Clarithromycin Ecositrin, 250 mg 14 pcs

Pharmacological group: macrolide antibiotic.

TAC code: J01FA09.

Pharmacological properties:

Pharmacodynamics. Semisynthetic broad-spectrum macrolide antibiotic. It disrupts protein synthesis of microorganisms (binds with 50S-subunit of ribosome of microbial cell). Acts on extra- and intracellularly located pathogens. Clarithromycin activity against most of the following microorganisms has been 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, Legionella pneumophila; etc. microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae; mycobacteria: Mycobacterium avium complex (MAC) – a complex including: Mycobacterium avium and Micobacterium intracellulare; Helycobacter pylori.

Beta-lactamases do not affect the activity of clarithromycin.

The in vitro activity of clarithromycin is aerobic gram-positive microorganisms: Listeria monocytogenes, Streptococcus agalactiae, Streptococci groups C,F,G, Streptococci group viridans; aerobic gram-negative microorganisms: Neisseriia gonorrhoeae, Bordetella pertussis, Pasteurella multocida; anaerobic gram-positive microorganisms: Clostridium perfringens, Peptococcus niger, Propionibacterium acnes; anaerobic gram-negative microorganisms: Bacteroides melaninogenicus; spirochetes: Borrelia burgdorferi, Treponema pallidum; mycobacteria: Mycobacterium leprae, Mucobacterium chelonae, Campylobacter: Campylobacter jejuni.

The microbiologically active metabolite of clarithromycin, 14-hydroxyclarithromycin, is twice as active as the parent compound against 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 bacterial strain.

Most strains of Staphylococcus aureus resistant to methicillin and oxacillin are resistant to clarithromycin.

Cross-resistance to clarithromycin and other macrolide antibiotics as well as to lincomycin and clindamycin may develop.

Pharmacokinetics

Absorption is rapid. Food slows absorption without significantly affecting bioavailability. The bioavailability of 250 mg tablets is 50%. Binding with plasma proteins is 65-75%. Two peaks of maximum concentration (Cmax) are registered after a single dose. The second peak is due to the ability of the drug to accumulate in the gallbladder with subsequent gradual or rapid entry into the intestine and absorption. The time to reach maximum concentration (TCmax) when taking 250 mg is 2-3 hours.

After oral administration 20-30% of the taken dose is rapidly hydroxylated in the liver by cytochrome CYP3A4, CYP3A5 and CYP3A7 isoenzymes to form the main metabolite – 14-hydroxyclarithromycin, which has marked antimicrobial activity against Haemophllus influenzae. It is an inhibitor of CYP3A4, CYP3A5 and CYP3A7 isoenzymes.

In regular use of 250 mg/day the equilibrium concentration (Css) of unchanged drug and its main metabolite is 1 and 0.6 mcg/ml, respectively; half-life is 3-4 and 5-6 hours respectively. When increasing the dose to 500 mg/day, Css of unchanged drug and its metabolite in plasma is 2.7-2.9 and 0.83-0.88 µg/ml, respectively; half-life is 4.8-5 and 6.9-8.7 h, respectively. In therapeutic concentrations it accumulates in the lungs, skin and soft tissues (in which concentrations are 10 times higher than in blood plasma levels of the antibiotic).

It is excreted by the kidneys and intestines (20-30% – in unchanged form, the rest – as metabolites). In a single dose of 250 and 1200 mg, 37.9 and 46% is excreted by the kidneys, and 40.2 and 29.1% by the intestines, respectively.

In impaired renal function, an increase in TCmax, Cmax and area under the concentration-time curve (AUC) of clarithromycin and its metabolite was noted.

Indications

Adults: Pharyngitis, tonsillitis, acute maxillitis, exacerbation of chronic bronchitis, community-acquired pneumonia, uncomplicated skin and subcutaneous tissue infections; disseminated infection caused by Mycobacteiium avium and Mycobacterium intracellulare.

Adults in combination with amoxicillin and omeprazole/lansoprazole as triple therapy in infections caused by Helicobacter рylori, including duodenal ulcer disease.

In children: pharyngitis, tonsillitis, community-acquired pneumonia, acute maxillary sinusitis, acute otitis media, uncomplicated skin and subcutaneous tissue infections; disseminated infection caused by Mycobacterium avium and Mycobacterium intracellulare.

Active ingredient

Composition

1 tablet contains:

Active substance:

clarithromycin – 250 mg.

Supplementary substances:

Lactulose – 300 mg,

Povidone-K25 – 9.1 mg,

magnesium stearate – 6.5 mg,

colloidal silica (aerosil) – 4.33 mg,

talc – 13 mg,

polacryline potassium – up to 650 mg.

Shell composition:

Hypromellose – 9.52 mg, talc – 1.14 mg, titanium dioxide – 5.171 mg, macrogol-4000 – 4.14 mg, dye azorubin – 0.029 mg.

How to take, the dosage

To be taken orally, the tablets should be swallowed without chewing, with a small amount of liquid.

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

In the treatment and prevention of infections caused by Mycobacterium avium, 500 mg twice daily. The maximum daily dose is 1000 mg. Duration of treatment is 6 months or more.

To eradicate Helicobacter pylori:

Combined treatment with three drugs:

clarithromycin 500 mg, lansoprazole 30 mg and amoxicillin 1000 mg 2 times daily for 10-14 days;

clarithromycin 500 mg, omeprazole 20 mg and amoxicillin 1000 mg 2 times daily for 10 days.

Combined treatment with two drugs:

Clarithromycin 500 mg 3 times daily, omeprazole 40 mg daily for 14 days, with omeprazole given at a dose of 20 mg daily for the next 14 days.

For patients with chronic renal insufficiency: (creatinine clearance less than 30 ml/min or serum creatinine concentrations greater than 3.3 mg/100 ml) the dose is reduced by 2 times or the interval is increased by 2 times. Maximum duration of treatment in patients in this group is 14 days.

Interaction

Co-administration of clarithromycin and drugs that are primarily metabolized by CYP3A isoenzymes may increase their concentrations, which may increase or prolong both therapeutic and adverse effects. Co-administration with astemizole, cisapride, pimozide, terfenadine, ergotamine and other ergot alkaloids as well as with lovastatin and simvastatin is contraindicated.

Drugs that are inducers of CYP3A (e.g., phenobarbital and St. John’s wort) may induce the metabolism of clarithromycin. This can lead to subtherapeutic levels of clarithromycin, resulting in reduced efficacy.

Prescribe with caution with carbamazepine, cilostazol, cyclosporine, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants (including quinidine, rifabutin, sildenafil, tacrolimus, vinblastine, as well as phenytoin, theophylline and valproic acid (metabolized through other cytochrome P450 isoenzymes). Use with caution with alprazolam, triazolam, midazolam for intravenous administration. Correction of the drug dose and control of blood concentrations are required.

The co-administration of cisapride, pimozide, terfenadine and astemizole may increase the blood concentration of the latter, increase the QT interval, and allow arrhythmias, including ventricular tachycardia (including pirouette) and ventricular fibrillation.

In co-administration with ergotamine and dihydroergotamine, acute poisoning by drugs of the ergotamine group (vasospasm, ischemia of the extremities and other tissues, including the central nervous system) may occur.

Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine (cytochrome P450 inducers) decrease plasma levels of clarithromycin and impair the therapeutic effect of the latter and, at the same time, increase 14-hydroxyclarithromycin levels.

The co-administration of fluconazole in dose of 200 mg daily and clarithromycin in dose of 1 g/day may increase Css and AUC of clarithromycin by 33% and 18%, respectively. No clarithromycin dose adjustment is required.

The co-administration of ritonavir 600 mg/day and clarithromycin 1 g/day may decrease the metabolism of clarithromycin (increase in Cmax by 31%, Css by 182% and AUC by 77%), complete inhibition of 14-hydroxyclarithromycin formation. In patients with chronic renal impairment, a dose adjustment is necessary: at a creatinine clearance (CK) of 30-

60 ml/min, the dose of clarithromycin should be reduced by 50%; at CK less than

30 ml/min by 75%. Ritonavir should not be taken together with clarithromycin at a dose greater than 1 g/day.

Ventricular pirouette tachycardia may occur when co-administered with quinidine and disopyramide. ECG monitoring (QT interval prolongation), serum concentrations of these drugs are necessary.

Clarithromycin increases concentrations of HMG-CoA reductase inhibitors (lovastatin, simvastatin). Rhabdomyolysis may occur in patients taking these drugs together.

When using clarithromycin and omeprazole, Cmax, AUC and half-life of omeprazole may be increased by 30%, 89% and 34%, respectively. Mean gastric pH over 24 h was 5.2 when taking omeprazole alone and 5.7 when taking omeprazole together with clarithromycin.

When using clarithromycin and indirect anticoagulants, the effects of the latter may be enhanced. Concomitant use with warfarin and other indirect anticoagulants should monitor the international normalized ratio and prothrombin time.

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

Coadministration of clarithromycin with theophylline and carbamazepine may increase concentrations of the latter in the systemic blood stream.

When using clarithromycin with tolterodine in patients with low metabolism through CYP2D6 a dose reduction of tolterodine in the presence of clarithromycin (CYP3A inhibitor) may be required.

The co-administration of clarithromycin

(1 g/day) with midazolam (oral) may increase the AUC of midazolam by 7-fold. Dose adjustments may be required when using midazolam (intravenous) and clarithromycin. The same precautions should be applied to other benzodiazepines that are metabolized by CYP3A. For benzodiazepines whose excretion is not dependent on CYP3A (temazepam, nitrazepam, lorazepam), a clinically significant interaction with clarithromycin is unlikely.

The effects of colchicine may be enhanced when clarithromycin is coadministered with colchicine. The possible development of clinical symptoms of colchicine intoxication must be monitored, especially in elderly patients and patients with chronic renal failure (fatal cases have been reported).

The serum concentrations of digoxin should be carefully monitored when coadministering clarithromycin and digoxin (elevated concentrations and potentially fatal arrhythmias are possible).

The concomitant administration of clarithromycin and zidovudine in HIV-infected adults may result in lower Css of zidovudine. Dose matching of clarithromycin and zidovudine is necessary. This type of interaction does not occur in HIV-infected children receiving clarithromycin in suspension form with zidovudine.

The co-administration of clarithromycin (l g/day) and atazanavir (400 mg/day) may increase the AUC of atazanavir by 28% and of clarithromycin by half, and decrease the AUC of 14-hydroxyclarithromycin by 70%. In patients with an IQ of 30-60 ml/min, the dose of clarithromycin should be reduced by 50%. Clarithromycin in doses greater than 1 g/day should not be coadministered with protease inhibitors.

The co-administration of clarithromycin and intraconazole may lead to a reciprocal increase in plasma concentrations. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely due to possible intensification or prolongation of pharmacological effects of these drugs.

Concomitant administration of clarithromycin (l g/day) and saquinavir (soft gelatin capsules, 1200 mg 3 times daily) may increase AUC and Css of saquinavir by 177% and 187%, respectively, and of clarithromycin by 40%. No dose adjustments are required when these two drugs are co-administered for a limited time in the doses/drug forms listed above.

When co-administered with verapamil, decreased blood pressure, bradyarrhythmia and lactic acidosis are possible.

Concomitant use of clarithromycin and oral hypoglycemic agents, including insulin, may cause hypoglycemia in rare cases. Close monitoring of blood glucose concentrations is recommended.

When concomitantly taken with clarithromycin (500 mg twice daily), etravirine decreases the plasma concentration of clarithromycin by 53% and increases the concentration of the active metabolite, 14-hydroxyclarithromycin, by 46%. Because 14-hydroxyclarithromycin has reduced activity against Mycobacterium avium complex (MAC), the overall activity of clarithromycin and its metabolite against this pathogen may be altered.

Special Instructions

In the presence of chronic liver disease it is necessary to carry out regular monitoring of serum enzyme activity.

With caution, use against the background of drugs that are metabolized by the liver (it is recommended to measure their blood concentrations).

In case of co-administration with warfarin or other anticoagulants, prothrombin time should be monitored.

In case of development of secondary infection, adequate therapy should be prescribed.

If severe diarrhea occurs during or after treatment, the diagnosis of pseudomembranous colitis should be excluded, which requires immediate withdrawal of the drug and appropriate treatment.

Contraindications

Hypersensitivity, porphyria, lactation, simultaneous use of cisapride, astemizole, pimozide, terfenadine, ergotamine and other ergot alkaloids, oral forms of midazolam, alprazolam, triazolam.

Children under 12 years of age (for this dosage form).

Lactose intolerance or lactase deficiency, and glucose-galactose malabsorption.

Concomitant use with lovastatin and simvastatin, with oral midazolam, with colchicine in patients with impaired renal or hepatic function, taking P-glycoprotein inhibitors or potent CYP3A4 isoenzyme inhibitors; Patients with a history of QT prolongation, ventricular arrhythmias, or pirouette-type ventricular tachycardia; history of cholestatic jaundice/hepatitis with clarithromycin; severe hepatic impairment concurrent with renal impairment; hypokalemia.

Hepatic and/or renal insufficiency, myasthenia gravis, concomitant use of drugs metabolized by the liver, concomitant use of colchicine.

Concomitant use with drugs inducing and metabolized by CYP3A4 isoenzyme, benzodiazepines (alprazolam, triazolam, midazolam for intravenous use), class IA and III antiarrhythmic drugs, “slow” calcium channel blockers, which are metabolized by CYP3A4 isoenzyme; in patients with CHD, severe CHD, hypomagnesemia, severe bradycardia, myasthenia gravis.

Side effects

Nervous system disorders: Headache, dizziness, drowsiness, restlessness, insomnia, “nightmare” dreams, tremors, seizures, depression; disorientation, hallucinations, psychosis, depersonalization, confusion, increased symptoms of myasthenia gravis, psychotic disorders, paresthesia, mania, intense sweating, anorexia, malaise, asthenia, chills, fatigue.

Digestive system disorders: nausea, belching, vomiting, flatulence, worsening of appetite gastritis, gastralgia, diarrhea, stomatitis, glossitis, candidiasis of the oral mucosa, color changes in the tongue and teeth, dry oral mucosa, acute pancreatitis, increased activity of “liver” transaminases, cholestasis, hepatocellular and cholestatic hepatitis, cholestatic jaundice, rarely – pseudomembranous colitis, liver failure with fatal outcome mainly against the background of severe comorbidities and/or concomitant drug therapy, dyspepsia, constipation.

Cardiovascular system: ventricular tachycardia, including “pirouette” type, ventricular flutter and fibrillation, increased QT interval on ECG.

Senses: noise, tinnitus, vertigo, change in taste (dysgeusia), agueusia; in single cases – hearing loss which disappears after discontinuation of the drug; impaired sense of smell, anosmia.

Skin and soft tissue disorders: erythrasis, acne, rye.

Muscular system disorders: myalgia, myopathy, chest pain.

Hematopoietic disorders: rare – thrombocytopenia, (unusual bleeding, hemorrhage), agranulocytosis, thrombocytosis, prolongation of prothrombin time, increased INR.

Urinary system disorders: interstitial nephritis, renal failure.

Laboratory parameters: leukopenia, neutropenia, eosinophilia, increased concentration of bilirubin in blood, hypoglycemia (including in concomitant use of hypoglycemic agents), urine color changes.

Allergic reactions – skin rash, pruritus, urticaria, skin hyperemia, erythema malignant exudative (Stevens-Johnson syndrome), toxic epidermal necrolysis, anaphylactic reactions, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), Schoenlein-Henoch purpura, hemorrhages.

Others: secondary infections (development of microbial resistance).

Overdose

Symptoms: abdominal pain, nausea, vomiting, diarrhea.

Treatment: gastric lavage, supportive therapy. Not removed by hemo- or peritoneal dialysis.

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Pregnancy use

Similarities