4.1. Therapeutic indications

Azithromycin is indicated for the treatment of the following infections when known or likely to be due to one or more susceptible microorganisms (see section 5.1):

- bronchitis

- community-acquired pneumonia

- sinusitis

- pharyngitis/tonsillitis (see section 4.4 regarding streptococcal infections)

- otitis media

- skin and soft tissue infections

- uncomplicated genital infections due to Chlamydia trachomatis and Neisseria gonorrhoeae.

Considerations should be given to official guidance regarding the appropriate use of antibacterial agents.

4.2. Posology and method of administration

Posology

Zithromax should be given as a single daily dose.

Zithromax Suspension can be taken with or without food.

Children over 45 kg body weight and adults, including elderly patients: The total dose of azithromycin is 1500 mg which should be given over three days (500 mg once daily).

In uncomplicated genital infections due to Chlamydia trachomatis, the dose is 1000 mg as a single oral dose. For susceptible Neisseria gonorrhoeae the recommended dose is 1000 mg or 2000 mg of azithromycin in combination with 250 mg or 500 mg ceftriaxone according to local clinical treatment guidelines. For patients who are allergic to penicillin and/or cephalosporins, prescribers should consult local treatment guidelines.

However, 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).

Paediatric population:

In children under 45 kg body weight: Zithromax Suspension should be used for children under 45 kg. There is no information on children less than 6 months of age. The dose in children is 10 mg/kg as a single daily dose for 3 days:

Up to 15 kg (less than 3 years): Measure the dose as closely as possible using the 10 ml oral dosing syringe provided. The syringe is graduated in 0.25 ml divisions, providing 10 mg of azithromycin in every graduation.

For children weighing more than 15 kg, Zithromax Suspension should be administered using the spoon provided according to the following guidance:

15-25 kg (3-7 years): 5 ml (200 mg) given as 1 x 5 ml spoonful, once daily for 3 days.

26-35 kg (8-11 years): 7.5 ml (300 mg) given as 1 x 7.5 ml spoonful, once daily for 3 days.

36-45 kg (12-14 years): 10 ml (400 mg) given as 1 x 10 ml spoonful, once daily for 3 days.

Over 45 kg: Dose as per adults.

See section 6.5 for appropriate pack size to use depending on age/body weight of child.

The specially supplied measure should be used to administer Zithromax suspension to children.

Renal impairment:

No dose adjustment is necessary in patients with GFR 10 – 80 ml/min. Caution should be exercised when azithromycin is administered to patients with GFR < 10 ml/min (see section 4.4 and section 5.2).

Hepatic impairment:

Since azithromycin is metabolised in the liver and excreted in the bile, the drug should not be given to patients suffering from severe liver disease. No studies have been conducted regarding treatment of such patients with azithromycin (see section 4.4).

Method of administration

Zithromax Suspension is for oral administration only.

4.3. Contraindications

Zithromax is contra-indicated in patients with a known hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic, or to any of the excipients (listed in section 6.1).

4.4. Special warnings and precautions for use

Hypersensitivity

As with erythromycin and other macrolides, serious allergic reactions including angioneurotic oedema and anaphylaxis (rarely fatal), Acute Generalized Exanthematous Pustulosis (AGEP) 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.

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 derivatives

In patients receiving ergot derivatives, ergotism has been precipitated by co-administration of some macrolide antibiotics. There are no data concerning the possibility of an interaction between ergot and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administrated.

Prolongation of the QT interval

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). The following situations may lead to an increased risk for ventricular arrhythmias (including torsades de pointes) which can lead to cardiac arrest (possibly fatal). Azithromycin should be used with caution in patients with ongoing proarrhythmic conditions (especially women and elderly patients) such as patients:

• With congenital or documented QT prolongation

• Currently receiving treatment with other active substance 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 case of hypokalaemia and hypomagnesemia

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

Superinfection

As with any antibiotic preparation, observation for signs of superinfection with non-susceptible organisms including fungi is recommended.

Clostridium difficile associated diarrhoea

Clostridium difficile associated diarrhoea (CDAD) has been reported with the use of nearly all antibacterial agents, including azithromycin, and may range in severity from mild diarrhoea to fatal colitis. 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 patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

Discontinuation of therapy with azithromycin and the administration of specific treatment for C. difficile should be considered.

Streptococcal infections

Penicillin is usually the first choice for treatment of pharyngitis/tonsillitis due to Streptococcus pyogenes and also for prophylaxis of acute rheumatic fever. Azithromycin is in general effective against streptococcus in the oropharynx, but no data are available that demonstrate the efficacy of azithromycin in preventing acute rheumatic fever.

Renal impairment

In patients with GFR <10 ml/min a 33% increase in systemic exposure to azithromycin was observed (see section 5.2).

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).

Diabetes

Caution in diabetic patients: 5 ml of reconstituted suspension contains 3.87 g of sucrose.

Paediatric population

Safety and efficacy for the prevention or treatment of Mycobacterium Avium Complex in children have not been established.

Excipients information

Zithromax suspension contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Zithromax suspension contains less than 1 mmol sodium (23 mg) per 5 ml of reconstituted suspension, that is to say essentially 'sodium-free'.

Zithromax Suspension is for oral administration only.

4.5. Interaction with other medicinal products and other forms of interaction

Antacids: In a pharmacokinetic study investigating the effects of simultaneous administration of antacid with azithromycin, no effect on overall bioavailability was seen, although peak serum concentrations were reduced by approximately 24%. In patients receiving both azithromycin and antacids, the drugs should not be taken simultaneously. 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.

Cetirizine: In healthy volunteers, co-administration of a 5-day regimen of azithromycin with 20 mg cetirizine at steady-state resulted in no pharmacokinetic interaction and no significant changes in the QT interval.

Didanosine (Dideoxyinosine): Co-administration of 1200 mg/day azithromycin with 400 mg/day didanosine in six HIV-positive subjects did not appear to affect the steady-state pharmacokinetics of didanosine as compared to placebo.

Digoxin and colchicine (P-gp substrates): 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-glycoprotein substrates such as digoxin are administered concomitantly, the possibility of elevated serum digoxin concentrations 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 1200 mg or 600 mg doses of azithromycin had little effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of azithromycin increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of this finding is unclear, but it may be of benefit to patients.

Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not believed to undergo the pharmacokinetic drug interactions as seen with erythromycin and other macrolides. Hepatic cytochrome P450 induction or inactivation via cytochrome-metabolite complex does not occur with azithromycin.

Ergot 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.

Atorvastatin: Co-administration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter the plasma concentrations of atorvastatin (based on a HMG CoA-reductase inhibition assay). However, post-marketing cases of rhabdomyolysis in patients receiving azithromycin with statins have been reported.

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 dose of 15 mg warfarin administered to healthy volunteers. There have been reports received in the post-marketing period of potentiated anticoagulation subsequent to co-administration of azithromycin and coumarin-type oral anticoagulants. Although a causal relationship has not been established, consideration should be given to the frequency of monitoring prothrombin time when azithromycin is used in patients receiving coumarin-type oral anticoagulants.

Ciclosporin: In a pharmacokinetic study with healthy volunteers who 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 ciclosporin, the resulting ciclosporin Cmax and AUC0-5 were found to be significantly elevated (by 24% and 21% respectively), however no significant changes were seen in AUC0-∞. Consequently, caution should be exercised before considering concurrent administration of these drugs. If co-administration of these drugs is necessary, ciclosporin levels should be monitored and the dose adjusted accordingly.

Efavirenz: Co-administration of a single dose of 600mg azithromycin and 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interactions.

Fluconazole: Co-administration of a single dose of 1200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. Total exposure and half-life of azithromycin were unchanged by the co-administration of fluconazole, however, a clinically insignificant decrease in Cmax (18%) of azithromycin was observed.

Indinavir: Co-administration 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, co-administration of 500 mg/day azithromycin for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single dose of 15 mg midazolam.

Nelfinavir: Co-administration 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 was required.

Rifabutin: Co-administration of azithromycin and rifabutin did not affect the serum concentrations of either drug. Neutropenia was observed in subjects receiving concomitant treatment of azithromycin and rifabutin. Although neutropenia has been associated with the use of rifabutin, a causal relationship to combination with azithromycin has not been established (see section 4.8.).

Sildenafil: In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC and Cmax, of sildenafil or its major circulating metabolite.

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.

Triazolam: In 14 healthy volunteers, co-administration of 500 mg azithromycin 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: Co-administration of trimethoprim/sulfamethoxazole DS (160 mg/800 mg) for 7 days with 1200 mg azithromycin 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 which are known to prolong the QT interval (see section 4.4): 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.

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.

Breast-feeding

Limited information available from published literature indicates that azithromycin is present in human milk at an estimated highest median daily dose of 0.1 to 0.7 mg/kg/day. No serious adverse effects of azithromycin on the breast-fed infants were observed. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from azithromycin therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy 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

There is no evidence to suggest that Zithromax may have an effect on a patient's ability to drive or operate machinery.

4.8. Undesirable effects

Zithromax is well tolerated with a low incidence of side effects.

The section below lists the adverse reactions identified through clinical trial experience and postmarketing 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)

Frequency Not Known

Infections and Infestations

Candidiasis

Vaginal infection

Pneumonia

Fungal infection

Bacterial infection

Pharyngitis

Gastroenteritis

Respiratory disorder

Rhinitis

Oral candidiasis

Pseudomembranous colitis (see section 4.4)

Blood and Lymphatic System Disorders

Leukopenia

Neutropenia

Eosinophilia

Thrombocytopenia

Haemolytic anaemia

Immune System Disorders

Angioedema

Hypersensitivity

Anaphylactic reaction (see section 4.4)

Metabolism and Nutrition Disorders

Anorexia

Psychiatric Disorders

Nervousness

Insomnia

Agitation

Aggression

Anxiety

Delirium

Hallucination

Nervous System Disorders

Headache

Dizziness

Paraesthesia

Dysgeusia

Somnolence

Hypoestheia

Syncope

Convulsion

Psychomotor hyperactivity

Anosmia

Ageusia

Parosmia

Myasthenia gravis (see Section 4.4)

Eye Disorders

Visual impairment

Ear and Labyrinth Disorders

Deafness

Ear disorder

Vertigo

Hearing impairment

Tinnitus

Cardiac Disorders

Palpitations

Torsades de pointes (see section 4.4) Arrhythmia (see section 4.4) including ventricular tachycardia

Electrocardiogram QT prolonged (see section 4.4)

Vascular Disorders

Hot flush

Hypotension

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Epistaxis

Gastrointestinal Disorders

Diarrhoea

Abdominal pain

Nausea

Flatulence

Vomiting

Dyspepsia

Constipation

Gastritis

Dysphagia

Abdominal distension

Dry mouth

Eructation

Mouth ulceration

Salivary hypersecretion

Pancreatitis

Tongue discolouration

Hepatobiliary Disorders

Hepatitis

Hepatic function abnormal

Jaundice cholestatic

Hepatic failure (which has rarely resulted in death) (see section 4.4)

Hepatitis fulminant

Hepatic necrosis

Skin and Subcutaneous Tissue Disorders

Rash

Pruritus

Stevens-Johnson syndrome

Photosensitivity reaction

Urticaria

Dermatitis

Dry skin

Hyperhidrosis

Acute Generalized Exanthematous Pustulosis (AGEP)*§

Drug reaction with eosinophilia and systemic symptoms (DRESS)*§

Toxic epidermal necrolysis (TEN)

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

Chest pain

Oedema

Malaise

Asthenia

Face edema

Pyrexia

Pain

Peripheral oedema

Investigations

Lymphocyte count decreased

Eosinophil count increased

Blood bicarbonate decreased

Basophils increased

Monocytes increased

Neutrophils increased

Aspartate aminotransferase

increased

Alanine aminotransferase increased

Blood bilirubin increased

Blood urea increased

Blood creatinine increased

Blood potassium abnormal

Blood alkaline phosphatase increased

Chloride increased

Glucose increased

Platelets increased

Hematocrit decreased

Bicarbonate increased

Abnormal sodium

Injury and poisoning

Post procedural complication

*ADR identified post-marketing

§ ADR frequency represented by the estimated upper limit of the 95% confidence interval calculated using the “Rule of 3”.

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:

Very Common

(≥ 1/10)

Common

(≥ 1/100 to < 1/10)

Uncommon

(≥ 1/1,000 to < 1/100)

Metabolism and Nutrition Disorders

Anorexia

Nervous System Disorders

Dizziness

Headache

Paraesthesia

Dysgeusia

Hypoesthesia

Eye Disorders

Visual impairment

Ear and Labyrinth Disorders

Deafness

Hearing impaired

Tinnitus

Cardiac Disorders

Palpitations

Gastrointestinal Disorders

Diarrhoea

Abdominal pain

Nausea

Flatulence

Abdominal discomfort

Loose stools

Hepatobiliary Disorders

Hepatitis

Skin and Subcutaneous Tissue Disorders

Rash

Pruritus

Stevens-Johnson syndrome Photosensitivity reaction

Musculoskeletal and Connective Tissue Disorders

Arthralgia

General Disorders and Administration Site Conditions

Fatigue

Asthenia

Malaise

Reporting of suspected adverse 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. The typical symptoms of an overdose with macrolide antibiotics include reversible loss of hearing, severe nausea, vomiting and diarrhoea. In the event of overdose, the administration of medicinal charcoal and general symptomatic treatment and supportive measures are indicated as required.