4.1. Therapeutic indications

Azithromycin as powder for solution for infusion is indicated for the treatment of community-acquired pneumonia due to susceptible microorganisms, (see Section 5.1) in adult patients where initial intravenous therapy is required.

Azithromycin as powder for solution for infusion is indicated for the treatment of pelvic inflammatory disease (PID) due to susceptible microorganisms (see Section 5.1), in patients where initial intravenous therapy is required.

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

4.2. Posology and method of administration

Posology

The recommended dose of Azithromycin (azithromycin as powder for solution for infusion) for the treatment of adult patients with community-acquired pneumonia due to the indicated susceptible microorganisms is of 500 mg administered as a single intravenous daily dose for at least two consecutive days. The intravenous therapy should be followed by the oral administration of azithromycin in a single daily dose of 500 mg up to 7 to 10 days of treatment. Transition to oral therapy should be carried out when indicated by the doctor and according to the clinical response.

The recommended dose of Azithromycin (azithromycin as powder for solution for infusion) for the treatment of adult patients with pelvic inflammatory disease (PID) due to the indicated susceptible microorganisms is of 500 mg administered as a single intravenous daily dose for one or two days. The intravenous therapy should be followed by the oral administration of azithromycin in a single daily dose of 250 mg up to 7 days of treatment. Transition to oral therapy should be carried out when indicated by the doctor and according to the clinical response.

Use in the elderly

No dose adjustment is required in elderly patients that require therapy with azithromycin.

Use in patients with renal impairment

No dose adjustment is recommended 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).

Use in patients with hepatic impairment

Dose adjustment is not required for patients with mild to moderate hepatic dysfunction but the medicinal product should be used with caution in patients with significant hepatic diseases (see Section 4.4).

Use in children

The efficacy and safety of azithromycin as powder for solution for infusion for the treatment of infections in children and adolescents has not been established.

Method of administration

Once Azithromycin (azithromycin as powder for solution for infusion) is reconstituted and diluted is intended to be administered by intravenous infusion. It should not be administered as an intravenous bolus or an intramuscular injection.

The concentration of the solution for infusion and the infusion rate of azithromycin as powder for solution for infusion should be 1 mg/ml for 3 hours or 2 mg/ml for 1 hour.

Preparation of the solution for intravenous administration

Reconstitution

The initial solution of azithromycin is prepared by adding 4.8 ml of sterile water for injections to the 500 mg vial and shaking the vial until all the drug is dissolved. It is recommended that a standard 5 ml (non-automated) syringe be used to ensure that the exact volume of 4.8 ml of sterile water for injections is dispensed. Each ml of reconstituted solution contains azithromycin dihydrate equivalent to 100 mg azithromycin (100 mg/ml).

Parenteral administration drugs should be inspected visually for particulate in suspension prior to administration. If particulate in suspension is evident in reconstituted solution, the drug solution should be discarded.

The reconstituted solution must be further diluted prior to administration as instructed below.

Dilution

To provide azithromycin over a concentration range of 1.0 - 2.0 mg/ml, transfer 5 ml of the 100 mg/ml azithromycin solution to the appropriate amount of any of the diluents listed in Section 6.6 Special precautions for disposal and other handling.

Final infusion solution concentration (mg/ml)

Amount of diluent (ml)

1.0 mg/ml

500 ml

2.0 mg/ml

250 ml

It is recommended that a 500 mg dose of azithromycin as powder for solution for infusion, diluted according to the instructions above, be administered as an intravenous infusion over at least 60 minutes.

4.3. Contraindications

Azithromycin is contraindicated in patients with a known hypersensitivity to azithromycin, erythromycin or any of the macrolide or ketolide antibiotics, or to any of the excipients (listed in Section 6.1).

Azithromycin should not be co-administered with ergot derivatives because of the theoretical possibility of ergotism.

4.4. Special warnings and precautions for use

Hypersensitivity

As with erythromycin and other macrolides, rare serious allergic reactions including angioneurotic oedema and anaphylaxis (rarely fatal), dermatologic reactions including acute generalised 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 drug 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.

Ergot derivatives

In patients receiving ergotamine 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. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarisation (see Section 4.8); therefore, caution is required when treating patients:

• With congenital or documented QT prolongation

• Currently receiving treatment with other active substance known to prolong QT interval such as antiarrhythmics of classes Ia and III, cisapride and terfenadine

• 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 (Pseudomembranous colitis - 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 antibiotics alters the normal flora of the colon allowing an overgrowth of C. difficile.

Strains of C. difficile producing hypertoxin A and B 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. Therefore, CDAD must be considered in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Careful medical history is necessary since CDAD has been reported to occur over two 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 severe renal impairment (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).

Safety and efficacy of azithromycin intravenous infusion for treatment of infections in children have not been established.

Safety and efficacy for prevention or treatment of MAC in children have not been established.

Azithromycin (azithromycin as powder for solution for infusion) should be reconstituted and diluted according to the instructions and should be administered as an intravenous infusion over at least 60 minutes.

It should not be administered as an intravenous bolus or an intramuscular injection (See Sections 4.2 and 6.6).

This medicinal product contains 114 mg (4.96 mmol) sodium per vial, equivalent to approximately 5.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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).

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 oral azithromycin, no effect on overall bioavailability was seen, although peak serum concentrations were reduced by approximately 24%. In patients taking azithromycin by oral administration, azithromycin should be taken at least 1 hour before or 2 hours after the antacid.

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

Didanosine (Dideoxyinosine): 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: 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 (Ergotamine): 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).

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 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 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 ciclosporin, the resulting ciclosporin Cmax and AUC were found to be significantly elevated (by 24% and 21% respectively), however no significant changes were seen in AUC0-5. 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 600 mg 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 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: 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 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: Co-administration 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 and 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of azithromycin in pregnant women. In reproduction toxicity studies in animals, azithromycin was shown to pass the placenta, but no teratogenic effects were observed (see Section 5.3). The safety of azithromycin has not been confirmed with regard to the use of the active substance during pregnancy. Therefore, Azithromycin should only be used during pregnancy if definitely indicated.

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 passes into breast milk. Because it is not known whether azithromycin may have adverse effects on the breast-fed infant, nursing should be discontinued during treatment with Azithromycin. Among other things diarrhoea, fungus infection of the mucous membrane as well as sensitisation is possible in the nursed infant. It is recommended to discard the milk during treatment and up until 2 days after discontinuation of treatment. Nursing may be resumed thereafter.

Fertility

Animal data do not suggest an effect of the treatment of azithromycin on male and female fertility. Human data are lacking.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable 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); 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:

System organ class

Adverse reaction

Frequency

Infections and infestations

Candidiasis, oral candidiasis, vaginal infection

Uncommon

Pseudomembranous colitis (See Section 4.4)

Not known

Blood and lymphatic system disorders

Leukopenia, neutropenia

Uncommon

Thrombocytopenia, haemolytic anaemia

Not known

Immune system disorders

Angioedema, hypersensivity

Uncommon

Anaphylactic reaction (See Section 4.4)

Not known

Metabolism and nutrition disorders

Anorexia

Common

Psychiatric disorders

Nervousness

Uncommon

Agitation

Rare

Aggression, anxiety

Not known

Nervous system disorders

Dizziness, headache, paraesthesia, dysgeusia

Common

Hypoaesethesia, somnolence, insomnia

Uncommon

Syncope, convulsion, psychomotor hyperactivity, anosmia, ageusia, parosmia, Myasthenia gravis (See Section 4.4)

Not known

Eye disorders

Visual impairment

Common

Ear and labyrinth disorders

Deafness

Common

Hearing impaired, tinnitus

Uncommon

Vertigo

Rare

Cardiac disorders

Palpitations

Uncommon

Torsades de pointes (See Section 4.4), arrhythmia (See Section 4.4) including ventricular tachycardia

Not known

Vascular disorders

Hypotension

Not known

Gastrointestinal disorders

Diarrhoea, abdominal pain, nausea, flatulence

Very common

Vomiting, dyspepsia

Common

Gastritis, constipation

Uncommon

Pancreatitis, tongue discolouration

Not known

Hepatobiliary disorders

Hepatitis

Uncommon

Hepatic function abnormal

Rare

Hepatic failure (See Section 4.4)**, hepatitis fulminant, hepatic necrosis, jaundice cholestatic

Not known

Skin and subcutaneous tissue disorders

Pruritus and rash

Common

Stevens-Johnson syndrome (SJS), photosensitivity reaction, urticaria

Uncommon

Acute Generalised Exanthematous Pustulosis (AGEP)

Rare

Drug reaction with eosinophilia and systemic symptoms (DRESS)

Very Rare

Toxic epidermal necrolysis (TEN), erythema multiforme

Not known

Musculoskeletal and connective tissue disorders

Arthralgia

Common

Renal and urinary disorders

Renal failure acute, nephritis interstitial

Not known

General disorders and administration site conditions

Pain and inflammation on the local injection site*, fatigue

Common

Chest pain, oedema, malaise, asthenia

Uncommon

Investigations

Lymphocyte count decreased, eosinophil count increased, blood bicarbonate decreased

Common

Aspartate aminotransferase increased, alanine aminotransferase increased, blood bilirubin increased, blood urea increased, blood creatinine increased, blood potassium abnormal

Uncommon

Electrocardiogram QT prolonged (See Section 4.4)

Not known

* have been reported with the intravenous administration of azithromycin.

** which has rarely resulted in death

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 (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, general symptomatic treatment and supportive measures are indicated as required.