Ecozitrin (Clarithromycin) tablets

Composition and form of issue 

Tablets, film-coated. 1 tablet contains:

clarithromycin (in terms of active substance) 250 or 500 mg

excipients: lactulose (300 mg); povidone-K25; magnesium stearate; silicon dioxide colloidal (Aerosil); talc; potassium polacrilin  

the composition of the shell: hypromellose; talc; titanium dioxide; macrogol-4000; dye azorubin  

Description of dosage form

Film-coated tablets, pink, capsule-shaped, biconvex. The cross-section view shows two layers, the inner layer is white or almost white.

Pharmacological action

Pharmacological action – antibacterial broad spectrum.

Pharmacodynamics

Semi-synthetic broad-spectrum macrolide antibiotic. Violates the protein synthesis of microorganisms (binds with 50S subunit of ribosome membrane of microbial cells). It acts on extracellular and intracellular pathogens.

Clarithromycin activity against most of the following microorganisms was proved in vitro and in clinical practice: aerobic gram-positive microorganisms-Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes; aerobic gram — negative microorganisms-Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, pneumoniae; other microorganisms; – Mycoplasma pneumoniae, Chlamydia pneumoniae; Mycobacterium — Mycobacterium avium complex (MAC) — complex including: Mycobacterium avium and Mycobacterium intracellulare; Helicobacter pylori.

Beta-lactamases do not affect the activity of clarithromycin.

Activity of clarithromycin in vitro: aerobic gram — positive microorganisms Listeria monocytogenes, Streptococcus agalactiae, Streptococci groups C,F,G, viridans group Streptococci;aerobic gram-negative microorganisms — Neisseriа gonorrhoeae, Bordetella pertussis, Pasteurella multocida; gram-positive anaerobic microorganisms — Сlostridium perfringens, Peptococcus niger, and Propionibacterium acnes; anaerobic gram — negative microorganisms Bacteroides melaninogenicus; spirochaetes — Borrelia burgdorferi, Treponema pallidum; Mycobacterium — leprae, Mycobacterium, chelonae Mуcobacterium, Campylobacter is Campylobacter jejuni.

The microbiologically active metabolite of clarithromycin-14-hydroxyclarithromycin is twice as active as the original compound with respect to Haemophilus influenzae.Clarithromycin and its metabolite in combination can have both additive and synergistic effects on Haemophilus influenzae in vitro and in vivo, depending on the strain of the bacterium.

Most strains of staphylococci resistant to methicillin and oxacillin are resistant to clarithromycin.

It is possible to develop cross resistance to clarithromycin and other antibiotics of the macrolide group, as well as lincomycin and clindamycin.

Lactulose, part Aconitine® as a bifidogenic factor is a synthetic disaccharide, a molecule which consists of residues of galactose and fructose. Lactulose in the stomach and upper intestine is not absorbed and is not hydrolyzed. Released from tablets Aconitine® lactulose as the substrate is fermented by normal microflora of the large intestine, stimulating the growth of bifidobacteria and lactobacilli. As a result of hydrolysis of lactulose in the colon, organic acids are formed — lactic, acetic and formic, suppressing the growth of pathogenic microorganisms and reducing the production of nitrogen-containing toxic substances.

Thus, lactulose in the composition of Ekozitrina® has a protective effect on the normal intestinal microflora, reduces the phenomenon of intoxication and eliminates the risk of side effects associated with dysbiosis.

Pharmacokinetics

Absorption is high. Food slows down absorption without significantly affecting bioavailability. The bioavailability of tablets of 250 mg — 50%. The plasma protein binding is 65% -75%. After a single dose Cmax of the two peaks is recorded. The second peak is due to the ability of the drug to accumulate in the gallbladder, followed by gradual or rapid entry into the intestine and absorption. Tmax when administered at a dose of 250 mg-2-3 h — 

After ingestion of 20-30% of the dose quickly gidrauxiliruetsa in the liver by isoenzymes of the cytochrome CYP3A4, CYP3A5 and CYP3A7 with the formation of the main metabolite — 14-hydroxyclarithromycin, possessing strong antimicrobial activity against Haemophillus influenzae. Is an inhibitor of CYP3A4 isoenzymes, CYP3A5 and CYP3A7.

With regular intake of 250 mg / day CSS unchanged drug and its main metabolite — 1 and 0.6 mg/ml, respectively; T1/2 — 3-4 and 5-6 h, respectively. When increasing the dose to 500 mg / day CSS unchanged drug and its metabolite in plasma-2.7-2.9 and 0.83-0.88 mg/ ml, respectively; T1/2 — 4,8–5 and 6,9-8,7 h respectively. In therapeutic concentrations, accumulates in the lungs, skin and soft tissues (concentrations 10 times higher than the level of antibiotic in the blood plasma).

Excreted by the kidneys and intestine (20% -30% in an unmodified form; the rest is in the form of metabolites). With a single dose of 250 mg and 1200 mg kidneys allocated 37,9% and 46%, the intestine — 40,2% and 29,1%, respectively.

In violation of kidney function, there is an increase in Tmax, Cmax and AUC clarithromycin and its metabolite.

Lactulose, part Aconitine®, has no effect on key pharmacokinetic parameters that characterize the bioavailability of clarithromycin.

The testimony of the drug Clarithromycin

Adults and children:

• pharyngitis;
• tonsillitis;
• acute maxillary sinusitis;
• community-acquired pneumonia;
• uncomplicated infections of the skin and subcutaneous tissue;
• disseminated infection caused by Mycobacterium avium and Mycobacterium intracellulare.

Adults additionally:

• the disease caused by Helicobacter pylori, peptic ulcer disease including duodenal ulcer (in combination therapy);
• exacerbation of chronic bronchitis.

Children additionally:

acute otitis media.

Contraindications

• hypersensitivity;
• porphyria;
• lactation;
• simultaneous reception of cisapride, astemizole, pimozide, terfenadine, ergotamine and other alkaloids of sporyn, oral dosage forms of midazolam, alprazolam, triazolam;
• lactose intolerance or lactase deficiency and glucose-galactose malabsorption;
• children under 12 years of age (for this dosage form).

Caution: renal and/or hepatic insufficiency, myastenia gravis,simultaneous administration of drugs metabolized in the liver, simultaneous administration of colchicine.

Application for pregnancy and breastfeeding

The safety of clarithromycin during pregnancy has not been established. In pregnancy, especially in the I trimester, it is recommended to appoint clarithromycin, if the benefits of its use exceeds the potential risk to the fetus and/or there is no safer alternative therapy. If pregnancy occurs while taking the drug, the patient should be warned about the possible risk to the fetus.

If necessary, the appointment of the drug during lactation should decide on the abolition of breastfeeding.

Side effect

From the nervous system: headache, dizziness, anxiety, insomnia, nightmares, convulsions, depression, disorientation, hallucinations, psychosis, depersonalization, confusion.

From the digestive system: nausea, vomiting, gastralgia, diarrhea, stomatitis, glossitis, candidiasis of the oral mucosa, changes in the color of the tongue and teeth, acute pancreatitis, increased activity of hepatic transaminases, hepatocellular and cholestatic hepatitis, cholestatic jaundice, rarely pseudomembranous colitis, hepatic insufficiency with a lethal outcome, mainly against the background of severe diseases or concomitant drug therapy.

Lactulose, a member of the drug,  eliminates the risk of side effects associated with the negative effect of antibiotics on intestinal microbiota.

From the side of cardiovascular system: ventricular tachycardia, including type “pirouette”, a fluttering and flickering of ventricles, increase QT interval on ECG.

On the part of the senses: noise, ringing in the ears, change in taste (dysgeusia), in isolated cases — hearing loss, passing after discontinuation of the drug, impaired sense of smell.

From the side of musculoskeletal system: myalgia.

Organs of hematopoiesis: rarely — thrombocytopenia (unusual bleeding, hemorrhage).

From the urinary system: interstitial nephritis.

Laboratory parameters: leukopenia, hypercreatininemia, hypoglycemia (including while taking hypoglycemic drugs).

Allergic reactions: skin rash, itching, urticaria, skin hyperemia, malignant exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis, anaphylactic reactions.

Other: secondary infections (development of resistance of microorganisms).

Interaction

During simultaneous administration of clarithromycin and drugs primarily metabolized by the isoenzyme СУР3А, perhaps a reciprocal increase in their concentration, which could increase or prolong both therapeutic and adverse effects. Contraindicated co-administration with astemizole, cisapride, pimozide, terfenadine, ergotamine and other ergot alkaloids; alprazolamum, midazolam, triazolam.

Use with caution with carbamazepine, Cilostazol, cyclosporine, disopyramide, lovastatin, methylprednisolone, omeprazole, indirect anticoagulants (including warfarin), quinidine, rifabutin, sildenafilum, simvastatin, tacrolimus, vinblastine and phenytoin, theophylline and valproic acid (metabolized via other cytochrome P450 isoenzymes).

When combined with cisapride, pimozide, terfenadine and astemizole may increase the concentration of the latter in the blood, increase THE Qt interval, the appearance of arrhythmia, including ventricular tachycardia, including “pirouette”, and ventricular fibrillation. Require dose adjustment of drugs and control of the concentration in the blood.

When used together with ergotamine and dihydroergotamine possible acute poisoning by preparations of ergotamine (vascular spasm, ischemia of the extremities and other tissues including the Central nervous system).

Efavirenz, nevirapine, rifampicin, rifabutin and rifapentin (inducers cytochrome P450) reduce the level of clarithromycin in plasma and weaken the therapeutic effect of the latter, and at the same time, increase the level of 14-gidroksiklaritromitsina.

During simultaneous administration of fluconazole in dose 200 mg daily and clarithromycin in a dose of 1 g/day may increase the CSS and AUC of clarithromycin by 33 and 18%, respectively. Dose adjustment of clarithromycin is required.

When co-administration of ritonavir 600 mg / day and clarithromycin 1 g / day may reduce the metabolism of clarithromycin (Cmax increase — by 31%, CSS — by 182% and AUC — by 77%), complete suppression of the formation of 14-gidroksiklaritromitsina. In patients with chronic renal failure requires dose adjustment: when Cl creatinine 30-60 ml/min dose clarithromycin should be reduced by 50%, <30 ml / min — 75%. Ritonavir should not be taken in conjunction with clarithromycin dose exceeding 1 g/day.

When co-administered with quinidine and dizopiramidom possible occurrence of ventricular tachycardia type “pirouette”. The necessary monitoring of ECG (increased QT interval), serum concentrations of these drugs.

Clarithromycin increases concentrations of HMG-COA reductase inhibitors (lovastatin, simvastatin). Perhaps the development of rhabdomyolysis in patients taking these drugs together.

During the application of clarithromycin and omeprazole may increase Cmax, AUC, and T1/2 omeprazole 30, 89 and 34%, respectively. The average pH in the stomach for 24 hours was 5.2-when taking only omeprazole and 5.7-when taking omeprazole together with clarithromycin.

When applying clarithromycin and indirect anticoagulants may increase the action of the latter.

When using clarithromycin with sildenafil, tadalafil or vardenafil (phosphodiesterase-5 inhibitors) may increase the inhibitory effect on phosphodiesterase. It may be necessary to reduce the dose of sildenafil, tadalafil and vardenafil.

With the joint application of clarithromycin with theophylline and carbamazepine may increase the concentration of the latter in the systemic blood flow.

When using clarithromycin with tolterodine in patients with low metabolism through CYP2D6 may require lower doses of tolterodine in the presence of clarithromycin (SUR3A inhibitor).

During simultaneous administration of clarithromycin (1 g/day) midazolam (oral) may increase the AUC of midazolam in 7 times. It is necessary to avoid joint oral administration of clarithromycin with midazolam and other benzodiazepines, which are metabolized by SUR3A (triazolam and alprazolam). With the use of midazolam (in/in) and clarithromycin may require dose adjustment. The same precautions should be applied to other benzodiazepines that are metabolized SUR3A. For benzodiazepines, the removal of which does not depend on SUR3A (temazepam, nitrazepam, lorazepam), it is unlikely clinically significant interaction with clarithromycin.

When co-administration of clarithromycin with colchicine may increase the action of colchicine. It is necessary to monitor the possible development of clinical symptoms of colchicine intoxication, especially in elderly patients and patients with chronic renal failure (reported cases with fatal outcome).

When co-administered clarithromycin and digoxin should carefully monitor the concentration of digoxin in serum (possibly increasing its concentration and the development of potentially lethal arrhythmias).

Concomitant administration of clarithromycin and zidovudine by adult HIV-infected patients can lead to a decrease in the CSS of zidovudine. Selection of clarithromycin and zidovudine doses is necessary. This type of interaction does not occur in HIV-infected children receiving clarithromycin in the form of a suspension in conjunction with zidovudine.

During simultaneous administration of clarithromycin (l g/day) and atazanavir (400 mg/day) may increase the AUC of atazanavir by 28%, clarithromycin 2 times and a decrease in the AUC of 14-hydroxyclarithromycin 70%. In patients with creatinine Cl 30-60 ml/min dose clarithromycin should be reduced by 50%. Clarithromycin in doses exceeding 1 g / day, can not be prescribed in conjunction with protease inhibitors.

When co-administration clarithromycin and intraconazole may increase the concentration of drugs in plasma. Patients, simultaneously taking Itraconazole and clarithromycin, should be carefully monitored because of the possible enhancement or extension of the pharmacological effects of these drugs.

While taking clarithromycin (l g/day) and saquinavir (soft gelatin capsules, 1200 mg 3 times a day) may increase AUC and CSS saquinavir 177 and 187% respectively, and clarithromycin — 40%. At joint appointment of these two LS for a limited time in doses/dosage forms specified above, dose adjustment is not required.

When co-administered with verapamil may reduce blood pressure, bradiaritmia and lactic acidosis.

Method of application and doses

Inside, they swallow whole, not liquid, squeezed small amount of liquid.

Adults and children over 12 years of age, weighing more than 33 kg:

• with pharyngitis and tonsillitis caused by Streptococcus pyogenes-250 mg every 12 h for 10 days;
• acute sinusitis-500 mg every 12 hours for 14 days;
• exacerbation of chronic bronchitis caused by Haemophilus influenzae-500 mg every 12 h for 7-14 days; caused Haemophilus parainfluenzae-500 mg every 12 h for 7 days; caused by Moraxella catarrhalis, Streptococcus pneumoniae-250 mg every 12 h for 7-14 days;
• community-acquired pneumonia caused by Haemophilus influenzae-250 mg every 12 hours for 7 days; — Streptococcus pneumoniae, Chlamydia pneumoniae, Mycoplasma pneumoniae-250 mg every 12 hours for 7-14 days;
• in uncomplicated skin and subcutaneous tissue infections caused by Staphylococcus aureus, Streptococcus pyogenes, – 250 mg every 12 h for 7-14 days;
• for the treatment and prevention of infections caused by Mycobacterium avium-500 mg 2 times a day. Maximum daily dose of 1000 mg Duration of treatment — 6 months or more.

For the purpose of eradication Helicobacter pylori:

Combined treatment with three drugs: clarithromycin-500 mg 2 times a day, lansoprazole-30 mg 2 times a day and amoxicillin-1000 mg 2 times a day for 10-14 days;

clarithromycin-500 mg 2 times a day, omeprazole — 20 mg 2 times a day and amoxicillin — 1000 mg 2 times a day for 10 days.

Combined treatment with two drugs: clarithromycin-500 mg 3 times a day, omeprazole — 40 mg/day for 14 days, with the appointment of omeprazole for the next 14 days at a dose of 20 mg/day.

For patients with chronic renal failure: (Cl creatinine less than 30 ml/min or serum creatinine concentration more than 3.3 mg / 100 ml) dose reduced by 2 times, or 2 times increase the interval between doses. The maximum duration of treatment in patients of this group — 14 days.

Overdose

Symptoms: abdominal pain, nausea, vomiting, diarrhea.

Treatment: gastric lavage, supportive therapy. Not removed by peritoneal or hemodialysis.

Special instruction

In the presence of chronic liver disease, it is necessary to conduct regular monitoring of the activity of enzymes in the blood serum.

With caution prescribed on the background of LS metabolized in the liver (it is recommended to measure their concentration in the blood).

In the case of a joint appointment with warfarin or other anticoagulants should be monitored PV.

With the development of secondary infection, adequate therapy should be prescribed.

In case of occurrence during or after treatment of severe diarrhea, the diagnosis of pseudomembranous colitis should be excluded, which requires immediate discontinuation of the drug and the appointment of appropriate treatment.

Storage conditions of the drug Clarithromycin

In a dry place protected from light, at a temperature not exceeding 25 °C.

Keep out of reach of children.