide) and III (e.g. dofetilide, amiodarone and sotalol), antipsychotic agents (e.g. pimozide), antidepressants (e.g. citalopram), fluoroquinolones (e.g. moxifloxacin and levofloxacin), cisapride, chloroquine and hydroxychloroquine.

Drug interaction information for azithromycin with potential concomitant medicinal products is summarised in the table and text below. The drug interactions described are based on clinical drug-drug interaction studies conducted with azithromycin or, where indicated, are potential drug interactions that may occur with azithromycin.

Table 2: Clinically relevant drug interactions between azithromycin and other medicinal products

Medicinal product (therapeutic area)

Interaction

Effect on exposure

Mechanism

Recommendation concerning co-administration

Atorvastatin (HMG CoA reductase inhibitor)

Azithromycin 500 mg orally once daily for 3 days.

Atorvastatin 10 mg orally once daily.

Azithromycin: ND

Atorvastatin:

↔ AUC

↔ Cmax

Atorvastatin is a CYP3A4 and P-gp substrate.

Caution should be exercised since post-marketing cases of rhabdomyolysis in patients receiving azithromycin concomitantly with statins have been reported.

Ciclosporin (immunosuppressant)

Azithromycin 500 mg orally once daily for 3 days.

Ciclosporin 10 mg/kg orally single dose.

Azithromycin: ND

Ciclosporin:

↔ AUC

↑Cmax 24 %

Ciclosporin is a CYP3A4 and P-gp substrate with narrow therapeutic index and/or competition for biliary excretion.

Clinical monitoring and therapeutic drug monitoring as appropriate should be performed during and after treatment with azithromycin. Ciclosporin dose should be adjusted if required.

Colchicine (gout)

Azithromycin: ND

Colchicine:

↑ 57% AUC0-t

↑ 22% Cmax

Colchicine is a P-gp substrate with narrow therapeutic index.

Clinical monitoring is needed during and after treatment with azithromycin.

Dabigatran (oral anticoagulant)

ND

Expected:

↑ Dabigatran

Dabigatran is a P-gp

substrate with narrow therapeutic index.

Caution should be exercised since post-marketing data suggest an increased risk for haemorrhages in patients receiving azithromycin concomitantly with dabigatran.

Digoxin (cardiac glycosides)

ND

Expected:

↑ Digoxin

Digoxin is a P-gp substrate with narrow therapeutic index.

Clinical monitoring, and possibly digoxin level monitoring, is needed during and after treatment with azithromycin.

Warfarin (oral anticoagulant)

Azithromycin 500 mg orally once daily for 1 day and then 250 mg orally once daily for 4 days.

Warfarin 15 mg orally single dose.

Azithromycin: ND

Warfarin: ND

No change in prothrombin time in clinical drug interaction study but post-marketing reports of potentiated anticoagulation of coumarin-type oral anticoagulants upon co-administration with azithromycin.

Not known.

A higher frequency of prothrombin time monitoring should be considered during and after treatment with azithromycin.

Note: statistically significant changes by more than 10% are indicated as “↑” or “↓”, no change as “↔”, not determined as “ND”.

No clinically relevant change in the exposure of azithromycin or the co-administered medicinal products was observed in clinical studies evaluating potential drug-drug interactions of azithromycin with oral antacids (aluminium hydroxide/magnesium hydroxide), carbamazepine, cetirizine, cimetidine, efavirenz, fluconazole, methylprednisolone, midazolam, rifabutin, sildenafil, theophylline, triazolam, trimethoprim/sulfamethoxazole and zidovudine.

Paediatric population

Interaction studies have only been performed in adults.

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 teratogenic effects was found. There are, however, no adequate and well-controlled studies in pregnant women.

There is a large amount of data from observational studies on exposure to azithromycin during pregnancy (more than 7000 azithromycin exposed pregnancies). Most of the studies do not suggest an increased risk of adverse foetal effects such as major congenital malformations or cardiovascular malformations.

Epidemiological evidence related to the risk of miscarriage following azithromycin exposure in early pregnancy is inconclusive. Animal studies do not indicate reproductive toxicity (see section 5.3). Azithromycin should only be used during pregnancy if clinically needed.

Breastfeeding

Azithromycin is excreted in human milk to substantial extent. No serious adverse effects of azithromycin on the breast-fed infants were observed, while effects such as diarrhoea, mucosal fungal infection as well as hypersensitivity can occur in breast-fed newborns/infants even at sub-therapeutic doses.

A decision must be made whether breast-feeding is discontinued or to discontinue/abstain from azithromycin therapy taking into account the benefit of breast-feeding 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

Azithromycin has a moderate influence on the ability to drive and use machines. Dizziness, drowsiness and convulsions have been reported in some patients taking azithromycin and some patients experienced visual and/or auditory impairment. This should be considered when assessing a patient's ability to drive and use machines (see section 4.8).

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions during treatment include diarrhoea, headache, vomiting, abdominal pain, nausea and abnormal laboratory test values. Other important adverse reactions include anaphylactic reactions, torsade de pointes, arrhythmia including ventricular tachycardia, pseudomembranous colitis and hepatic failure (see section 4.4). Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP) have been reported in association with azithromycin treatment (see section 4.4).

Tabulated list of adverse reactions

Adverse reactions identified through clinical trial experience and post marketing surveillance are listed below, by system organ class and frequency.

Frequencies of adverse reaction occurrence are defined as 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 (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 3: Tabulated list of adverse reactions

System organ class

Very common

Common

Uncommon

Rare

Not known

Infections and infestations

Candida infection

Pneumonia

Fungal infection

Bacterial infection

Vaginal infection

Pharyngitis

Gastroenteritis

Rhinitis

Oral candidiasis

Blood and lymphatic system disorders

Lymphocyte count decreased

Eosinophil count increased

Basophil count increased

Monocyte count increased

Neutrophil count increased

Leukopenia

Neutropenia

Eosinophilia

Platelet count increased

Haematocrit decreased

Thrombocytopenia

Haemolytic anaemia

Immune system disorders

Angioedema

Hypersensitivity (see section 4.4)

Anaphylactic reaction

Metabolism and nutrition disorders

Decreased appetite#2

Psychiatric disorders

Nervousness

Insomnia

Agitation

Anxiety

Delirium

Hallucination

Aggression

Nervous system disorders

Headache

Dizziness#2

Dysgeusia#2

Paraesthesia#2

Somnolence

Myasthenia gravis (see section 4.4)

Seizure

Anosmia

Ageusia

Hypoaesthesia#3

Psychomotor hyperactivity

Parosmia

Syncope

Eye disorders

Visual impairment#2

Ear and labyrinth disorders

Ear disorder

Vertigo

Deafness#2

Hypoacusis#3

Tinnitus#3

Cardiac disorders

Palpitations

Torsades de pointes (see section 4.4)

Arrhythmia including ventricular tachycardia (see section 4.4)

Electrocardiogram QT prolonged (see section 4.4)

Vascular disorders

Hot flush

Hypotension

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Respiratory disorder

Epistaxis

Gastrointestinal disorders

Diarrhoea

Abdominal discomfort*

Vomiting

Abdominal pain#1

Nausea#1

Gastritis

Constipation

Dyspepsia

Dysphagia

Abdominal distension

Dry mouth

Mouth ulceration

Salivary hypersecretion

Eructation

Flatulence#1

Pancreatitis

Pseudomembranous colitis (see section 4.4)

Tongue discolouration

Hepatobiliary disorders

Hepatitis*

Aspartate aminotransferase increased

Alanine aminotransferase increased

Blood bilirubin increased

Blood alkaline phosphatase increased

Hepatic function abnormal

Jaundice cholestatic

Hepatic failure (see section 4.4)

Hepatitis fulminant

Hepatic necrosis

Skin and subcutaneous tissue disorders

Rash#2

Pruritus#2

Urticaria

Dermatitis

Dry skin

Hyperhidrosis

Acute generalised exanthematous pustulosis (AGEP)

Drug reaction with eosinophilia and systemic symptoms (DRESS)

Photosensitivity reaction#3

Toxic epidermal necrolysis

Stevens-Johnson syndrome#3

Erythema multiforme

Musculoskeletal and connective tissue disorders

Osteoarthritis

Myalgia

Back pain

Neck pain

Arthralgia#2

Renal and urinary disorders

Dysuria

Renal pain

Blood urea increased

Blood creatinine increased

Acute kidney injury

Tubulointerstitial nephritis

Reproductive system and breast disorders

Intermenstrual bleeding

Testicular disorder

General disorders and administration site conditions

Oedema

Asthenia

Malaise

Fatigue#2

Face oedema

Chest pain

Pyrexia

Pain

Peripheral oedema

Investigations

Blood bicarbonate decreased

Blood potassium abnormal

Blood chloride increased

Blood glucose increased

Blood bicarbonate increased

Blood sodium abnormal

Injury, poisoning and procedural complications

Post procedural complication

* These ADRs were only seen during azithromycin administration for MAC prophylaxis and/or therapy

#1 In MAC the frequency of these ADRs was Very Common (>1/10).

#2 In MAC the frequency of these ADRs was Common (>1/100 to <1/10).

#3 In MAC the frequency of these ADRs was Uncommon (>1/1 000 to <1/100).

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

Symptoms

Adverse reactions experienced in higher than recommended doses were similar to those seen at normal doses (see section 4.8). The typical symptoms of an overdose with azithromycin include gastrointestinal symptoms, i.e. nausea, vomiting, abdominal pain and diarrhoea.

Treatment

In the event of an overdose, general symptomatic and support of vital functions are indicated, and if required, administration of medicinal charcoal or gastric lavage.

There are no data on the effects of dialysis on the elimination of azithromycin. However, due to the elimination mechanism of azithromycin, dialysis is unlikely to result in significant removal of the active substance.