1. Name of the medicinal product
    AZIX
    Azithromycin 500 mg Tablets
  2. Qualitative and quantitative composition
    1 film-coated tablet contains azithromycin monohydrate equivalent to 500 mg
    azithromycin
    Excipient with known effect:
    Soya lecithin (see section 4.4)
    For the full list of excipients, see section 6.1.
  3. Pharmaceutical form
    Film-coated tablet
    500 mg film-coated tablets: white to off-white, oblong, film-coated, deep score line on one side and scoreline on other side. The tablet can be divided into equal doses.
  4. Clinical particulars
    1. Therapeutic indications
      Azithromycin tablets can be applied for the treatment of the following infections, when caused by microorganisms sensitive to azithromycin (see sections 4.4 and 5.1):
      • acute bacterial sinusitis (adequately diagnosed)
      • acute bacterial otitis media (adequately diagnosed)
      • pharyngitis, tonsillitis
      • acute exacerbation of chronic bronchitis (adequately diagnosed)
      • 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.
    2. Posology and method of administration
      Posology
      • Adults
        In uncomplicated Chlamydia trachomatis urethritis and cervicitis the dosage is 1000 mg as a single oral dose.
        For all other indications the dose is 1500 mg, to be administered as 500 mg per day for three consecutive days. As an alternative the same total dose (1500 mg) can also be administered over a period of five days with 500 mg on the first day and 250 mg on the second to the fifth day.
      • Older people
        The same dosage as in adult patients is used for older people. Since older people 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
        Azithromycin tablets should only be administered to children weighing more than 45 kg when normal adult dose should be used. For children under 45 kg other pharmaceutical forms of azithromycine, e.g. suspensions, may be used.
        In 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).
        In 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
        Azithromycin Tablets should be given as a single daily dose. The tablets may be taken with food.
    3. Contraindications
      The use of azithromycin is contraindicated in patients with hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic, or to any of the excipients listed in section 6.1.
    4. Special warnings and precautions for use
      As with erythromycin and other macrolides, rare serious allergic reactions including angioneurotic oedema and anaphylaxis (rarely fatal), have been reported. Some of these reactions with azithromycin have resulted in recurrent symptoms and required a longer period of observation and treatment.
      Since liver is the principal route of elimination for azithromycin, the use of azithromycin should be undertaken with caution in patients with significant hepatic disease. Cases of fulminant hepatitis potentially leading to life-threatening liver failure have been reported with azithromycin (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.
      In patients receiving ergotamine derivatives, ergotism has been precipitated by coadministration of some macrolide antibiotics. There are no data concerning the possibility of an interaction between ergotamine derivatives and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administered (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 including azithromycin (see section 4.8). Therefore as the following situations may lead to an increased risk for ventricular arrhytmias (including torsade de pointes) which can lead to cardiac arrest, azithromycin should be used with caution in patients with ongoing proarrhythmic conditions (especially women and older people) such as patients:
      • With congenital or documented QT prolongation.
      • Currently receiving treatment with other active substances 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 cases of hypokalaemia and hypomagnesaemia
      • With clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.
      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 all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antimicrobial agents. In case of CDAD anti- peristaltics are contraindicated.
      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).
    5. Interaction with other medicinal products and other forms of interaction
      Effects of other medicinal products on azithromycin:
      • Antacids
        In a pharmacokinetic study investigating the effects of simultaneous administration of antacids and azithromycin, no effect on overall bioavailability was seen, although the peak serum concentrations were reduced by approximately 25%. In patients receiving both azithromycin and antacids, the drugs should not be taken simultaneously. Azithromycin must be taken at least 1 hour before or 2 hours after the antacids.
        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.
      • Fluconazole
        Coadministration 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 coadministration of fluconazole, however, a clinically insignificant decrease in Cmax (18%) of azithromycin was observed.
      • Nelfinavir
        Coadministration 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 is required.
      • Rifabutin
        Coadministration 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).
      • 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.
      • 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.
      Effect of azithromycin on other medicinal products:
      • Ergotamine derivatives
        Due to the theoretical possibility of ergotism, the concurrent use of azithromycin with ergot derivatives is not recommended (see section 4.4).
      • Digoxin (P-gp substrates)
        Concomitant administration of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin, has been reported to result in increased serum levels of the P-glycoprotein substrate. Therefore, if azithromycin and P-gp substrates such as digoxin are administered concomitantly, the possibility of elevated serum concentrations of the substrate should be considered.
      • 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 coadministration 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.
      • Cyclosporin
        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 cyclosporin, the resulting cyclosporin Cmax and AUC0-5 were found to be significantly elevated. Consequently, caution should be exercised before considering concurrent administration of these drugs. If coadministration of these drugs is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.
      • Theophylline
        There is no evidence of a clinically significant pharmacokinetic interaction when azithromycin and theophylline are co-administered 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.
      • Trimethoprim/sulfamethoxazole
        Coadministration 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.
      • 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.
      • Astemizole, alfentanil
        There are no known data on interactions with astemizole 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 macrolid antibiotic erythromycin.
      • Atorvastatin
        Coadministration 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.
      • 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.
      • Cetirizine
        In healthy volunteers, coadministration 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.
      • Didanosins (Dideoxyinosine)
        Coadministration of 1200 mg/day azithromycin with 400 mg/day didanosine in 6 HIV-positive subjects did not appear to affect the steady-state pharmacokinetics of didanosine as compared with placebo.
      • Efavirenz
        Coadministration of a 600 mg single dose of azithromycin and 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interactions.
      • 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.
      • Methylprednisolone
        In a pharmacokinetic interaction study in healthy volunteers, azithromycin had no significant effect on the pharmacokinetics of methylprednisolone.
      • Midazolam
        In healthy volunteers, coadministration 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.
      • 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.
      • Triazolam
        In 14 healthy volunteers, coadministration 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.
    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 the benefit outweighs the risk.
      • Breast-feeding
        Azithromycin has been reported to be secreted into human breast milk, but there are no adequate and well-controlled clinical studies in nursing women that have characterized the pharmacokinetics of azithromycin excretion into human 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
        In fertility studies conducted in rat, reduced pregnancy rates were noted following administration of azithromycin. The relevance of this finding to humans is unknown.
    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.
    8. Undesirable effects
      Działania niepożądane zostały określone w następujący sposób: często (?1/100, <1/10); niezbyt często (?1/1000, <1/100); rzadko (?1/10 000, <1/1000).
      • Zaburzenia krwi i układu chłonnego Rzadko: trombocytopenia. W badaniach klinicznych obserwowano lekkie i przemijające zmniejszenie liczby granulocytów obojętnochłonnych (neutropenia), ale nie potwierdzono czy jest to związane z leczeniem azytromycyną.
      • Zaburzenia psychiczne Rzadko: zachowanie agresywne, niepokój, lęk, nerwowość.
      • Zaburzenia układu nerwowego Niezbyt często: zawroty głowy, senność, bóle głowy, drgawki (obserwowane również podczas stosowania innych makrolidów), zaburzenia smaku i węchu, utrata przytomności. Rzadko: parestezje i astenia, bezsenność i nadmierna ruchliwość.
      • Zaburzenia ucha i błędnika Rzadko: uszkodzenia słuchu obserwowano podczas stosowania antybiotyków makrolidowych. U niektórych pacjentów leczonych azytromycyną opisywano osłabienie słuchu, głuchotę i szumy uszne. Większość z tych przypadków odnosi się do badań doświadczalnych, w których azytromycyna była przyjmowana w dużych dawkach przez długi okres. Jednakże aktualnie dostępne dane potwierdzają, iż większość spośród tych zaburzeń jest przemijająca.
      • Zaburzenia oka Rzadko: zaburzenia widzenia.
      • Zaburzenia serca Rzadko: kołatanie serca, arytmie z tachykardią komorową (które występują także podczas stosowania innych makrolidów). Istnieje ryzyko wydłużenia odstępu QT i torsade de pointes (patrz punkt 4.4).
      • Zaburzenia naczyniowe Rzadko: obniżenie ciśnienia tętniczego.
      • Zaburzenia żołądka i jelit Często: nudności, wymioty, biegunka, uczucie dyskomfortu w jamie brzusznej (ból, skurcze). Niezbyt często: luźne stolce, wzdęcia, zaburzenia trawienia, jadłowstręt. Rzadko: zaparcia, zapalenie języka, rzekomobłoniaste zapalenie okrężnicy, zapalenie trzustki.
      • Zaburzenia wątroby i dróg żółciowych Rzadko: zapalenie wątroby i żółtaczka cholestatyczna z nieprawidłowymi wartościami testów czynności wątroby, martwica wątroby i niewydolność wątroby, rzadko prowadzące do zgonu.
      • Zaburzenia skóry i tkanki podskórnej Niezbyt często: reakcje alergiczne takie, jak świąd i wysypka. Rzadko: reakcje alergiczne takie, jak obrzęk naczynioruchowy, pokrzywka i uczulenie na światło; ciężkie reakcje skórne, jak rumień wielopostaciowy, zespół Stevensa-Johnsona i martwica toksyczno- rozpływna naskórka.
      • Zaburzenia mięśniowo-szkieletowe i tkanki łącznej Niezbyt często: bóle stawów.
      • Zaburzenia nerek i dróg moczowych Rzadko: śródmiąższowe zapalenie nerek, ostra niewydolność nerek.
      • Zaburzenia układu rozrodczego i piersi Niezbyt często: zapalenie pochwy.
      • Zaburzenia układu immunologicznego Rzadko: anafilaksja (rzadko prowadząca do zgonu), w tym obrzęk naczynioruchowy.
      • Zakażenia i zarażenia pasożytnicze Rzadko: kandydozy.
      • Zaburzenia ogólne Rzadko: osłabienie, uczucie zmęczenia.
    9. Overdose
      Adverse events experienced in higher than recommended doses were similar to those seen at normal doses. In the event of overdosage genaral symptomatic and general supportive measures are indicated as required.
  5. Pharmacological properties
    1. Pharmacodynamic properties
      Pharmacotherapeutic group: antibacterials for systemic use; macrolids; azithromycin,
      ATC code: J01FA10
      • Mode of action:
        Azithromycin is an azalide, a sub-class of the macrolid 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
        EUCAST (European Committee on Antimicrobial Susceptibility Testing):
        • Haemophilus influenzae i H. parainfluenzae: wrażliwe ?0,125 mg/l; oporne >4 mg/l
        • Streptococcus pneumoniae i S. pyogenes: wrażliwe ?0,25 mg/l; oporne >0,5 mg/l
        • Staphylococcus aureus: wrażliwe ?1 mg/l; oporne >2 mg/l
        • Neisseria gonorrhoeae: wrażliwe ?0,25 mg/l; oporne >0,5 mg/l.
      • 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.
    2. Pharmacokinetic properties
      • Absorption
        After oral administration the bioavailability of azithromycin is approximately 37%. Peak plasma levels are reached after 2-3 hours (Cmax after a single dose of 500 mg orally was approximately 0.4 mg/l).
      • Distribution
        Kinetic studies have shown markedly higher azithromycin levels in tissue than in plasma (up to 50 times the maximum observed concentration in plasma) indicating that the active substance is heavily tissue bound (steady state distribution volume of approximately 31 l/kg). 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 the phagocytes, freeing is stimulated by active phagocytosis. In animal studies this process appeared to contribute to the accumulation of azithromycin in the tissue. In serum the protein binding of azithromycin is variable and depending on the serum concentration varies from 50% in 0.05 mg/l to 12% in 0.5 mg/l.
      • Excretion
        Plasma terminal elimination half-life closely reflects the tissue depletion half-life of 2 to 4 days. About 12% of an intravenously administered dose is excreted in the urine unchanged over a period of 3 days; the majority in the first 24 hours. Biliary excretion of azithromycin, predominantly in unchangedform, is a major route of elimination. The identified metabolites (formed by N- and O- demethylising, by hydroxylising of the desosamine and aglycone rings, and by the splitting of the cladinose conjugate) are microbiologically inactive. After a 5 day treatment slightly higher (29%) AUC values were seen in the elderly volunteers (!65 years of age) compared to the younger volunteers ( !45 years of age). However these differences are not regarded as clinically relevant; therefore a dose adjustment is not recommended.
      Pharmacokinetics in special populations
      • Renal insufficiency
        Following a single oral dose of azithromycin 1 g, mean Cmax and AUC0-120 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 Cmax and AUC0-120 increased 61% and 33% 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 Cmax 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 t1/2 of 36 h in the older children was within the expected range for adults.
    3. Preclinical safety data
      In high-dose animal studies, giving active substance concentrations 40 fold higher than those expected in clinical practice, azithromycin has been noted to cause reversible phospholipidosis, generally without discernible toxicological consequences. There is no evidence that this is of relevance to the normal use of azithromycin in humans.
      • Carcinogenic potential: Long-term studies in animals have not been performed to evaluate carcinogenic potential.
      • Mutagenic potential: Azithromycin has shown no mutagenic potential in standard laboratory tests: mouse lymphoma assay, human lymphocyte clastogenic assay, and mouse bone marrow clastogenic assay.
      • Reproductive toxicity: No teratogenic effects were observed in animal studies of embryotoxicity in mice and rats. In rats, azithromycin dosages of 100 and 200 mg/kg bodyweight/day led to mild retardations in foetal ossification and in maternal weight gain. In peri-/postnatal studies in rats, mild retardations following treatment with 50 mg/kg/day azithromycin and above were observed.
  6. Pharmaceutical particulars
    1. List of excipients
      Core:
      Microcrystalline cellulose
      Pregelatinised maize starch
      Sodium starch glycolate Type A
      Colloidal anhydrous silica
      Sodium laurilsulfate
      Magnesium stearate
      Coating:
      Polyvinyl alcohol
      Titanium dioxide (E 171)
      Talc
      Soya Lecithin
      Xanthan Gum.
    2. Incompatibilities
      Not applicable.
    3. Shelf life
      3 years
    4. Special precautions for storage
      This medicinal product does not require any special storage conditions.
    5. Nature and contents of container
      PVC/PVdC/Aluminium blister
      Pack sizes:
      500 mg: 3
    6. Special precautions for disposal and other handling
      No special requirements.
  7. Marketing authorisation holder
    ETHIFARM Sp. z o.o. Sp. komandytowa
    ul. Hiacyntowa 39
    60-175 Poznań
  8. Date of revision of the text
    30/08/2013