INSTRUCTION

for medical use of the preparation

AZICLAR 250,

AZICLAR 500 

Composition:

Active substance: 1 tablet contains: clarithromycin 250mg or 500mg;

Inactive substances: lactose monohydrate, corn starch, povidone, sodium croscarmellose, microcrystalline cellulose, talc, sodium lauryl sulfate, filmy coating (hydroxypropylmethyl cellulose, colorant brilliant blue Е133, polyethylene glycol) (tablets 250 mg) lactose monohydrate, corn starch, povidone, sodium croscarmellose, magnesium stearate, microcrystalline cellulose, talc, sodium lauryl sulfate, filmy coating (hydroxypropylmethyl cellulose, colorant tartrazine Е102, polyethylene glycol) (tablets 500 mg)

Medicinal form. Film coated Tablets.

Pharmacotherapeutical group. Antimicrobial agents for systemic use. Macrolides. АТС code J01F A09.

Clinical characteristics. 

Indications.

Infections, caused by susceptible to clarithromycin microorganisms: 

– ENT-organs (streptococcal pharyngitis, tonsillitis, acute otitis media, acute sinusitis, maxillary sinusitis);

– respiratory tract (pneumonia, including atypical one, acute condition of chronic bronchitis);

– infections of skin and soft tissues (folliculitis, furunculosis, impetigo, abscesses, cellulitis, streptococcal impetigo, staphylococcal pyoderma);

– gastric or duodenal ulcer, associated with Helicobacter pylori (compulsory in combination with other medicinal agents).

Contraindications.

Hypersensitivity to clarithromycin or any other component of the preparation or other macrolide antibiotics; concomitant use with ergot derivatives, cisapride, pimozide, terphenadine, astemizole and other macrolides (may lead to prolongation of the QT interval and cause arrhythmia, as well as ventricular fibrillation and Тorsades de Рointes). Clarithromycin is not indicated to the patients with hypokalemia (prolongation of the QT interval).
 

Way of introduction and doses.

Tablets should be taken as a whole (do not crush, do not chew) with liquid. Food intake practically does not influence the absorption of the preparation, but it may somewhat delay this process.

Adults and children over12 years old: usually it is indicated clarithromycin 250 mg twice a day; for sever infections the dose may be increased up to 500 mg twice a day. As a rule the course of treatment lasts 7 - 14 days. The treatment should last at least 2 more days after disappearance of the main symptoms of the disease.

The duration of treatment depends on the clinical course and is determined by the doctor individually for every patient. For acute otitis media the duration of treatment may last for 5 - 6 days. For treatment of infections caused by M. avium соmplex, the day dose is 1 g, divided into two intakes.

Eradication of Helicobacter pylori in adults.

In patients with gastric or duodenal ulcer, associated with Helicobacter pylori, clarithromycin is used in dosed of 500 mg  twice a day together with amoxicillin 1000 mg twice a day and omeprazole 20 mg twice a day. The duration of treatment is 7 days.

In patients with severe renal dysfunction (creatinine clearance <30 ml/min) total dayly dose should be half-reduced, i.e. to 250 mg once a day or 250 mg twice a day in severe infections.
 

Side effects.

The most frequent side effects are diarrhea, nausea, taste alteration, dyspepsia, abdominal pain and headache.

Disturbance from the side of blood-vascular system and lymphatic system: leukopenia, eosinophilia; seldom thrombocytopenia, neurtopenia. 

Allergic reactions: urticaria, skin rash, anafilaxia; very seldom – Stevens-Johnson syndrome and toxic epidermal necrolysis.

Mental disorders: very seldom – agitation, insomnia, hallucination, mental confusion.

Disturbance from the side of the central and peripheral nervous system:  headache, very seldom – giddiness, paresthesia, crumps. Disturbance from the side of organ of hearing: tinnitus; very seldom – reversible loss of hearing.

Cardiac disorders: very seldom – ventricular arrhythmia, including ventricular tachycardia, prolongation of the QT interval, rapid ventricular tachycardia and ventricular fibrillation.

Gastrointestinal disorders: nausea, vomiting, abdominal pain, diarrhea, dyspepsia, stomatitis, glossitis, reversible coloration of teeth and tongue, taste alteration (metal or bitter taste); very seldom – pancreatitis, pseudomembranous colitis.

Hepatobiliary disorders: seldom – hepatocellular and/or cholestatic hepatitis with jaundice or without it, hepatic dysfunction associated with pre-existing disease, and in patients concomitantly using hepatotoxic preparations. 

Muscular and skeletal disorders: arthralgia, myalgia.

Disturbance from the side of kidneys: very seldom – interstitial neuritis, renal insufficiency.

Laboratory values: increasing of blood urea nitrogen; seldom – prolongation of prothrombin time, increasing of creatinine level in the serum, transient increasing of liver enzymes (AST, ALT, LDH, alkaline phosphatase, bilirubin); very seldom – hypoglycemia in patients using hypoglycemic preparations or insulin.
Overdose.

Symptoms: gastrointestinal disorders, headache, hypoglycemia, hypoxemia.

Treatment: there is no specific antidote. Gastric lavage, use of activated charcoal. Appropriate symptomatic treatment for maintenance of vital organs and systems. It is unlikely that hemodialysis or peritoneal dialysis can influence the level of clarithromycin in serum, so these procedures are not recommended. In case of over dose the use of clarithromycin should be discontinued and appropriate symptomatic treatment should be started.

Use in pregnancy and lactation.

The safety of use of the preparation during pregnancy and lactation has not been established.  The use of the preparation is possible when the potential benefit for the mother prevails over the potential risk for the fetus or the baby. Clarithromycin is excreted in breast milk, so during treatment breast-feeding should be discontinued.

Children.

There is no experience of use of the preparation in children under 6 months old. For children under 12 years old and body weight <30 kg it is recommended to use another medicinal form of the preparation – suspension.

Peculiarities of administration.  

The preparation is excreted by liver and kidneys. The preparation should be used with caution in patients with hepatic insufficiency, with renal insufficiency of moderate or severe degree. Hypersensitivity to clarithromycin may develop in patients sensitive to lincomycin or clindamycin. That is why to such patients the preparation should be indicated with caution.

If during treatment there developed expressed diarrhea, it is necessary to exclude the possibility of the development of pseudomembranous colitis.

There have been reports of increasing symptoms of myasthenia gravis in patients using clarithromycin.

The preparation should be used with caution in patients with severe heart diseases, with disorders of electrolyte balance in anamnesis. Due to the risk of prolongation of the QT interval it is necessary to be careful using clarithromycin in patients with ischemic heart disease, ventricular fibrillation in anamnesis, severe cardiac insufficiency or in case of concomitant use with other agents having the effect of prolongation of the QT interval.

Prolonged or repeated use of clarithromycin may lead to the development of superinfection caused by microorganisms insensitive to the preparation.

The preparation contains lactose,so the patients with rare inherited forms of galactose intolerance, lactose deficiency or syndrome of glucose galactose malabsorbtion should not use the preparation.

The ability to influence the reaction time when driving and working with other mechanisms.

Before ascertaining the individual reaction to the preparation it is recommended to be careful when driving or operating complicated machines, espessially at the beginning of the treatment or altering the dose.

Interaction with other drugs and other forms of interaction.  

Clarithromycin is metabolized in liver where it inhibits the activity of certain enzymes of cytochrome Р450system. Accordingly may decrease metabolism of different preparations transforming with the help of these enzymes (such as alprazolam, astemizole, terfenadine, cisapride, pimozide, carbamazapine, hexobarbital, bromocriptine, valproate, rifabutin, warfarin, digoxin, алкалоїди ріжків, triazolam, midazolam, methylprednisolone, quinidine, sildenafil, disopyramide, phenytoin, cyclosporine, tacrolimus, zidovudine, theophylline, vinblastine). It leads to increasing of their concentration in the serum; there may occur toxic effects. That is why clinical control, and if needed – determination of the concentration these preparations in serum, is required.

Post-marketing research indicates that concomitant use of clarithromycin and ergotamine or dihydroergotamine associates with signs of acute ergotism characterized by angiospasm and limb and tissue ischemia, including central nervous system. 

Clarithromycin inhibits metabolism of HMG-CoA reductase inhibitors which leads to increased concentration of the last in plasma. Seldom patients using clarithromycin withsimvastatin, lovastatin or atorvastatin, developed rhabdomyolysis, so such patients should be controlled as for the appearance of myopathy.

Powerful inductors of cytochrome Р450 enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapetine may enhance metabolism of clarithromycin decreasing its concentration plasma, but increasing the concentration of 14-ОН-clarithromycin – microbiological active metabolite. As microbiological activity of clarithromycin and 14-ОН-clarithromycin is different as for different bacteria, the expected therapeutic effect may not be achieved due to the concomitant use of clarithromycin and inductors of cytochrome Р450 enzymes.

Use of clarithromycin in patients, receiving warfarin, may cause increasing effects of the last. That is why in such patients it is important to monitor prothrombin time.

There are post-marketing reports about development of pirouette ventricular tachycardia, caused by concomitant use of clarithromycin and quinidine or disopyramide. It is recommended to carry out FCG-monitoring for timely detection of prolongation of the QT interval. During therapy with clarithromycin it is necessary to control the concentration these preparations in serum.

During post-marketing observation there have been reports about increased serum concentrations of digoxin in patients using clarithromycin with digoxin. Some patients have developed the signs of digitalis intoxication, including potentially fatal arrhythmias. It is necessary to control serum concentrations of digoxin when it is used with clarithromycin.

Use of clarithromycin in combination with omeprazole may lead to increasing balanced concentrations of omeprazole, but there is no need to change the dose. 

There is a possibility of increased plasma concentrations of phosphodiesterase inhibitors(sildenafil, tadalafil and vardenafil) at their concomitant use with clarithromycin due to which there can be needed lowering of the dose of phosphodiesterase inhibitors. 

Concomitant use of clarithromycin with colchicin, especially in elderly patients with renal dysfunction increases toxicity of the last. There have been reports about development of colchicine toxicity (including those with lethality) at concomitant use of clarithromycin and colchicine.

At concomitant use of ritonavir serum concentration of clarithromycin increases, so it should not be indicated at doses higher than 1 g a day.  For patients with renal dysfunction daily dose should be lowered by 50 % (creatinine clearance 30-60 ml/min) or by 75 % (creatinine clearance < 30 ml/min).

There is possible drug interaction between clarithromycin and atazanavir, itraconasole, sacvinavir.

Clarithromycin does not influence the efficirncy of oral contraceptives. 

Pharmacological properties. 

Pharmacodynamics.

Clarithromycin is a semisynthetic antibiotic of macrolide group. Its  antibacterial action is a result of protein synthesis inhibition due to binding with 50S-subunit of sucseptible baiteria ribosomes. It acts mainly bacteriostatically, but as for some microorganisms it produces bactericidal effect. The preparation has high specific activity as for wide spectrum of aerobic and anaerobic gram-positive and gram-negative microorganisms. Minimal inhibiting concentrations for clarithromycin, as a rule, twice lower than for erythromycin.

 
Clarithromycin is active as for the following microorganisms:

–  resistance < 10 %: 

aerobic gram-positive microorganisms: Streptococcus of groups A, B, C, F, G; 

aerobic gram-negative microorganisms: Moraxella catarrhalis, Pasteurella multocida, Legionella spp; 

anaerobic microorganisms: Bacteroides spp., Peptococcus spp., Peptostreptococcus spp., Fusobacterium spp., Clostridium spp. (except Clostridium difficile); 

intracellular microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae (trachomatis), Mycobacterium avium, Mycobacterium leprae іand all microbacterias, except M. tuberculosis.

–  resistance > 10 %: 

aerobic gram-positive microorganisms: Staphylococcus aureus (including strains, sucseptible to methicillin), Streptococcus pneumonia;

aerobic gram-negative microorganisms: Haemophilus influenzae, Helicobacter pylori;

– resistant microorganisms:

aerobic gram-positive microorganisms: Staphylococcus aureus (resistance to methicillin or erythromycin), Enterococcus spp. 

The spectrum of antibacterial action of clarithromycin is similar to that of erythromycin, except that it is active as for atypical microbacteria.

Pharmacokinetics. Clarithromycin absorbs quickly and effectively from gastro-intestinal tract, mainly in small intestine; it preserves its activity in presence of gastric juice; concomitant use of food slightly slows the absorption, but does not influence the degree of absorption. The bioavailability of the preparation is approximately 55 %.

It is metabolized in liver by cytochrome Р450 system with participation of isoenzyme CYP3A4 in three main ways (demethylation, hydroxylation and hydrolysis) to 8 metabolites. After absorption about 20% of the preparation is metabolized with formation of 14-hydroxyclarithromycin, which has biologic activity similar to those of clarithromycin.

Clarithromycin and its main metabolite distribute widely in tissues and biological fluids of the organism. High concentrations are observed in nose mucus, tonsils and lung tissues. Concentrations in tissues are higher than in circulating blood due to high intracellular concentrations; it is easily penetrates into leucocytes and macrophages; it also penetrates into gastric mucus.

Maximal serum concentrations of clarithromycin are achieved in 2-3 h and constitute 1-2 mcg/ml after administration at the dose of 250 mg twice a day and 3- mcg/ml after administration at the dose of 500 mg twice a day. Approximately 80 % of the preparation is bound to plasma proteins. The half-life increases from 2-4 h after administration of 250 mg of clarithromycin twice a day to 5 h after administration of 500 mg of the preparation twice a day. The half-life of active 14-hydroxymetabolite varies from 5 to 6 h after administration of 250 mg of clarithromycin twice a day.

It is 70 - 80 % excreted with feces, approximately 20-30 % – with urine in unchanged state. This portion increases with increasing of the dose of the preparation. In case of renal insufficiency plasma concentration of clarithromycin increases if the dose is not decreased.

Pharmaceutical characteristics.

Main physical and chemical properties: 

250 mg tablets: round, biconvex tablets, covered with blue filmy coating;

500 mg tablets: oblong, biconvex tablets, covered with yellow filmy coating.

Shelf life: 3 years.

Storage conditions. Store at temperature below 30єC in the original package. 

Keep out of the reach of children.

Packing. 10 tablets in a blister; 1 blister in a carton.  

Category of dispensing. On prescription.   

Name and address of the manufacturer. 

Flamingo Pharmaceuticals Ltd. 7/1, Corporate Park, Sion-Trombai Road, Chembur, Mumbai – 400071, India.

Name and address of the marketing company.

Ananta Medicare Ltd.

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