Zimbactar - instructions for use, doses, side effects, contraindications

Excipients: microcrystalline cellulose 41.5 / 83.0 mg, croscarmellose sodium 19.3125 / 38.626 mg, povidone K 30 19.375 / 38.75 mg, microcrystalline silicate cellulose 46.5 / 93 mg, magnesium stearate 7.8125 / 15.624 mg;

sheath: hypromellose 8,3915 / 16,784 mg, talc 0,759 / 1,518 mg, titanium dioxide 1,5995 / 3,198 mg, dye nileylake quinoline yellow varnish C.I. 47005: 1 0.075 / 0.15 mg, propylene glycol 1.675 / 3.350 mg.

Description:

Biconvex tablets are oval in shape, covered with a coating of light yellow color.

On the fracture from white to almost white.

Pharmacotherapeutic group:Antibiotic-macrolide

ATX: & nbsp

J.01.F.A.09 Clarithromycin

Pharmacodynamics:

Semisynthetic macrolide antibiotic of broad spectrum of action. It breaks the synthesis of the protein of microorganisms (binds to the 50S subunit of the ribosome membrane of the microbial cell). It acts on extracorporeal and intracellular pathogens.

Beta-lactamases do not affect the activity of clarithromycin. The minimum inhibitory concentrations (MPC) of clarithromycin for most pathogens are less than the erythromycin MPC.

The activity of clarithromycin against most strains of the following microorganisms is proved both 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; other microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae; Mycobacterium: Mycobacterium avium complex (MAC) - complex, including: Mycobacterium avium and Mycobacterium intracellulare; Helicobacter pylori.

Activity of clarithromycin in vitro - aerobic Gram-positive microorganisms: Listeria monocytogenes, Streptococcus agalactiae, Streptococci groups C, F, G, Streptococci group viridans; aerobic gram-negative microorganisms: Neisseria 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; Mycobacterium: Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum; Campylobacteria: Campylobacter jejuni.

The microbiologically active metabolite of clarithromycin - 14-uydroxyclarithromycin, is twice as active as the parent compound in relation 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 bacteria. For most other microorganisms, the microbiological activity of the metabolite is the same as that of the starting material, or 1-2 times weaker.

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 to lincomycin and clindamycin.

Pharmacokinetics:

Suction and distribution

Clarithromycin is rapidly and well absorbed in the gastrointestinal tract (GIT).

Bioavailability when taking tablets at a dose of 250 mg is about 50%. Food somewhat slows down absorption, without significantly affecting bioavailability. When the drug was administered at a dose of 250 mg twice a day, the equilibrium concentration (Css) of clarithromycin in plasma was established after 2-3 days and averaged 1 μg / ml for the unchanged drug and 0.6 μg / ml for the main metabolite (14-hydroxyclarithromycin ), while the half-life (T_1/2) of the parent compound and its metabolite were 3-4 and 5-6 hours, respectively. When the drug was administered at a dose of 500 mg twice a day, Css of clarithromycin and its hydroxylated metabolite in plasma averaged 2.7-2.9 μg / ml and 0.88-0.83 μg / ml, respectively. The half-life of the initial compound with the administration of a dose of 500 mg was 5-7 hours, 14-hydroxyclarithromycin - 7-9 hours.With the appointment of higher doses of the drug, a further increase in the values of Css and T_1/2, which indicates a nonlinear character of the pharmacokinetics of clarithromycin.

Clarithromycin, when used in therapeutic doses, binds to plasma proteins approximately 65-75%. In therapeutic concentrations accumulates in the tonsillar and pulmonary tissues, the skin, penetrate the mucous membrane of the stomach. Concentrations in tissues are usually several times higher than in serum.

Metabolism and excretion

Metabolised in the liver with the participation of CYP3A isoenzymes of the cytochrome P450 system. The main metabolite is the microbiologically active metabolite 14-hydroxyclarithromycin.

In adults with a single intake of clarithromycin in doses of 250 or 1200 mg, 37.9% and 46.0% of the kidneys are excreted by the kidneys, 40.2% of the intestines and 29.1% of the dose, respectively. In chronic renal failure (CRF), the values of the maximum plasma concentration (C_max), T_1/2and AUC (area under the pharmacokinetic curve "concentration-time") of clarithromycin and its metabolite.

Indications:

Infectious diseases caused by microorganisms sensitive to clarithromycin:

Adults:

- infections of the lower respiratory tract (bronchitis, pneumonia);

- infections of the upper respiratory tract (including pharyngitis, tonsillitis, sinusitis);

- infections of the skin and soft tissues (folliculitis, phlegmon, erysipelas);

- common or localized mycobacterial infections caused by Mycobacterium avium and Mycobacterium intracellulare. Localized infections caused by Mycobacterium chelonae, Mycobacterium fortuitum and Mycobacterium kansasii;

- prevention of the spread of infection caused by the complex Mycobacterium avium (MAC), in HIV-infected patients with a CD4 T-cell (T-helper lymphocyte) count no more than 100 in 1 mm³;

- eradication Helicobacter pylori in patients with peptic ulcer of the duodenum or stomach (always in combination with other drugs).

Children from 12 years old:

- pharyngitis, tonsillitis, community-acquired pneumonia, acute sinusitis, acute otitis media, uncomplicated infections of the skin and subcutaneous tissue;

- disseminated infection caused by Mycobacterium avium and Mycobacterium intracellulare.

Contraindications:

Hypersensitivity to clarithromycin, other macrolides or other components of the drug, porphyria, lactation period, children under 12 years of age, and / or body weight less than 33 kg (for this dosage form), concurrent administration of midazolam for oral administration, astemizole, cisapride, pimozide, terfenadine, ergotamine, and others.ergot alkaloids, lovastatin, simvastatin (risk of myopathy, rhabdomyolysis), colchicine in patients with impaired renal and hepatic function taking inhibitors of P-glycoprotein or potent inhibitors of isoenzyme CYP3A4 (see. Section "Interaction with other drugs"), QT interval elongation in the history of ventricular fibrillation or ventricular tachycardia by type "pirouette", including in the anamnesis; cholestatic jaundice and / or hepatitis arising when applying clarithromycin (history), severe liver failure, occurs simultaneously with renal insufficiency, hypokalemia (risk of QT interval elongation).

Carefully:

Renal and / or hepatic insufficiency of moderate and severe severity; myasthenia gravis gravis (Possibly increased symptoms), pregnancy, simultaneous reception with colchicine (except as indicated in the section "Contra '), with simultaneous reception drugs metabolized isoenzyme CYP3A4 (carbamazepine, cilostazol, ciclosporin, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants (for example, warfarin), quinidine, rifabutin, sildenafil, tacrolimus, vinblastine), with preparations inducing the isoenzyme CYP3A4 (phenobarbital, rifampicin, phenytoin, carbamazepine, St. John's wort); simultaneous reception with benzodiazepines (alprazolam, triazolam, midazolam for intravenous administration), simultaneous reception with antiarrhythmic drugs of class IA (quinidine, procainamide) and III (dofetilide, amiodarone. sotalol), simultaneous reception with blockers of "slow" calcium channels, which are metabolized by the isoenzyme CYP3A4 (verapamil, amiodarone, diltiazem), in patients with ischemic heart disease (CHD), severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats per minute).

Pregnancy and lactation:

The safety of clarithromycin in pregnant and lactating women has not been studied.

Application in pregnancy (especially in the first trimester) is possible only if the potential benefit to the mother exceeds the possible risk to the fetus and / or there is no safer therapy with alternative drugs.

Clarithromycin is excreted in breast milk. If it is necessary to use the drug during lactation, the question of abolishing breastfeeding should be resolved.

Dosing and Administration:

Inside, the tablets are taken regardless of food intake.

Adults and children 12 years of age and / or body weight over 33 kg:

Infectious diseases of the respiratory tract, skin and soft tissues

The usual recommended dose is 250 mg twice a day. In more severe cases, the dose may be increased to 500 mg twice a day. The duration of treatment with clarithromycin in most cases is from 6 to 14 days.

Infectious diseases caused by mycobacteria

The recommended dose is 500 mg twice a day.

In case of common infections caused by MAC, in patients with AIDS treatment should be continued until there is a clinical and microbiological confirmation of the effectiveness of the therapy. Clarithromycin should be administered in combination with other antimicrobials.

In infectious diseases caused by mycobacteria, in addition to tuberculosis, the duration of treatment is determined by the doctor.

In order to eradicate Helicobacter pylori in combination with other drugs

Combined treatment with three drugs:

- clarithromycin 500 mg twice a day in combination with lansoprozol 30 mg twice a day and amoxicillin 1000 mg twice a day for 10 days;

- clarithromycin 500 mg twice a day in combination with amoxicillin 1000 mg twice a day and omeprazole 20 mg twice a day for 7-10 days.

Combined treatment with two drugs:

- clarithromycin 500 mg 3 times daily in combination with omeprazole at a dose of 40 mg / day for 14 days, with the appointment within the next 14 days of omeprazole at a dose of 20-40 mg / day.

- clarithromycin 500 mg 3 times daily in combination with lansoprazole at a dose of 60 mg / day for 14 days. To fully heal the ulcer, an additional decrease in the acidity of the gastric juice may be required.

Dosage regimen for renal failure

Patients with creatinine clearance (CC) less than 30 ml / min are prescribed half the usual dose of clarithromycin, i.e. 250 mg once a day or, for more severe infections, 250 mg twice a day. The maximum duration of treatment in patients of this group is 14 days.

Dosage regimen for hepatic impairment

If normal renal function is maintained in patients with moderate or severe hepatic insufficiency, dose adjustment is not required.

Dosage regimen in the elderly

Dose reduction in the elderly is not required.

Side effects:

In adults, the most frequent side effects when using the drug are - diarrhea (3%), nausea (3%), taste alteration (3%), dyspepsia (2%), the pain / discomfort in the stomach (2%), headache (2 %).

Frequency of adverse events according to the WHO classification: very often (≥10%), often (≥1% and <10%), infrequently (≥0.1% and <1%), rarely (≥0.01% and <0.1%), very rarely (<0.01%), including individual cases.

Infectious and parasitic diseases: often - candidiasis of the oral mucosa. As with the use of other antibiotics, secondary infections (the development of resistance of microorganisms) are also possible.

Violations of the blood and lymphatic system: very rarely - thrombocytopenia (unusual bleeding, hemorrhage); frequency unknown - agranulocytosis, thrombocytosis, increased INR level (international normalized ratio), prolongation of prothrombin time.

Immune system disorders: often - skin rash; rare allergic reactions (pruritus, urticaria, angioneurotic edema, anaphylactic reactions), the frequency is unknown - drug rash with eosinophilia and systemic symptoms (DRESS-syndrome), Henoch-Schonlein purpura (haemorrhage).

Disorders of the psyche: infrequently - depression; very rare - anxiety, hallucinations, psychosis, disorientation, depersonalisation, "nightmarish" dream, confusion.

Disturbances from the nervous system: often - insomnia, headache, impaired sense of smell; infrequently - drowsiness; very rarely - dizziness, paresthesia, convulsions, tremor; frequency unknown - psychotic disorders.

Hearing disorders and labyrinthine disorders: infrequently - vertigo; rarely - noise, ringing in the ears; very rarely - hearing loss that occurs after the drug is discontinued.

Heart Disease: very rarely - prolongation of QT interval on ECG, ventricular tachycardia, incl. type "pirouette" ("torsade de pointes"), flutter and fibrillation of the ventricles.

Disorders from the gastrointestinal tract: Often - nausea, diarrhea, vomiting, abdominal pain, dyspepsia, stomatitis, glossitis, reversible change in color of tongue and teeth, reversible distortion of taste ( "metal" or bitter taste), rarely - anorexia, decreased appetite, abdominal distension, constipation, , dry mouth; very rarely - pancreatitis, pseudomembranous colitis; frequency is unknown - eructation, flatulence, gastritis, agevzia (loss of taste sensations).

Disorders from the liver and bile ducts: infrequently - a violation of liver function, usually after passing the drug; hepatocellular and cholestatic hepatitis, cholestasis with jaundice or without it; very rarely - liver failure with a lethal outcome (usually in patients with underlying liver disease and / or concomitant therapy with hepatotoxic drugs).

Disturbances from the skin and subcutaneous tissues: often - intense sweating; very rarely malignant exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis; frequency is unknown - acne.

Disturbances from musculoskeletal and connective tissue: frequency unknown - myopathy, increased myasthenia gravis symptoms gravis.

Disorders from the kidneys and urinary tract: very rarely - interstitial nephritis; frequency unknown - renal failure.

Laboratory indicators: infrequently - eosinophilia, hypercreatininaemia, leukopenia, neutropenia, increased activity of "liver" transaminases; very rarely - hypoglycemia (with simultaneous administration of hypoglycemic drugs), the frequency is unknown - hyperbilirubinemia, a change in the color of urine.

General disorders: infrequently - malaise, asthenia, pain in the chest, chills, fatigue.

Other: frequency unknown - parosmia, anosmia.

Overdose:

Symptoms: abdominal pain, nausea, vomiting, diarrhea, headache, confusion.

Treatment: gastric lavage, symptomatic therapy. Hemodialysis and peritoneal dialysis do not lead to a significant change in the concentration of clarithromycin in the blood serum.

Interaction:

When the combined use of clarithromycin and drugs (drugs), primarily metabolized by CYP3A isoenzymes, there may be a mutual increase in their concentrations, which may enhance or prolong both the therapeutic and side effects.

Contraindicated joint administration with astemizole, cisapride, pimozide, terfenadine, ergotamine and other ergot alkaloids, as well as midazolam (oral dosage forms).

When combined with cisapride, pimozide, terfenadine and astemizole, it is possible to increase the concentration of the latter in the blood, prolong the QT interval, the occurrence of arrhythmia, including ventricular tachycardia, including. type "pirouette" and ventricular fibrillation.

When combined with ergotamine and dihydroergotamine, acute poisoning with drugs of the ergotamine group (vascular spasm, ischemia of extremities and other tissues, including the central nervous system) is possible (see the section "Contraindications").

Clarithromycin increases the concentration of inhibitors of HMG-CoA reductase (lovastatin, simvastatin) - the risk of rhabdomyolysis.

When statin use is required, it is recommended to choose statins that are not substrate of CYP3A (for example, fluvastatin).

Carefully prescribe with phenobarbital, carbamazepine, cilostazol, cyclosporine, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants (including warfarin), quinidine, rifampicin, rifabutin, sildenafil, tacrolimus, vinblastine, phenytoin, theophylline and valproic acid, preparations of St. John's wort are metabolized through other isoenzymes of cytochrome P450). It is necessary to adjust the dose of drugs and control the concentration in the blood.

Efavirenz, nevirapine, etravirine, rifampicin, rifabutin and rifapentin (inducers of cytochrome P450) reduce the concentration of clarithromycin in plasma and weaken its therapeutic effect, and, at the same time, increase the concentration of 14-hydroxyclarithromycin.Since the microbiological activity of clarithromycin and its metabolite differ, in particular, the low activity of 14-hydroxycylarithromycin in relation to Mycobacterium avium complex (MAC) is known, alternative treatment should be considered for MAC treatment.

With the simultaneous administration of fluconazole at a dose of 200 mg daily and clarithromycin at a dose of 1 g / day, an increase in Css and AUC of clarithromycin is possible by 33% and 18%, respectively. Correction of the dose of clarithromycin is not required.

With the simultaneous use of ritonavir 600 mg / day and clarithromycin 1 g / day, a decrease in the metabolism of clarithromycin is possible (increase in Stach by 31%, Css by 182% and AUC by 77%), complete suppression of 14-hydroxyclarithromycin. Due to the wide therapeutic range of clarithromycin in patients with normal renal function, dose reduction is not required. In patients with renal insufficiency, dose adjustment is necessary: with a QC of 30-60 ml / min, the dose of clarithromycin should be reduced by 50%, with a QC of less than 30 ml / min - by 75%. Ritonavir should not be taken with clarithromycin in a dose exceeding 1 g / day.

With simultaneous use of clarithromycin with insulin and / or oral hypoglycemic drugs, such as nateglinide, pioglitazone, repaglinide, rosiglitazone, due to the ability of clarithromycin to inhibit CYP3A, pronounced hypoglycemia may develop. A careful control of the concentration of glucose in the blood is recommended.

When combined with quinidine and disopyramide, there may be a ventricular tachycardia such as pirouette. It requires ECG monitoring (increasing the QT interval), serum concentrations of these drugs.

When using clarithromycin and omeprazole, an increase in C_mOh, AUC and T_1/2omeprazole by 30%, 89% and 34%, respectively. The mean pH in the stomach for 24 hours was 5.2 with only omeprazole and 5.7 with omeprazole together with clarithromycin.

With the combined use of clarithromycin and indirect anticoagulants (warfarin), a marked increase in INR and prothrombin time, bleeding is possible. Careful monitoring of MNO and prothrombin time is necessary.

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

With the combined use of clarithromycin with theophylline and carbamazepine, an increase in the concentration of the latter in the systemic circulation is possible.

When using clarithromycin with tolterodine in patients with a low activity of the CYP2D6 isoenzyme, a dose reduction of tolterodine in the presence of clarithromycin (inhibitor of CYP3A isoenzymes) may be required.

With the simultaneous use of clarithromycin (1 g / day) with midazolam (oral), an increase in the AUC of midazolam is 7-fold. It is necessary to avoid the combined oral administration of clarithromycin and midazolam, and other benzodiazepines, which are metabolized by CYP3A isoenzymes. When using midazolam (intravenous) and clarithromycin, a dose adjustment may be required. The same precautions should also be applied to other benzodiazepines, which are metabolized by CYP3A isoenzymes (triazolam and alprazolam). For benzodiazepines, the removal of which does not depend on CYP3A isozymes (temazepam, nitrazepam, lorazepam), clinically significant interaction with clarithromycin is unlikely.

With the combined use of clarithromycin and triazolam, the central nervous system (CNS) may be affected, for example, drowsiness and confusion.

When taking clarithromycin with colchicine, the effect of colchicine may be enhanced.It is necessary to monitor the possible development of clinical symptoms of colchicine intoxication, especially in elderly patients and patients with chronic renal failure (fatal cases have been reported).

With the joint administration of clarithromycin and digoxin, the concentration of digoxin in the serum should be carefully monitored (possibly increasing its concentration and the development of potentially fatal arrhythmias).

Simultaneous reception of clarithromycin and zidovudine in adult HIV-infected patients may lead to a decrease in Cs zidovudine. It is necessary to select doses of clarithromycin and zidovudine. Because the clarithromycin influences the absorption of zidovudine when taken orally, interactions can be largely avoided by taking clarithromycin and zidovudine with an interval of 4 hours.

There are data on the interaction of inhibitors of CYP3A, including clarithromycin, with drugs that are not metabolized by CYP3A - phenytoin and valproic acid. For these drugs, when combined with clarithromycin, it is recommended to determine their serum concentrations, since there are reports of an increase in serum concentrations.

With the simultaneous use of clarithromycin (1 g / day) and atazanavir (400 mg / day), an increase in Atazanavir AUC by 28%, an increase in the effect of clarithromycin by a factor of 2 with a decrease in the effect of 14-hydroxycylarithromycin by 70%. In patients with moderate renal insufficiency (CK 30-60 ml / min), the dose of clarithromycin should be reduced by 50%, in patients with CK less than 30 ml / min - by 75%. Clarithromycin in doses exceeding 1 g / day, can not be used in conjunction with protease inhibitors.

With the joint administration of clarithromycin and itraconazole, a mutual increase in the concentration of drugs in the plasma is possible. For patients who simultaneously take itraconazole and clarithromycin, careful observation is necessary because of the possible increase or prolongation of the pharmacological effects of these drugs.

With concurrent administration of clarithromycin (1 g / day) and saquinavir (in soft gelatin capsules, 1200 mg three times daily), augmentation of AUC and Css of saquinavir is possible by 177% and 187%, respectively, and clarithromycin by 40%. When these two medicines are used together for a limited time in the doses and dosage forms mentioned above, dose adjustment is not required.

When combined with slow calcium channel blockers, which are metabolized by the CYP3A4 isoenzyme, for example, verapamil, amlodipine, diltiazem, it is possible to lower blood pressure, bradyarrhythmia, and lactic acidosis.

Special instructions:

It is necessary to pay attention to the possibility of cross-resistance between clarithromycin and other antibiotics from the macrolide group, as well as lincomycin and clindamycin.

With prolonged use of the drug, the development of superinfection is possible.

Against the background of the use of clarithromycin, myasthenia symptoms may worsen gravis.

In case of acute hypersensitivity reactions such as anaphylactic reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptomatology (DRESS syndrome), purpura Shenlaine-Genocha, the use of clarithromycin should be discontinued and appropriate therapy initiated.

Given the increased resistance Streptococcus pneumoniae, Staphylococcus aureus and Streptococcus pyogenes to macrolides, it is recommended to conduct a sensitivity test before the appointment of clarithromycin in community-acquired pneumonia.

There is information about the development of hepatic dysfunction against the background of taking clarithromycin (see the section "Side effect"), as a rule, reversible. Cases of severe hepatic insufficiency with a lethal outcome developed mainly on the background of previous chronic liver diseases and / or simultaneous reception of hepatotoxic drugs. When symptoms of hepatitis such as anorexia, jaundice, darkening of the urine, pruritus, tenderness of the abdomen during palpation, it is necessary to stop the treatment with clarithromycin.

In the presence of chronic liver disease, it is necessary to regularly monitor the activity of enzymes in the blood serum.

Caution is prescribed against a background of drugs metabolized by the liver (it is recommended to measure their concentration in the blood).

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

When developing a secondary infection, adequate therapy should be prescribed.

If a severe and prolonged diarrhea occurs during or after treatment, the diagnosis of pseudomembranous colitis should be deleted, which requires immediate discontinuation of the drug and the appointment of appropriate treatment.Contraindicated use of drugs that inhibit intestinal peristalsis.

Effect on the ability to drive transp. cf. and fur:

Since the administration of the drug in rare cases, it is possible to develop side effects (including disorientation, dizziness), care should be taken when driving vehicles and engaging in other potentially dangerous activities requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:Film-coated tablets, 250 mg or 500 mg.

Packaging:

For 7 tablets in the blister PVC-PVDC / AL.

2 blisters with instructions for use in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of 15 to 25 ° C.

Store in original packaging.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-000864

Date of registration:14.10.2011

Expiration Date:14.10.2016

The owner of the registration certificate:Hemofarm ADHemofarm AD Serbia

Manufacturer: & nbsp

HEMOFARM, A.D. Serbia

Representation: & nbspHEMOFARM A.D. HEMOFARM A.D. Serbia

Information update date: & nbsp13.10.2017

Illustrated instructions

Instructions

Zimbaktar (Zimbaktar)