Gerard Laboratories

Azromax 250 mg Film-coated Tablets

Each film-coated tablet contains 250 mg azithromycin (as azithromycin monohydrate).

Excipients:

Each film-coated tablet contains 0.18 mg of soya lecithin.

For a full list of excipients, see section 6.1.

Film-coated tablet.

White to off-white, elongated, unmarked on its sides.

Azithromycin is indicated for the following bacterial infections induced by micro-organisms sensitive to azithromycin (see section 4.4 and 5.1):

• Infections of the lower respiratory tract: acute bronchitis and mild to moderate community-acquired pneumonia

• Infections of the upper respiratory tract: sinusitis and pharyngitis/tonsillitis

• Acute otitis media

• Infections of the skin and soft tissues of mild to moderate severity e.g. folliculitis, cellulitis, erysipelas

• Uncomplicated Chlamydia trachomatis urethritis and cervicitis.

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

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

For oral use.

Azithromycin tablets should be given as a single daily dose. The tablets can be taken with or without food. The duration of treatment in each of the infectious diseases is given below.

Adults, elderly, children and adolescents over 45 kg body weight

The total dosage of azithromycin is 1500 mg which is spread over three days (500 mg once daily).

Alternatively, the dosage can be spread over five days (500 mg as a single dose on the first day and thereafter 250 mg once daily).

In uncomplicated Chlamydia trachomatis urethritis and cervicitis the dosage is 1000 mg as a single oral dose.

For sinusitis, treatment is indicated for adults and adolescents over 16 years of age.

Children and adolescents under 45 kg body weight

Tablets are not indicated for these patients. Other pharmaceutical forms of azithromycin, e.g. suspensions may be used.

Elderly

No dose adjustments are required for elderly patients.

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 (Child-Pugh class A or B) (see section 4.4).

Hypersensitivity to azithromycin, to any of the related macrolide antibiotics, to soya oil or to any of the excipients.

Allergic reactions

In rare cases azithromycin is reported to have caused serious allergic reactions (rarely fatal) such as angioneurotic oedema and anaphylaxis.

Some of these reactions have caused recurrent symptoms and have required longer observation and treatment.

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).

Hepatic impairment

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 alkaloids and azithromycin

The concurrent use of ergot alkaloids and macrolide antibiotics has been found to accelerate the development of ergotism. The interactions between ergot alkaloids and azithromycin have not been studied. The development of ergotism is however possible, so that azithromycin and ergot alkaloid derivatives should not be administered simultaneously.

QT prolongation

Prolonged cardiac repolarisation and QT interval have been seen in treatment with other macrolides. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk of cardiac effects. Therefore:

• Azithromycin should not be used in patients with congenital or documented acquired QT prolongation.

• Azithromycin should not be used concurrently with other active substances that prolong QT interval such as antiarrhythmics of classes IA and III, cisapride and terfenadine (see section 4.5).

• Azithromycin should not be used in patients with electrolyte disturbance, particularly in cases of hypokalaemia and hypomagnesaemia

• Azithromycin should not be used in patients with clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.

The following should be considered before prescribing azithromycin:

Azithromycin film-coated tablets are not suitable for treatment of severe infections where a high concentration of the antibiotic in the blood is rapidly needed.

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.

The main causative agent of soft tissue infections, Staphylococcus aureus, is frequently resistant to azithromycin. Therefore, susceptibility testing is considered a precondition for treatment of soft tissue infections with azithromycin.

Pharyngitis/tonsillitis

Azithromycin is not the substance of first choice for the treatment of pharyngitis and tonsillitis caused by Streptococcus pyogenes. For this and for the prophylaxis of acute rheumatic fever penicillin is the treatment of first choice.

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. pallidum should be excluded.

Superinfections

Attention should be paid to possible symptoms of superinfections caused by non-sensitive causal agents such as fungi. A superinfection may require an interruption of the azithromycin treatment and initiation of adequate measures.

Neurological or psychiatric diseases

Azithromycin should be administered with caution to patients suffering from neurological or psychiatric diseases.

Pseudomembranous colitis

After the use of macrolide antibiotics pseudomembranous colitis has been reported. This diagnosis should therefore be considered for patients who suffer from diarrhoea after start of the treatment with azithromycin. Should pseudomembranous colitis be induced by azithromycin, then anti-peristaltics should be contraindicated.

Long-term use

There is no experience regarding the safety and efficacy of long-term use of azithromycin for the mentioned indications. In case of rapid recurrent infections, treatment with another antibiotic should be considered.

Due to cross-resistance existing among macrolides, in areas with a high incidence of erythromycin resistance, it is especially important to take into consideration the evolution of the pattern of susceptibility to azithromycin and other antibiotics (see section 5.1).

Antacids

When studying the effect of simultaneously administered antacid on the pharmacokinetics of azithromycin, no overall change has been observed in the bioavailability, although the peak concentrations of azithromycin measured in the plasma did fall by 30 %. Azithromycin should be taken at least 1 hour before or 2 hours after the antacid.

Ergotamine

The combined use of ergotamine and azithromycin may in theory cause ergotism, and consequently their combined use is not recommended (see also section 4.4).

Coumarin-like oral anticoagulants

An increased tendency towards haemorrhaging has been reported in connection with the concurrent use of azithromycin and warfarin or coumarin-like oral anticoagulants. Attention should be paid to the frequency of prothrombin time monitoring.

Digoxin

In some patients certain macrolide antibiotics have been reported to have impaired the metabolism of digoxin in the intestine. Consequently, in the case of patients receiving azithromycin and digoxin, the possibility of a rise in the digoxin concentrations should be borne in mind.

Zidovudine

1000 mg single doses and 1200 mg or 600 mg multiple doses of azithromycin had only a slight effect upon the pharmacokinetics of zidovudine or its glucuronide metabolite in the plasma or upon excretion in the urine. However, the administration of azithromycin increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in mononuclear cells in the peripheral circulation. The clinical significance of this finding is unclear, but it may be of benefit to patients.

Didanosine

Daily dosages of 1200 mg azithromycin co-administered with didanosine in 6 HIV-positive volunteers appeared to have no effect on the pharmacokinetics of didanosine compared to placebo.

Rifabutin

Coadministration of azithromycin and rifabutin did not affect the serum concentrations of either active substance. 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.

Theophylline

Azithromycin has not affected the pharmacokinetics of theophylline when healthy volunteers received azithromycin and theophylline simultaneously. Theophylline levels may be increased in patients taking azithromycin.

CYP3A4 substrates

Even though azithromycin does not appear to inhibit the enzyme CYP3A4, caution is advised when combining the medicinal product with quinidine, ciclosporin, cisapride, astemizole, terfenadine, ergot alkaloids, pimozide or other medicinal products with a narrow therapeutic index predominantly metabolised by CYP3A4.

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.

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.

Ciclosporin

Since pharmacokinetic and clinical studies on the possible combined effects of azithromycin and ciclosporin have not been carried out, the therapeutic situation should be carefully considered before these active substances are administered simultaneously. If combination treatment is considered justifiable, the ciclosporin levels should be carefully monitored and the dosage should be adjusted accordingly.

Terfenadine

In pharmacokinetic studies there are no reports of interactions 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.

Azithromycin should be administered with caution in combination with terfenadine.

Cisapride

Cisapride is metabolized in the liver by the enzyme CYP3A4. Because macrolides inhibit this enzyme, concomitant administration of cisapride may cause the increase of QT interval prolongation, ventricular arrhythmias and torsade de pointes.

Astemizol, triazolam, midazolam, alfentanil

No data are available on interactions with astemizol, triazolam, midazolam and alfentanil. Caution should be exercised with concomitant use of these agents and azithromycin in view of the described potentation of its effect during concomitant use of the macrolide antibiotic erythromycin.

Substances that prolong the QT interval

Azithromycin should not be used concurrently with other active substances that prolong the QT interval (see section 4.4).

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 only be used in life-threatening cases during pregnancy.

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.

No studies on the effects on the ability to drive and use machines have been performed. However, the possibility of undesirable effects like dizziness and convulsions should be taken into account when performing these activities.

About 13% of patients included in clinical trials reported adverse events, mostly commonly gastro-intestinal disorders.

In very rare cases soya oil may cause allergic reactions.

The undesirable effects at dosages in excess of the recommended dosages were similar to those after normal dosages.

Symptoms

The typical symptoms of an overdose with macrolide antibiotics include reversible loss of hearing, severe nausea, vomiting and diarrhoea.

Treatment

In cases of overdose administration of medicinal charcoal and general symptomatic treatment and measures to support vital functions are indicated where necessary.

Pharmacotherapeutic group: Antibacterials for systemic use; macrolides.

ATC Code: J01FA10.

Azithromycin is a macrolide antibiotic belonging to the azalide group.

The molecule is constructed by adding a nitrogen atom to the Iactone ring of erythromycin A. The chemical name of azithromycin is 9-deoxy-9a-aza-9a-methyl-9a-homo-erythromycin A. The molecular weight is 749.0.

Mode of action

The action mechanism of azithromycin is based upon the suppression of bacterial protein synthesis, by binding to the 50 S subunit and thus inhibiting the translocation of peptides.

(Cross)-resistance

Generally, the resistance of different bacterial species to macrolides has been reported to occur by three mechanisms associated with target site alteration, antibiotic modification, or altered antibiotic transport (efflux). The efflux in streptococci is conferred by the mef genes and results in a macrolide-restricted resistance (M phenotype). Target modification is controlled by erm encoded methylases.

A complete cross-resistance exists among erythromycin, azithromycin, other macrolides and lincosamides for Streptococcus pneumoniae, beta-haemolytic streptococci of group A, Enterococcus spp. and Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA).

Penicillin-sensitive S. pneumoniae are more likely to be susceptible to azithromycin than are penicillin-resistant strains of S. pneumoniae. Methicillin-resistant S. aureus (MRSA) is less likely to be susceptible to azithromycin than methicillin-sensitive S. aureus (MSSA).

The induction of significant resistance in both in vitro and in vivo models is 1 dilution rise in MICs for S. pyogenes, H. influenzae and Enterobacterciae after nine sub-lethal passages of active substance and three dilution increase for S. aureus and development of in vitro resistance due to mutation is rare.

Breakpoints:

Azithromycin susceptibility breakpoints for typical bacterial pathogens:

EUCAST (2008):

• Staphylococcus spp.: susceptible 1 mg/l and resistant >2 mg/l

• Haemophilus spp.: susceptible 0.12 mg/l and resistant > 4 mg/l

• Moraxella catarrhalis: susceptible 0.5 mg/l and resistant > 5 mg/l

• Streptococcus spp. including groups A, B, C, G and Streptococcus pneumoniae: susceptible 0. 25 mg/l and resistant > 0.5 mg/l

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 1: Antibacterial spectrum of azithromycin

⁺ Resistance is greater than 50%.

Absorption

Following oral administration the bio-availability of azithromycin is approximately 37%. Peak plasma levels are reached after 2-3 hours. The mean maximum concentration observed (Cmax) after a single dose of 500 mg is approximately 0.4 μg/ml.

Distribution

Orally administered azithromycin is widely distributed throughout the body. Pharmacokinetic studies have shown considerably higher azithromycin concentrations in the tissues (up to 50 times the maximum concentration observed in the plasma). This indicates that the substance is extensively bound in the tissues (steady-state volume of distribution approximately 31 l/kg). With the recommended dosage no accumulation in the serum/plasma occurs. Accumulation does occur in the tissues where the levels are much higher than in the serum/plasma. Concentrations in target tissues such as lung, tonsil, and prostate exceed the MIC90 for likely pathogens after a single dose of 500 mg.

In experimental in vitro and in vivo studies, azithromycin accumulates in phagocytes; release is promoted by active phagocytosis. In animal models this process appears to contribute to the accumulation of azithromycin in tissue.

The binding of azithromycin to plasma proteins is variable and varies from 52% at 0.005 μg/ml to 18% at 0.5 μg/ml.

Metabolism and Excretion

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

Approximately 12% of an intravenously administered dose is excreted in unchanged form with the urine over a period of 3 days; the major proportion in the first 24 hours. Concentrations of up to 237 μg/ml azithromycin, 2 days after a 5-day course of treatment, have been found in human bile, together with 10 metabolites (formed by N- and O-demethylation, by hydroxylation of the desosamine and aglycone rings, and by splitting of the cladinose conjugate). Investigations suggests that the metabolites do not play a role in the micro-biological activity of azithromycin.

Pharmacokinetics in special populations

Renal insufficiency

Following a single oral dose of azithromycin 1g, 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 (GFR < 10 ml/min), 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. There are no data on azithromycin use in cases of more severe hepatic impairment.

Elderly

The pharmacokinetics of azithromycin in elderly men was similar to that of young adults; however, in elderly women, although higher peak concentrations (increased by 30-50%) were observed, no significant accumulation occurred.

In elderly volunteers (>65 years), higher (29 %) AUC values were always observed after a 5-day course than in younger volunteers (<45 years). However, these differences are not considered to be clinically relevant; no dose adjustment is therefore recommended.

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 μg/l in children aged 0.6-5 years and after 3 days dosing and 383 μg/l in those aged 6-15 years. The t_1/2 of 36h in the older children was within the expected range for adults.

In animal studies using exposures 40 times those achieved at the clinical therapeutic dosages, azithromycin was found to have caused reversible phospholipidosis, but as a rule there were no associated toxicological consequences. 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.

Carcinogenic potential

Long-term studies in animals have not been performed to evaluate carcinogenic potential.

Mutagenic potential

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

Reproductive toxicity

No teratogenic effects were observed in embryotoxicity studies in rats after oral administration of azithromycin. In rats, azithromycin dosages of 100 and 200 mg/kg body weight/day led to mild retardations in fetal ossification and in maternal weight gain. In peri- and postnatal studies in rats, mild retardations following treatment with 50 mg/kg/day azithromycin and above were observed.

Tablet Core:

Microcrystalline cellulose (E460)

Pregelatinised starch (maize starch)

Sodium starch glycolate (Type A)

Anhydrous colloidal silica (E551)

Sodium lauryl sulphate

Magnesium stearate (E470b)

Tablet Film-coating:

Polyvinyl alcohol (partially hydrolysed)

Titanium dioxide (E171)

Talc (E553b)

Soya lecithin

Xanthan gum (E415).

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

PVC/PVDC/aluminium blister pack.

Pack sizes: 4, 6, 12, 24, 50, 100 film-coated tablets.

Not all pack sizes may be marketed.

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.

McDermott Laboratories Limited

T/a Gerard Laboratories

35/36 Baldoyle Industrial Estate

Grange Road

Dublin 13

PA 577/122/1

Date of first authorisation: 4^th June 2010

October 2011