Azithromycin 200 mg/ 5 ml Powder for Oral Suspension

Each 5 ml prepared suspension contains 204.8 mg azithromycin monohydrate equivalent to 200 mg azithromycin.

Each 1 ml prepared suspension contains 40.96 mg azithromycin monohydrate equivalent to 40 mg azithromycin.

Excipients:

Sucrose 3.70483 g/ 5 ml

Aspartame (E951) 0.030 g/ 5 ml

For a full list of excipients see section 6.1.

Powder for oral suspension.

White or off-white crystalline powder.

Azithromycin powder for oral suspension is indicated for the treatment of the following infections, when caused by microorganisms sensitive to azithromycin (see section 4.4 and 5.1):

- upper respiratory tract infections: sinusitis, pharyngitis, tonsillitis

- acute otitis media

- lower respiratory tract infections: acute bronchitis and mild to moderately severe community acquired pneumonia

- skin and soft tissue infections

- uncomplicated Chlamydia trachomatis urethritis and cervicitis

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

Azithromycin is not the first choice for the empiric treatment of infections in areas where the prevalence of resistant isolates is 10% or more (see section 5.1).

Adults

In uncomplicated Chlamydia trachomatis urethritis and cervicitis, the dosage is 1000 mg in one single oral dose.

For all other indications the dosage is 1500 mg, to be administered as 500 mg per day for three consecutive days. Alternatively the same total dosage (1500 mg) can also be given over a period of 5 days with 500 mg on the first day and then 250 mg on days 2 to 5.

To treat these patients other pharmaceutical forms are also available.

Elderly

In the elderly the same dosage as for adults can be given.

Children and adolescents (< 18 years)

The total dosage in children aged 1 year and older is 30 mg/kg administered as 10 mg/kg once daily for three days, or over a period of five days starting with a single dose of 10 mg/kg on the first day, followed by doses of 5 mg/kg per day for the following 4 days, according to the tables shown below. There are limited data on use in children younger than 1 year.

The dosage for the treatment of pharyngitis caused by Streptococcus pyogenes is an exception: in the treatment of pharyngitis caused by Streptococcus pyogenes Azithromycin has proved to be effective when it is administered to children as a single dose of 10 mg/kg or 20 mg/kg for 3 days with a maximum daily dosage of 500 mg. At these two dosages a comparable clinical effect was observed, even if the eradication of the bacteria was more significant at a daily dosage of 20 mg/kg.

Penicillin is however the drug of first choice in the treatment of pharyngitis caused by Streptococcus pyogenes and the prevention of subsequent rheumatic fever.

Patients with renal impairment

No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10-80 ml/min) (see section 4.4).

Patients with hepatic impairment

A dose adjustment is not necessary for patients with mild to moderately impaired liver function (see section 4.4).

Method of administration

Before use the powder should be reconstituted with water into a white to off white coloured, homogenous suspension, see section 6.6. After reconstitution the drug can be administered using a PE/PP syringe for oral use.

After taking the suspension a bitter after-taste can be avoided by drinking fruit juice directly after swallowing. Azithromycin powder for oral suspension should be given in a single daily dosage. The suspension may be taken together with food.

Hypersensitivity to azithromycin, to other macrolide antibiotics, or to any of the excipients.

As with erythromycin and other macrolide antibiotics serious allergic reactions are rarely reported, these include angio-oedema and anaphylaxis (rarely fatal). Some of these reactions have resulted in recurrence of symptoms whereby a longer period of observation and treatment was necessary.

As is true of all antibiotics, it is advisable to be alert to signs of superinfection by non-sensitive micro-organisms including fungi.

Pseudomembranous colitis has been reported with the use of macrolide antibiotics. This diagnosis should also be considered in patients who get diarrhoea after starting treatment with azithromycin.

There is no experience of the safety and effectiveness of long-term use of azithromycin in the above-mentioned indications. In the event of quickly recurring infections, just as is the case with other antibiotics, treatment with another antibacterial drug should be considered.

Due to the theoretical possibility of ergotism, azithromycin and ergotamine derivatives should not be given at the same time (see section 4.5).

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. Therefore azithromycin should not be used:

- in patients with congenital or documented acquired QT prolongation.

- with other active substances that prolong QT interval such as antiarrhythmics of classes IA and III, cisapride and terfenadine.

- in patients with electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesaemia

- in patients with clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.

The following should be considered before prescribing azithromycin:

Azithromycin powder for oral suspension is not suitable for treatment of severe infections where a high concentration of the antibiotic in the blood is rapidly needed.

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/ tonsilitis

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.

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.

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. palladium should be excluded.

Azithromycin should be used with caution in patients with neurological or psychiatric disorders.

Use in renal impairment: No dose adjustment is necessary in patients with mild to moderate renal impairment (GFR 10–80 ml/min). Caution is advised in patients with severe renal impairment (GFR < 10 ml/min) as systemic exposure may be increased (see section 5.2).

Use in hepatic impairment: Since azithromycin is metabolised in the liver and excreted in the bile, the medicinal product should not be given to patients suffering from severe liver disease. No studies have been conducted regarding the treatment of such patients with azithromycin. When severe liver impairment occurs, the treatment with azithromycin should be ceased.

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

Theophylline

Pharmacokinetic research has shown no interaction between azithromycin and theophylline on co-administration 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.

Oral coumarin-type anticoagulants

In pharmacokinetic research in healthy volunteers, azithromycin did not alter the anticoagulant effect of one dose of 15 mg warfarin. There are reports of enhanced anticoagulation in co-administration of azithromycin with oral coumarin-type anticoagulants. Although a causal connection has not been established, attention should be paid to the frequency of measurement of the prothrombin time.

Carbamazepine

In a pharmacokinetic interaction study in healthy volunteers, no significant effect was seen on the pharmacokinetics of carbamazepine or the active metabolite of carbamazepine.

Ergotamine derivatives

In patients who are being treated with ergotamine derivatives, ergotism may be induced by co-administration of some macrolide antibiotics. There are no known data on a possible interaction between ergotamine derivatives and azithromycin. As there is a theoretical possibility of ergotism, azithromycin and ergotamine derivatives should not be combined.

Ciclosporin

On the basis of limited pharmacokinetic data on interaction between azithromycin and ciclosporin in healthy volunteers, caution should be exercised in concurrent administration of these medicinal products. If concurrent administration is necessary, the ciclosporin levels must be checked and if necessary the ciclosporin dosage adjusted.

Digoxin

It is known that some macrolide antibiotics limit the metabolism of digoxin in the bowel. In patients who are treated concurrently with azithromycin and digoxin, account should be taken of potentially raised digoxin levels and these levels must be monitored.

Antacids

In a pharmacokinetic study into the effect of concurrent administration of antacids and azithromycin, no effect was seen on the total biological availability, although peak serum levels were reduced by 30%. Azithromycin must be taken at least 1 hour before or 2 hours after antacids.

Cimetidine

A single dose of cimetidine administered 2 hours before azithromycin had no effect on the pharmacokinetics of azithromycin.

Methylprednisolone

In a pharmacokinetic interaction study in healthy volunteers, no significant effect was seen on the pharmacokinetics of methylprednisolone.

Zidovudine

Single doses of 1000 mg azithromycin and multiple doses of 600 mg or 1200 mg Azithromycin had no effect on the plasma pharmacokinetics or the renal excretion of zidovudine or its glucuronide metabolite. However, on administration of azithromycin the concentration of phosphorylated zidovudine, the clinically active metabolite, increased in the peripheral mononuclear blood cells. The clinical significance of this finding is still unclear, but may possibly be an advantage for patients.

Terfenadine

Azithromycin has no effect on the pharmacokinetics of terfenadine, given every 12 hours at the recommended dosage of 60 mg. Addition of azithromycin did not result in a significant change of cardiac repolarization (QT interval), measured at a steady state dosage of terfenadine.

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.

Didanosine

On comparison with a placebo in 6 test subjects, daily doses of 1200 mg azithromycin with didanosine appeared to have no effect on the pharmacokinetics of didanosine.

Rifabutin

Concurrent administration of azithromycin and rifabutin had no effect on the serum concentration of either medicinal product. Neutropenia was seen in patients who were given simultaneous treatment with azithromycin and rifabutin. In spite of the fact that neutropenia has been associated with the use of rifabutin, no causal connection with the combination with Azithromycin could be established.

Astemizole, triazolam, midazolam, alfentanil

There are no known data on interactions with astemizole, triazolam, midazolam or alfentanil. Caution is advised in the co-administration of these medicines with azithromycin because of the known enhancing effect of these medicines when used concurrently with the macrolide antibiotic erythromycin.

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.

Nelfinavir

Concomitant administration of 1200 mg azithromycin and steady state nelfinavir (750 mg 3 times daily) resulted in on average 16% decrease of nelfinavir AUC, an increase of azithromycin AUC and Cmax with 113% and 136% respectively. No dose adjustment is necessary but patients should be monitored for known side effects of azithromycin.

Pregnancy

There are no adequate and well controlled studies in pregnant women. Animal reproduction studies show passage across the placenta. No teratogenic effects were observed in rat reproduction studies (see further 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 not be used during pregnancy except in life threatening cases when no adequate alternatives are available.

Lactation

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.

There are no known data on the effect of azithromycin on the ability to drive and use machines. When performing these functions, account should be taken of the occurrence of the adverse effects of dizziness and convulsions.

In this section undesirable effects are defined as follows:

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 group, undesirable effects are listed in order of decreasing seriousness.

Cardiac disorders

Rare: Palpitations, arrhythmia (including ventricular tachycardia).

There is a potential risk of QT lengthening and torsades in predisposed patients (see section 4.4).

Blood and lymphatic system disorders

Rare: Thrombocytopenia, haemolytic anaemia and transient episodes of mild neutropenia have been observed in clinical research. No causal connection with the use of azithromycin could be established for this.

Nervous system disorders

Uncommon: Dizziness, convulsions, headache, somnolence, changes in smell and/or taste.

Rare: Paresthesia, syncope, insomnia, hyperactivity.

Ear and labyrinth disorders

Rare: Loss of hearing including deafness and/or tinnitus has been reported in long-term use of high doses of azithromycin during clinical research. In those cases where follow-up data were available, the majority of these undesirable effects proved to be reversible.

Gastrointestinal disorders

Common: Nausea, vomiting, diarrhoea, gastrointestinal symptoms (pain/cramps).

Uncommon: Very watery faeces (as a consequence of infrequent dehydration of the system), flatulence, digestive disturbances.

Rare: Constipation, discolouration of the tongue, pancreatitis. Discolouration of the teeth and pseudomembranous colitis have been reported.

Renal and urinary disorders

Rare: Interstitial nephritis, acute renal failure.

Skin and subcutaneous tissue disorders

Uncommon: Allergic reactions including skin rash and pruritis.

Rare: Allergic reactions including angio-oedema, urticaria, photosensitivity. Serious skin reactions including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders

Uncommon: Arthralgia.

Metabolism and nutrition disorders

Uncommon: Anorexia.

Infections and infestations

Uncommon: Vaginitis.

Rare: Candidiasis.

Vascular disorders

Rare: Hypotension.

General disorders and administration site conditions

Rare: Asthenia, fatigue, malaise.

Immune system disorders

Rare: Anaphylaxis, including oedema (rarely fatal) (see section 4.4).

Hepatobiliary disorders

Rare: Abnormal liver function, including hepatitis and cholestatic jaundice have been reported, as also have rare cases of hepatic necrosis and liver failure, which in rare cases, have resulted in death.

Psychiatric disorders

Rare: Aggressive reactions, restlessness, anxiety, nervousness, depersonalization, in older patients delirium can occur.

The symptoms that occurred at higher than recommended dosages were equivalent to known undesirable effects at normal dosage. Characteristic symptoms of overdose with macrolide antibiotics are: reversible loss of hearing, serious nausea, vomiting and diarrhoea. In cases of overdose, gastric lavage and general supportive measures are indicated.

General properties

Pharmacotherapeutic group: antibacterials for systemic use; macrolides; azithromycin, ATC code: J01FA10

Mode 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.

PK/PD relationship

For azithromycin the AUC/MIC is the major PK/PD parameter correlating best with the efficacy of azithromycin.

Mechanism of resistance

Resistance to azithromycin may be inherent or acquired. There are three main mechanisms of resistance in bacteria: target site alteration, alteration in antibiotic transport and modification of the antibiotic.

Complete cross resistance exists among Streptococcus pneumoniae, betahaemolytic streptococcus of group A, Enterococcus faecalis and Staphylococcus aureus, including methicillin resistant S. aureus (MRSA) to erythromycin, azithromycin, other macrolides and lincosamides.

Breakpoints

According to the CLSI (Clinical and Laboratory Standards Institute) the following breakpoints have been defined for azithromycin:

- susceptible ≤ 2 µg/ml; resistant ≥ 8 µg/ml

- Haemophilus spp.: susceptible ≤ 4 µg/ml

- Streptococcus pneumoniae and Streptococcus pyogenes: susceptible ≤ 0.5 µg/ml; resistant ≥ 2 µg/ml.

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

* Clinical effectiveness is demonstrated by sensitive isolated organisms for approved clinical indications.

Absorption

The biological availability of azithromycin after oral administration is approximately 37%. Peak plasma levels are achieved 2-3 hours after taking the medicinal product.

Distribution

After oral administration, azithromycin is distributed throughout the entire body. Pharmacokinetic studies have shown clearly higher azithromycin levels in the tissues than in the plasma (up to 50 times the maximum observed concentration in plasma). This indicates that the substance is bound in the tissues in considerable quantities.

Concentrations in the infected tissues, such as lungs, tonsil and prostate are higher than the MRC90 of the most frequently occurring pathogens after a single dose of 500 mg.

The protein binding of azithromycin in serum is variable and varies, depending on the serum concentration, from 52% at 0.05 mg/l to 12% at 0.5 mg/l. The steady state distribution volume is 31.1 l/kg.

Elimination

The terminal plasma-elimination half-life closely follows the tissue depletion half-life from 2 to 4 days.

Approximately 12% of an intravenously administered dose of azithromycin is, over a period of 3 days, excreted unchanged in the urine. High concentrations of unchanged azithromycin were found in human bile. In this, ten metabolites were also detected (formed by N- and O- desmethylation, by hydroxylation of the desosamin and aglycon rings and by splitting the cladinose conjugate). A comparison of fluid chromatography and microbiological assessment methods shows that the metabolites are microbiologically inactive.

In animal models high concentrations of azithromycin were found in phagocytes. Also it has been shown that during active phagocytosis higher concentrations of azithromycin are released than during inactive phagocytosis. In animal models this process was shown to contribute to the accumulation of azithromycin in infectious tissue.

Pharmacokinetics in special populations

Renal insufficiency

Following a single oral dose of azithromycin 1 g, mean C_max and AUC_0-120 increased by 5.1% and 4.2% respectively, in subjects with mild to moderate renal impairment (glomerular filtration rate of 10-80 ml/min) compared with normal renal function (GFR > 80 ml/min). In subjects with severe renal impairment, the mean C_max and AUC_0-120 increased 61% and 35% 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.

Infants, toddlers, children and adolescents

Pharmacokinetics have been studied in children aged 4 months – 15 years taking capsules, granules or suspension.. At 10 mg/kg on day 1 followed by 5 mg/kg on days 2-5, the C_max achieved is slightly lower than adults with 224 ug/l in children aged 0.6-5 years and after 3 days dosing and 383 ug/l in those aged 6-15 years. The t_1/2 of 36 h in the older children was within the expected range for adults.

In animal tests in which the dosages used amounted to 40 times the clinical therapeutic dosages, azithromycin was found to have caused reversible phospholipidosis, but as a rule no true toxicological consequences were observed which were associated with this. The relevance of this finding to humans receiving azithromycin in accordance with the recommendations is unknown.

Electrophysiological investigations have shown that azithromycin prolongs the QT interval.

Mutagenic potential:

There was no evidence of a potential for genetic and chromosome mutations in in-vivo and in-vitro test models.

Reproductive toxicity:

In embryotoxicity studies in mice and rats no teratogenic effects were observed. In rats, azithromycin dosages of 100 and 200 mg/kg bodyweight/day led to slight retardations in fetal ossification and in maternal weight gain. In peri-/postnatal studies in rats, slight retardations in physical development and delay in reflex development were observed following treatment with 50 mg/kg/day azithromycin and above.

Sucrose

Xanthan gum

Hydroxypropylcellulose

Trisodium phosphate anhydrous

Silica, colloidal anhydrous (E551)

Aspartame (E951)

Cream caramel flavour

Titanium dioxide (E171)

Not applicable.

Unopened bottle with dry powder: 36 months.

Reconstituted suspension: 10 days.

Unopened bottle: Do not store above 30 °C.

Reconstituted suspension: Do not store above 25 °C.

HDPE bottles with a PP/ PE- childproof closure with retaining ring.

PE/PP-dosage syringe (10 ml), graduated in 0.25 ml divisions.

Content of the bottle after reconstitution: 15 ml (600 mg), 20 ml (800 mg), 22.5 ml (900 mg), 30 ml (1200 mg) or 37.5 ml (1500 mg).

Not all pack sizes may be marketed.

Preparation of the suspension:

Shake the dry powder loose. Add the amount of water described below to the powder.

For 15 ml (600 mg) bottle: add 7.5 ml water.

For 20 ml (800 mg) bottle: add 10.0 ml water.

For 22.5 ml (900 mg) bottle: add 11.0 ml water.

For 30 ml (1200 mg) bottle: add 15.0 ml water.

For 37.5 ml (1500 mg) bottle: add 18.5 ml water.

Shake well until a white to off white coloured, homogenous suspension is achieved. For administration the syringe adapter should be placed in the neck of the bottle and the stopper should be opened.

Sandoz Ltd

Frimley Business Park,

Frimley,

Camberley,

Surrey,

GU16 7SR.

United Kingdom

PL 04416/0782

06/08/2007

12/2010