CONFIRMED

  The Order of the Ministry of

Healthcare of Ukraine

       23.05.2012     No  373_

Registration certificate

  No UA/12158/01/01

  No UA/12158/01/02

  No UA/12158/01/03

 

CHANGES ARE INTRODUCED

The Order of the Ministry of

Healthcare of Ukraine

04.08.2015     No  489_

 

 

 

 

INSTRUCTION

for medical use of the preparation

 

AZITHROMYCIN 250

AZITHROMYCIN 500

AZITHROMYCIN 1000

 

Composition:

Active substance: azithromycin;

1 tablet contains azithromycin equivalent to 250 mg, 500 mg or 1000 mg azithromycin anhydrous;

Auxiliary substances:

Azithromycin 250: microcrystalline cellulose, calcium hydrophosphate, corn starch, povidone, magnesium stearate, talcum, titanium dioxide colloidal anhydrous, sodium lauryl sulfate, sodium starchglycolate (type А), hydroxypropylmethylcellulose, titanium dioxide (E 171), iron oxide yellow (Е 172);

Azithromycin 500: microcrystalline cellulose, corn starch, povidone, magnesium stearate, talcum, titanium dioxide colloidal anhydrous, sodium lauryl sulfate, натрію sodium starchglycolate (type А), hydroxypropylmethylcellulose, titanium dioxide (E 171), iron oxide yellow (Е 172);

Azithromycin 1000: calcium hydrophosphate, corn starch, povidone, microcrystalline cellulose, magnesium stearate, talcum, titanium dioxide colloidal anhydrous, sodium starchglycolate (type А);

Film coating: hydroxypropylmethylcellulose, polyethyleneglycol 6000, titanium dioxide (E 171), talcum, iron oxide yellow (Е 172).

Medicinal form. Film coated tablets.

Pharmacotherapeutical group. Antimicrobial agents for systemic use. Macrolides, lincosamides and streptogramines. Azithromycin. ATC code J01F A10.

Clinical characteristics.

Indications.

Infections caused by azithromycin- sensitive microorganisms:

• Ø infections of ENT-organs (bacterial pharyngitis/tonsillitis, sinusitis, and otitis media).
• Ø infections of respiratory tracts (bacterial bronchitis, community-acquired pneumonia).
• Ø infections of skin and soft tissues: migratory erythema (initial stage of Lyme disease), erysipelas, impetigo, secondary pyodermatosis. Treatment of uncomplicated forms of acne vulgaris.
• Ø sexually transmitted infections: uncomplicated urethritis/cervicitis caused by Chlamydia trachomatis.

Contraindications.

Hypersensitivity to the active substance, any component of the preparation or other macrolide antibiotics. Due to theoretical possibility of ergotism, azithromycin should not be indicated concomitantly with ergot derivatives.

The way of administration and doses.

Adults, including elderly patients, and children with bodyweight over 45 kg.

Azithromycin should be administrated one hour before or two hours after meals, as concomitant administration with food disturbs its absorption. The preparation is taken once a day. Tablets should be swallowed without chewing.

In case of infections of ENT-organs, respiratory tracts, skin and soft tissues (except migratory erythema): 500 mg (as a single dose) a day for 3 days.

In case of migratory erythema: adults – once a day for 5 days: Day 1 – 1 g, then – 500 mg from Day 2 to Day 5.

In case of sexually transmitted infections (uncomplicated urethritis/cervicitis):

1 g as a single dose; course dose is 1 g.

In case of acne vulgaris: course dose is 6 g. The recommended scheme of treatment is as follows: for first

3 days – 500 mg once a day, for the following 9 weeks –500 mg once a week, and in week 2 the tablet is taken in 7 days after the previous intake.

If 1 dose of the preparation is missed, it should be taken as soon as possible, and the following – with 24-hour intervals.

Renal insufficiency

In patients with insignificant liver dysfunction (creatinine clearance >40 ml/min) there is no need to adjust the dose. No studies have been conducted in patients with creatinine clearance <40 ml/min. That is why azithromycin should be used with caution in such patients.

Hepatic insufficiency

As azithromycin is metabolized in liver and excreted with bile, the preparation should not be used in patients with serious liver diseases.

Side effects.

Azithromycin is well tolerated and has low frequency of side effects.

Side effects indicated below are classified according to the frequency of their manifestation: very frequent           (≥ 10 %); frequent (≥ 1 %, < 10 %); not frequent (≥ 0.1 %, < 1 %); seldom (≥ 0.01 %, < 0.1 %); very seldom (<0.01 %), including single reports.

from the side of blood system and lymphatic system: seldom – thrombocytopenia.

In clinical studies there have been single reports on periods of transitory, obliterated neutropenia. However, causal relationship with azithromycin therapy has not been proved.

from the side of psyche:  seldom – aggressiveness, hyperactivity, anxiety and nervousness.

from the side of the nervous system: not frequent – dizziness/vertigo, sleepiness, syncope, headache, convulsions (it has been determined that they are also caused by other macrolide antibiotics), parageusia and parosmia; seldom – paresthesia, astenia, insomnia.

from the side of hearing organ: there are seldom reports that macrolide antibiotics cause hearing impairment. In some patients, who took azithromycin, there were registered hearing impairment, deafness development and ringing in the ears. Most of these cases are associated with experimental investigations, where azithromycin was used at high doses during long period of time. According to available follow-up reports, most of these problems were reversible.

from the side of cardiovascular system: seldom – palpitation, arrhythmia, connected with ventricular tachycardia (it has been determined that they are also caused by other macrolide antibiotics). There were rare reports about QT prolongation and torsade de pointes, arterial hypotension.

from the side of digestive tract: frequent – nausea, vomiting, diarrhea, unpleasant feelings in the stomach (pain/spasms); not frequent – watery stool, meteorism, disturbed digestion, anorexia; seldom – constipation, change of tongue color. There were reports about pseudomembranous colitis, pancreatitis.

from the side of liver and gallbladder: seldom – hepatitis and cholestatic jaundice, including pathological indexes of liver function test; hepatic necrosis and liver dysfunction, which in rare cases leads to lethal outcome.

from the side of skin: not frequent – allergic reactions, including itch and rash; seldom – allergic reactions, including angioneurotic edema, urticaria and photosensitivity; serious skin reactions,

in particular: erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis.

from the side of musculoskeletal system: not frequent – arthralgia.

from the side of urinary tracts: seldom - interstitial nephritis and acute renal insufficiency.

from the side of reproductive system: not frequent – vaginitis.

System disorders: seldom - anaphylactic reaction, including edema (in rare cases leads to lethal outcome), candidiasis.

general disorders: not frequent – fatigue.

investigations: frequent – lymphocytopenia, decreased level of blood bicarbonates; not frequent – increased level of aspartate aminotransferase, increased level of alanine aminotransferase, increased level of blood bilirubin, increased level of blood urea, increased level of blood creatinine, alteration of blood potassium indexes.

Overdose.

Typical overdose symptoms: reversible hearing impairment, evident nausea, vomiting, diarrhea.

In case of overdose, it is necessary to take activated charcoal and conduct symptomatic therapy aimed at maintaining vital functions of the organism.

Administration during pregnancy and lactation.

Azithromycin crosses placenta and reaches the fetus, however, harmful influence of the preparation to the fetus has not been revealed. Appropriate and well controlled investigations in pregnant women have not been conducted. That is why azithromycin should be taken during pregnancy only in those cases when the expected benefit of treatment for the mother overcomes the potential risk for the fetus.

There are no studies conducted to investigate if the preparation is excreted into human milk, that is why azithromycin should be used during breast feeding only when there are no other adequate alternative preparations.

Children.

For treatment in children with body weight below 45 kg, azithromycin is indicated in other pharmaceutical forms, such as suspension.

Peculiarities of the use. 

Allergic reactions: in rare cases it has been reported that azithromycin causes serious (seldom – lethal) reactions, such as angioneurotic edema and anaphylactic reaction. Some of these reactions caused the development of recurrent symptoms and required more prolonged observation and treatment.

Prolonged cardiac repolarization and QT interval, which increased the risk of development of cardiac arrhythmia and torsade de pointes, were observed at treatment with other macrolide antibiotics. Such an effect of azithromycin cannot be fully excluded in patients with increased risk of prolonged cardiac repolarization.

Streptococcic infections: azithromycin is generally efficient in treatment streptococcus in oropharynx, but there is no data that demonstrate the efficiency of azithromycin in prevention of the acute polyarticular rheumatoid arthritis.

Superinfections: similar to other antibacterial preparations, there is a possibility of superinfection development (for example, mycosis).

Myasthenia gravis: there are reports on exacerbation of myasthenia gravis symptoms or new development of myasthenic syndrome in patients, who receive azithromycin therapy.

Capacity to influence reaction rate when driving or operating other mechanisms.

Due to the fact that azithromycin may cause certain disorders from the side of the nervous system (see Section “Side effects”), it is not recommended to use the preparation when there is a need to drive or operate other mechanisms.

Interaction with other medicinal preparations and other forms of interaction. 

Azithromycin should be indicated with caution with other medicinal preparations, which may prolong QT interval.

Antiacids: in studies of concomitant use of antiacids on azithromycin pharmacokinetics, in general no changes in bioavailability are observed, though maximal plasma concentrations of azithromycin decreased by 30 %. Azithromycin should be taken at least one hour before or 2 hours after antiacid intake.

Carbamazepine: in studies of pharmacokinetic interaction in healthy volunteers, azithromycin does not reveal any significant influence on plasma levels of carbamazepine or its active metabolites.

Cyclosporine: some of related macrolide antibiotics influence cyclosporine metabolism. Due to the fact that no pharmacokinetic or clinical studies on possible interaction at concomitant use of azithromycin and cyclosporine have been conducted, it is necessary to estimate the therapeutic situation thoroughly before indicating concomitant administration of these medicinal preparations. If combined treatment is considered to be reasonable, it is necessary to conduct careful monitoring of cyclosporine levels and adjust the dosing respectively.

Coumarinic anticoagulants: there are reports on increased tendency to hemorrhages due to concomitant use of azithromycin and warfarin or coumarin-like oral anticoagulant. It is necessary to pay attention to frequent monitoring of prothrombin time.

Digoxin: there are reports, that in some patients certain macrolide antibiotics influence digoxin metabolism in the intestine. Due to the fact that in case of concomitant use of azithromycin and digoxin there is a possibility of increased concentration of digoxin, it is necessary to conduct monitoring of digoxin level.

Methylprednisolone: in studies of pharmacokinetic interaction in healthy volunteers, azithromycin does not reveal any significant influence on methylprednisolone pharmacokinetics.

Terfenadine: pharmacokinetic studies have not revealed any interaction between azithromycin and terfenadine. Similar to other macrolide antibiotics, it is necessary to exercise caution when indicating azithromycin in combination with terfenadine.

Theophylline: azithromycin has no influence on theophylline pharmacokinetics at concomitant use of azithromycin and theophylline in healthy volunteers. Combined use of theophyllineу and other macrolide antibiotics sometimes leads to increased serum levels of theophylline.

Zidovudine: single doses of 1000 mg and multiple doses of 1200 mg or 600 mg of azithromycin have no influence on plasma pharmacokinetics or excretion with urine of either zidovudine or its glucuronid metabolites. However, azithromycin intake increases the concentration of phosphorylated zidovudine, clinically active metabolite in mononuclear leukocytes in peripheral circulation. Clinical importance of these data is not certain, but may be useful for patients.

Didanosine: at concomitant use of daily doses of azithromycin 1200 mg with didanosine in six subjects, no influence on didanosine pharmacokinetics against placebo has been found.

Rifabutin: concomitant use of azithromycin and rifabutin has no influence on plasma contentrations of either preparations. Neutropenia has been observed in subjects, who took concomitantly azithromycin and rifabutin. In spite of the fact that neutropenia was associated with rifabutin use, casual relationship with concomitant use of azithromycin has not been found.

Pharmacological properties. 

Pharmacodynamics.

Azithromycin is a representative of the group of macrolide antibiotics, azalides, which have broad spectrum of antimicrobial action. The mechanism of action of azithromycin lies in inhibiting synthesis of bacterial protein due to binding with ribosome 50 S-subunit and prevention of peptide translocation on condition of no influence on polynucleotide synthesis.

Resistance mechanism:

Resistance to azithromycin may be congenital or acquired. Complete cross resistance exists in Streptococcus pneumoniae, beta-hemolytic streptococcus of group А, Enterococcus faecalis and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA), to erythromycin, azithromycin, other macrolides and lincosamides.

Spectrum of antimicrobial action of azithromycin.

 

Aerobic gram-positive bacteria

Staphylococcus aureus (methicillin-sensitive)

Streptococcus pneumoniaе (penicillin-sensitive)

Streptococcus рyogenes (gr. А)

Aerobic gram-negative bacteria

Haemophilus influenzaе

Haemophilus parainfluenzae

Legionella pneumophila

Moraxella catarrhalis

Pasteurella multocida

Anaerobic bacteria

Сlostridium perfringens

Fusobacterium spp.

Prevotella spp.

Porphyromonas spp.

Other bacteria

Chlamydia trachomatis

Species that acquire resistance in single cases

Aerobic gram-positive bacteria

Streptococcus pneumoniae

with intermediate resistance to penicillin

penicillin-resistant

Congenital resistant microorganisms

Aerobic gram-positive bacteria

Enterococcus faecalis

Staphylococci МRSA, MRSE (methicillin-resistant Staphylococcus aureus)

Anaerobic bacteria

Group of bacteroides Bacteroides fragilis

 

Pharmacokinetics. Bioavailability after oral intake is approximately 37 %. Maximal serum concentration is achieved in 2-3 hours after intake of the preparation. Following oral intake, azithromycin distributes in the whole organism. In pharmacokinetic studies it has been demonstrated that tissue concentration of azithromycin is much higher (50-fold) in comparison with plasma one, which indicates strong binding of the preparation with tissues.

Binding with serum proteins varies due to plasma concentrations and is from 12 % at 0.5 µg/ml to 52% at 0.05 µg/ml in serum. Virtual steady-state volume of distribution (VV_ss) was 31.1 L/kg.

Final period of plasma half-life fully reflects half-life period from tissues within 2-4 days.

About 12 % of IV dose of azithromycin is excreted with urine in unchanged state within the following three days. Especially high concentrations of unchanged azithromycin have been revealed in human bile. In addition, in bile there have been found ten metabolites, which form with the help of N- and O- demethylation, hydroxylation of the desosamine and aglycone rings, and by cleavage of the cladinose conjugate. Comparison of the results of liquid chromatography and microbiological analyses has demonstrated that metabolites of azithromycin are not microbiologically active.

Pharmaceutical characteristics.

Main physical and chemical properties:

tablets 250 mg: yellow, round, biconvex film-coated tablets;

tablets 500 mg: yellow, elongated, biconvex film-coated tablets, with a score mark on one side and plain on the other;

tablets 1000 mg: yellow, elongated, biconvex film-coated tablets, with a score mark on one side and plain on the other.

Shelf-life.  2 years.

Do not use after expiration date indicated on the package.

Storage conditions. Store at temperature below 25 °С. Keep out of the reach of children.

Packaging.

Azithromycin 250: 6 tablets in a blister, 1 blister in a carton.

Azithromycin 500:  3 tablets in a blister, 1 blister in a carton.

Azithromycin 1000: 4 tablets in a blister, 1 blister in a carton.

Category of dispensing. On prescription.

Manufacturer. Flamingo Pharmaceuticals Ltd.

Location.

Manufacturing site address. E-28, Opp. Fire Brigade, MIDC, Taloja, Dist. Raigad, Maharashtra, IN-410 208, India

Applicant.

Ananta Medicare Ltd.

Location. Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.

Date of the last review.  04.08.2015.