Clarithromycin - instructions for use, dose, side effects, contraindications

Excipients: starch pregelatinized 49.4 mg, microcrystalline cellulose 35.0 mg, croscarmellose sodium 19.0 mg, povidone-K30 19.0 mg, silicon dioxide colloid 3.8 mg, magnesium stearate 3.8 mg;

sheath: Opaprai II white (polyvinyl alcohol, titanium dioxide, macrogol, talc) 11.0 mg.

Dosage 500 mg:

active substance: clarithromycin 500.0 mg;

Excipients: starch pregelatinized 100.8 mg, microcrystalline cellulose 68.0 mg, croscarmellose sodium 38.0 mg, povidone-K30 38.0 mg, silicon dioxide colloid 7.6 mg, magnesium stearate 7.6 mg;

shell: Opaprai II white (polyvinyl alcohol, titanium dioxide, macrogol, talc) 22, 0 mg.

Description:

Dosage of 250 mg: tablets of round shape, biconvex, covered with a coat of white color.

Dosage 500 mg: tablets of the oval form, biconcave, covered with a cover of white color.

Pharmacotherapeutic group:Antibiotic-macrolide

ATX: & nbsp

J.01.F.A.09 Clarithromycin

Pharmacodynamics:

Semisynthetic bacteriostatic macrolide antibiotic of broad spectrum of action.It breaks the synthesis of the protein of microorganisms (binds to the 50S subunit of the ribosomes of the microbial cell). It acts on extracorporeal and intracellular pathogens. The activity of clarithromycin against most strains of the following microorganisms is proved as in vitro, and in clinical practice:

- aerobic Gram-positive microorganisms: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes;

- aerobic gram-negative microorganisms: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Legionella pneumophila;

- other microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae;

- mycobacteria: Mycobacterium leprae, Mycobacterium chelonae, Mycobacterium kansasii, Mycobacterium fortuitum; Mycobacterium avium complex (MAC) - complex, including: Mycobacterium avium and Mycobacterium inlracellulare; Helicobacter pylori.

Beta-lactamases do not affect the activity of clarithromycin.

Enterobacteriaceae and Pseudomonas spp., as well as other, non-lactose-fermenting gram-negative bacteria, are not sensitive to clarithromycin.

Activity of clarithromycin in vitro:

- aerobic Gram-positive microorganisms: Streptococcus agalactiae, Streptococci groups C, F, G, Streptococci group of viridans;

- aerobic gram-negative microorganisms: 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;

- Campylobacteria: Campylobacter jejuni.

The main metabolite of clarithromycin in the human body is the microbiologically active metabolite 14-hydroxyclarithromycin (14 (R) -clarithromycin).The microbiological activity of the metabolite is the same as that of the starting material, or 1-2 times weaker in respect of most microorganisms. The exception is N.influenzae, in relation to which the efficiency of the metabolite is twice as high. The starting material and its main metabolite exert either an additive or a synergistic effect on N.influenzae in conditions in vitro and in vivo depending on the strain of bacteria.

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:

Absorption is fast. The intake of food immediately before taking the drug increased the bioavailability of the drug by an average of 25%. Bioavailability is about 50%. The connection with plasma proteins is 65-75%. After a single dose, 2 peaks of the maximum equilibrium concentration in the blood plasma are recorded (CmOh). The second peak is due to the ability of the drug to accumulate in the gallbladder, followed by a gradual or rapid intake into the intestine and absorption.Time to reach Cmah (TSmah) - 2-3 hours.

After oral administration of 20-30% of the accepted dose of clarithromycin is rapidly hydroxylated in the liver by cytochrome isoenzymes CYP3A4, CYP3A5 and CYP3A7 with formation of the main metabolite - 14 (R) -claritromycin, which has a pronounced antimicrobial activity against Haemophilus influenzae. Is an inhibitor of isoenzymes CYP3A4, CYP3A5 and CYP3A7.

With a regular intake of 250 mg / day, the equilibrium concentration (Css) unchanged drug and its main metabolite - 1.0 and 0.6 μg / ml, respectively; the half-life (T1 / 2) is 3-4 and 5-6 hours, respectively. When the dose is increased to 500 mg / day Css unchanged drug and its metabolite in plasma - 2.7-2.9 and 0.83-0.88 μg / ml, respectively; T1 / 2 - 4.8-5.0 and 6.9-8.7 hours, respectively.

Clarithromycin and its metabolite are well distributed in tissues and body fluids. Tissue concentrations are usually several times higher than serum concentrations.

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

When using clarithromycin at a dose of 250 mg every 12 hours, approximately 20% of the dose is excreted by the kidneys unchanged.When using clarithromycin in a dose of 500 mg every 12 hours, approximately 30% of the dose is excreted by the kidneys unchanged. The renal clearance of clarithromycin is substantially independent of the dose and approaches the normal glomerular filtration rate. The main metabolite found in urine is 14 (R) -claritromycin, the proportion of which is 10-15% of the dose (250 mg or 500 mg every 12 hours).

In patients with impaired renal function who received the drug inside at a dose of 500 mg repeatedly, T1 / 2, Cmah, the minimum equilibrium concentration in the blood plasma (Cmin) and the area under the pharmacokinetic curve "concentration-time" (AUC) of clarithromycin and metabolite were higher than in healthy people. The deviations of these parameters correlated with the degree of renal failure: with more pronounced renal dysfunction, the differences were more significant.

In adult patients with HIV infection who received the drug in normal doses, Css clarithromycin and its metabolite were similar to those of healthy people. However, when using clarithromycin at higher doses, which may be required in the treatment of mycobacterial infections, antibiotic concentrations can be significantly higher than usual.

Indications:

Infectious-inflammatory diseases caused by microorganisms sensitive to clarithromycin:

- infections of the lower respiratory tract (including exacerbation of chronic bronchitis, community-acquired pneumonia);

- infections of the upper respiratory tract and ENT organs (including pharyngitis, tonsillitis, acute sinusitis, acute otitis media);

- uncomplicated infections of the skin and soft tissues (including folliculitis, inflammation of the subcutaneous tissue, erysipelas);

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

- eradication Helicobacter pylori and a decrease in the frequency of recurrences of duodenal ulcers;

- prevention of the spread of infection caused by the complex Mycobacterium avium (MAC), in HIV-infected patients with lymphocyte content Cd4 (T-helper lymphocytes) not more than 100 in 1 mm³;

- odontogenic infections.

Contraindications:

- Hypersensitivity to clarithromycin, other antibiotics of the macrolide group and other components of the drug;

- simultaneous reception of clarithromycin with the following drugs: astemizole, cisapride, pimozide, terfenadine, ergotamine, dihydroergotamine;

- simultaneous reception of simvastatin, lovastatin, midazolam for oral administration;

- simultaneous reception of colchicine in patients with impaired renal or hepatic function;

- the patients have an extension of the interval QT in the anamnesis, a ventricular arrhythmia or a ventricular tachycardia of type "pirouette";

- hypokalemia;

- Cholestatic jaundice / hepatitis, developed with the use of clarithromycin (in anamnesis);

- severe hepatic insufficiency, which occurs simultaneously with renal insufficiency;

- porphyria;

- hypokalemia;

- the period of breastfeeding;

- children under 12 years (taking into account the dosage form and dosage).

Carefully:

Renal failure of medium and severe degree, hepatic insufficiency of moderate and severe degree, myasthenia gravis gravis, simultaneous administration with benzodiazepines (alprazolam, triazolam, midazolam for intravenous administration), isozyme inducing drugs CYP3A4 (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort), blockers of "slow" calcium channels, which are metabolized by isoenzyme CYP3A4 (e.g., verapamil, amlodipine, diltiazem); ischemic heart disease, severe heart failure, hypomagnesemia, severe bradycardia (heart rate less than 50 beats per minute), simultaneous use of antiarrhythmic drugs IA class (quinidine, procainamide) and III class (dofetilide, amiodarone, sotalol), pregnancy. Simultaneous reception with drugs that are metabolized by isoenzyme CYP3A, eg, carbamazepine, cilostazol, ciclosporin, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants (for example, warfarin), quinidine, rifabutin, sildenafil, tacrolimus, vinblastine.

Pregnancy and lactation:

The use of the drug in pregnancy (especially in the first trimester) is possible only if there is no alternative therapy, and the prospective benefit for the mother exceeds the potential risk to the fetus.

Clarithromycin excreted in breast milk, so if you need to use the drug during lactation, breastfeeding should be discontinued.

Dosing and Administration:

Tablets are taken orally, regardless of food intake.

Usually adults and children over 12 years of age are prescribed 250 mg of clarithromycin twice a day.In more severe cases, the dose is increased to 500 mg twice a day.

Usually the duration of treatment is from 5 to 14 days. The exception is community-acquired pneumonia and sinusitis, which require treatment for 6 to 14 days.

With the aim of eradication Helicobacter pylori in combination with other medicines:

Combination treatment with three drugs

Clarithromycin - 500 mg, lansoprazole - 30 mg and amoxicillin - 1000 mg, all medicines twice a day, for 10 days; clarithromycin - 500 mg, omeprazole - 20 mg and amoxicillin - 1000 mg, all medicines twice a day, for 7-10 days;

Combination 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 20-40 mg / day.

Clarithromycin 500 mg 3 times a day + lansoprazole 60 mg / day for 14 days.

To fully heal the ulcer, an additional decrease in the acidity of the gastric juice may be required.

With odontogenic infections The dose of clarithromycin is 250 mg 2 times a day for 5 days.

Doses for the treatment of mycobacterial infections other than tuberculosis: with mycobacterial infections, a dose of clarithromycin 500 mg 2 times a day is recommended. Treatment of disseminated MAC infections in AIDS patients should be continued as long as there is clinical and microbiological efficacy. Clarithromycin should be used in combination with other antimicrobial agents active against these pathogens. The duration of treatment of other non-tuberculosis mycobacterial infections is determined by the doctor.

For the prevention of infections caused by MAC: the recommended dose of clarithromycin for adults is 500 mg twice a day.

Patients with renal insufficiency

Patients with creatinine clearance less than 30 ml / min are prescribed half of the usual dose of clarithromycin, i.e. 250 mg once a day or, for more severe infections, 250 mg twice a day. Treatment of such patients continues no more than 14 days.

Side effects:

Classification of adverse reactions according to the frequency of development (number of reported cases / number of patients): very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), unknown (side effects from the post-marketing application experience, the frequency can not be estimated based on available data).

Allergic reactions

Often: rash.

Infrequently: anaphylactoid reaction¹, hypersensitivity, dermatitis bullous¹, itching, urticaria, maculopapular rash³.

Unknown: anaphylactic reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS -syndrome).

From the nervous system

Often: headache, insomnia.

Infrequently: loss of consciousness¹, dyskinesia¹, dizziness, drowsiness, tremor, anxiety, increased excitability³, shouting³.

Unknown: convulsions, psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, dreaming ("nightmarish" dreams), paresthesia, mania.

From the skin

Often: intensive sweating.

Unknown: acne, purpura Shenlaine-Henoch, hemorrhage.

From the urinary system

Unknown: renal failure, interstitial nephritis.

From the side of metabolism and nutrition

Infrequently: anorexia, impaired appetite.

Unknown: hypoglycemia.

From the side of the musculoskeletal system

Infrequently: muscular spasm³, musculoskeletal stiffness¹, myalgia².

Unknown: rhabdomyolysis² , myopathy, increased myasthenia gravis symptoms gravis.

From the digestive system

Often: diarrhea, vomiting, dyspepsia, nausea, pain in the abdomen.

Infrequently: esophagitis¹, gastroesophageal reflux disease², gastritis, proctalgia², stomatitis, glossitis, bloating⁴, constipation, dry mouth, eructations, flatulence, cholestasis⁴, hepatitis incl. cholestatic or hepatocellular⁴.

Unknown: acute pancreatitis, discoloration of the tongue and teeth, hepatic insufficiency, jaundice.

From the respiratory system

Infrequently: asthma¹, nose bleed², pulmonary embolism¹.

From the sense organs

Often: dysgeusia, perversion of taste.

Infrequently: vertigo, hearing loss, ringing in the ears.

Unknown: deafness, agevzia (loss of taste sensations), parosmia, anosmia.

From the side of the cardiovascular system

Often: vasodilation¹.

Infrequently: heart failure¹, atrial fibrillation¹, lengthening the interval QT on an electrocardiogram, an extrasystole¹, atrial flutter.

Unknown: ventricular tachycardia, including the "pirouette" type.

Laboratory indicators

Often: deviation in the hepatic test.

Infrequently: increase in creatinine concentration¹, increased urea concentration¹, a change in the albumin-globulin ratio¹, leukopenia, neutropenia⁴, eosinophilia⁴, thrombocythemia³, increased concentration in the blood: alanine aminotransferase (ALT), aspartate aminotransferase (ACT), gamma glutamyl transferase (GGTP)⁴, alkaline phosphatase⁴, lactate dehydrogenase (LDH)⁴.

Unknown: agranulocytosis, thrombocytopenia, an increase in the value of the international normalized ratio (INR), prolongation of prothrombin time, a change in the color of urine, an increase in the concentration of bilirubin in the blood.

General disorders

Infrequently: malaise⁴, hyperthermia³, asthenia, chest pain⁴, chills⁴, fatigue⁴.

Infectious and parasitic diseases

Infrequently: cellulite³, candidiasis, gastroenteritis², secondary infections³ (including vaginal).

Unknown: pseudomembranous colitis, erysipelas, erythrasma.

Patients with depressed immunity

In patients with AIDS and other immunodeficiencies receiving clarithromycin at higher doses for a long time to treat mycobacterial infections, it is often difficult to distinguish the undesirable effects of the drug from the symptoms of HIV infection or a concomitant disease.

The most frequent adverse events in patients taking a daily dose of clarithromycin equal to 1000 mg were: nausea, vomiting, taste distortion, abdominal pain, diarrhea, rash, flatulence, headache, constipation, hearing impairment, increased concentration ACT and ALT in the blood. There have also been cases of adverse events with a low incidence, such as shortness of breath, insomnia and dry mouth.

In patients with suppressed immunity, laboratory indicators were evaluated, analyzing their significant deviations from the norm (a sharp increase or decrease). Based on this criterion, 2-3% patients who received clarithromycin in a dose of 1000 mg daily, there was a significant increase in concentration ACT and ALT in the blood, as well as a decrease in the number of leukocytes and platelets. A small number of patients also reported an increase in the concentration of residual urea nitrogen.

* In some reports of rhabdomyolysis clarithromycin was taken together with other drugs, the reception of which is known to be associated with the development of rhabdomyolysis (statins, fibrates, colchicine or allopurinol).

¹These adverse reactions were reported only when applied clarithromycin, lyophilizate for the preparation of a solution for infusions.

²Reports of these adverse reactions were obtained only with the use of clarithromycin, prolonged-release tablets coated with a film coat.

³Reports of these adverse reactions were obtained only with the use of clarithromycin, a powder for the preparation of a suspension for oral administration.

⁴Reports of these adverse reactions were obtained only with the use of clarithromycin, film-coated tablets.

Overdose:

Symptoms: abdominal pain, nausea, vomiting, diarrhea.

Treatment: gastric lavage, maintenance therapy. It is not removed during hemo- or peritoneal dialysis.

Interaction:

Use of the following drugs in conjunction with clarithromycin is contraindicated in connection with the possibility of developing serious side effects

Cisapride, pimozide, terfenadine and astemizole

With the simultaneous use of clarithromycin with cisapride / pimozide / terfenadine / astemizole, an increase in the concentration of the latter in the blood plasma was reported, which may lead to an increase in the interval QT and the occurrence of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and ventricular pirouette tachycardia (see "Contraindications"),

Alkaloids of ergot

Postmarketing studies show that with the combined use of clarithromycin with ergotamine or dihydroergotamine, the following effects associated with acute poisoning with drugs of the ergotamine group are possible: vascular spasm, ischemia of limbs and other tissues, including the central nervous system. Simultaneous use of clarithromycin and ergot alkaloids is contraindicated (see the section "Contraindications"),

The effect of other drugs on clarithromycin

Preparations that are inducers of isoenzyme CYP3A4 (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort pitted), can induce the metabolism of clarithromycin. This can lead to a subtherapeutic concentration of clarithromycin, which leads to a decrease in its effectiveness. In addition, it is necessary to observe the concentration of the inducer of the isoenzyme СUR3А4 in blood plasma, which can increase due to inhibition of the isoenzyme CYP3A4 clarithromycin.With the combined use of rifabutin and clarithromycin, an increase in the plasma concentration of rifabutin and a decrease in the plasma concentration of clarithromycin with an increased risk of uveitis have been observed.

The following drugs have a proven or suspected effect on the concentration of clarithromycin in the blood plasma; In the case of their combined use with clarithromycin, dosage adjustment or alternate treatment may be required.

Efavirenz, nevirapine, rifampicin, rifabutin and rifapentin

Strong inductors of the cytochrome P450 system, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentin can accelerate the metabolism of clarithromycin and, thus, lower the concentration of clarithromycin in the plasma and weaken the therapeutic effect, and at the same time increase the concentration of 14 (R) -claritromycin-metabolite, which is also microbiologically active. Since the microbiological activity of clarithromycin and 14 (R) -claritromycin differs with respect to different bacteria, the therapeutic effect may decrease with the combined use of clarithromycin and inducers of cytochrome P450 isoenzymes.

Etravirine

The concentration of clarithromycin decreases with the use of etravirine, but the concentration of the active metabolite 14 (K) -claritromycin increases. Since 14 (11) -claritromycin has a low activity against infections Mycobacterium avium complex (MAC), the overall activity against these pathogens may change, therefore, for treatment MAC alternative treatment should be considered.

Fluconazole

The simultaneous administration of fluconazole at a dose of 200 mg daily and clarithromycin at a dose of 500 mg twice daily in 21 healthy volunteers resulted in an increase in the mean C_min and AUC by 33% and 18%, respectively. At the same time, the combined administration did not significantly affect the average equilibrium concentration of the active metabolite 14 (R) -clarithromycin. Correction of the dose of clarithromycin in the case of concurrent administration of fluconazole is not required.

Ritonavir

A pharmacokinetic study showed that a joint intake of ritonavir at a dose of 200 mg every eight hours and clarithromycin at a dose of 500 mg every 12 hours led to a marked suppression of the metabolism of clarithromycin. With the joint administration of ritonavir C_max clarithromycin increased by 31%, C_min increased by 182% and AUC increased by 77%. Full suppression of education was noted14 (R) -clarithromycin.Due to the wide therapeutic range of clarithromycin, a reduction in its dose in patients with normal renal function is not required. In patients with renal insufficiency it is advisable to consider the following options for dose adjustment: with a QC of 30-60 ml / min, the dose of clarithromycin should be reduced by 50%; with QC less than 30 ml / min, the dose of clarithromycin should be reduced by 75% using the appropriate form of clarithromycin. Ritonavir should not be used together with clarithromycin in doses exceeding 1 g / day.

Oral hypoglycemic agents / insulin

With the combined use of clarithromycin and oral hypoglycemic agents and / or insulin, pronounced hypoglycemia can be observed. Against the background of simultaneous reception of clarithromycin and some drugs that reduce the concentration of glucose, such as nateglinide, pioglitazone, repaglinide and rosiglitazone, there may be an inhibition of the isoenzyme CYP3A clarithromycin, which may result in hypoglycemia. Careful monitoring of glucose concentration is recommended.

Action of clarithromycin on other drugs

Antiarrhythmic drugs (quinidine and disopyramide)

Possible occurrence of ventricular tachycardia of the "pirouette" type when combined use of clarithromycin and quinidine or disopyramide. When concurrently taking clarithromycin with these drugs should regularly monitor the electrocardiogram for increasing the interval QT, and plasma concentrations of these drugs should be monitored.

Interactions due to the isoenzyme CYP3A

Joint reception of clarithromycin, which is known to inhibit isoenzyme CYP3A, and drugs, primarily metabolized by isoenzyme CYP3A, can be associated with a mutual increase in their concentrations, which can enhance, or prolong both the therapeutic and side effects. Clarithromycin should be used with caution for patients receiving drugs that are substrates of isoenzyme CYP3A, especially if these drugs have a narrow therapeutic range (for example, carbamazepine), and / or are extensively metabolized by this enzyme. If necessary, a dose adjustment of the drug taken with clarithromycin should be performed.Also, if possible, monitoring of plasma concentrations of drugs that are primarily metabolized CYP3A.

Metabolism of the following drugs / classes is carried out by the same isoenzyme CYP3A, as the metabolism of clarithromycin, for example, alprazolam, carbamazepine, cilostazol, ciclosporin, disopyramide, methylprednisolone, midazolam, omeprazole, indirect anticoagulants (for example, warfarin), quinidine, rifabutin, sildenafil, tacrolimus, triazolam and vinblastine. Also to isoenzyme agonists CYP3A include the following drugs, contraindicated for joint use with clarithromycin: astemizole, cisapride, pimozide, terfenadine, lovastatin, simvastatin and ergot alkaloids (see the section "Contraindications"). To drugs interacting in a similar way through other isoenzymes within the cytochrome P450 system, phenytoin, theophylline and valproic acid.

Inhibitors of HMG-CoA reductase (statins)

The combined administration of clarithromycin with lovastatin or simvastatin is contraindicated (see the section "Contraindications") due to the fact that these statins are largely metabolized by the isoenzyme CYP3A4, and combined use with clarithromycin increases their plasma concentrations, which leads to an increased risk of myopathy, including rhabdomyolysis. There have been reports of rhabdomyolysis in patients taking clarithromycin together with these drugs. If it is necessary to use clarithromycin, you should stop taking lovastatin or simvastatin for the duration of therapy.

Clarithromycin should be used with caution in combination therapy with statins. In case of need of joint admission, it is recommended to take the lowest dose of statin. It is necessary to use statins that do not depend on the isoenzyme metabolism CYP3A (eg, fluvastatin).

Indirect anticoagulants

With the concomitant administration of warfarin and clarithromycin, bleeding is possible, a marked increase in INR and prothrombin time. In the case of combined use with warfarin or other indirect anticoagulants, it is necessary to monitor INR and prothrombin time.

Omeprazole

Clarithromycin (500 mg every 8 hours) was tested in healthy adult volunteers in combination with omeprazole (40 mg daily).With the combined use of clarithromycin and omeprazole, equilibrium plasma concentrations of omeprazole were increased (C_max, AUC0-24 and T1/2 increased by 30%, 89% and 34% respectively). The average pH value of the stomach for 24 hours was 5.2 when taking omeprazole alone and 5.7 when taking omeprazole together with clarithromycin.

Sildenafil, tadalafil and vardenafil

Each of these phosphodiesterase inhibitors is metabolized, at least in part, by the participation of an isoenzyme CYP3A. At the same time, isoenzyme CYP3A can be inhibited in the presence of clarithromycin. The combined use of clarithromycin with sildenafil, tadalafil or vardenafil may lead to an increase in the inhibitory effect on phosphodiesterase. When using these drugs together with clarithromycin should consider the possibility of reducing the dose of sildenafil, tadalafil and vardenafil.

Theophylline, carbamazepine

With the combined use of clarithromycin and theophylline or carbamazepine, an increase in the concentration of these drugs in the systemic circulation is possible.

Tolterodin

Primary metabolism of tolterodine is via isoenzyme 2D6 cytochrome P450 (CYP2D6). However, in the part of the population deprived of isoenzyme CYP2D6, metabolism occurs through isoenzyme CYP3A. In this population, suppression of the isoenzyme CYP3A leads to much higher concentrations of tolterodine in plasma. In a population with a low level of metabolism via isoenzyme CYP2D6, a dose reduction of tolterodine in the presence of inhibitors of the isoenzyme CYP3A, such as clarithromycin.

Benzodiazepines (e.g., alprazolam, midazolam, triazolam)

When combined with midazolam and clarithromycin tablets (500 mg twice daily), there was an increase AUC midazolam: 2.7 times after intravenous administration of midazolam and 7 times after oral administration. Contraindicated joint oral administration of midazolam and clarithromycin. If, together with clarithromycin, the intravenous form of midazolam is used, the patient's condition should be carefully monitored for possible dose adjustment. The same precautions should be applied to other benzodiazepines, which are metabolized by the isoenzyme CYP3A, including triazolam and alprazolam. For benzodiazepines, the excretion of which does not depend on the isoenzyme CYP3A (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. In this regard, in the case of joint application, it is recommended to follow the symptoms of the CNS disorder.

Interactions with other drugs

Colchicine

Colchicine is a substrate as an isoenzyme CYP3A, and the carrier protein, P-glycoprotein (Pgp). It is known that clarithromycin and other macrolides inhibit isoenzyme CYP3A and Pgp. When co-administered with clarithromycin and colchicine, inhibition Pgp and / or isoenzyme CYP3A can lead to an increase in the action of colchicine. It should monitor the development of clinical symptoms of colchicine poisoning. Post-marketing reports on cases of colchicine poisoning during its simultaneous administration with clarithromycin are registered, more often in elderly patients. Some of the cases described occurred with patients with renal insufficiency. As reported, some cases ended in a fatal outcome.In patients with normal renal and hepatic function, a dose of colchicine should be lowered with simultaneous use with clarithromycin. The simultaneous use of clarithromycin and colchicine is contraindicated in patients with impaired liver or kidney function (see "Contraindications"),

Digoxin

It is assumed that digoxin is a substrate Pgp. It is known that clarithromycin inhibits Pgp. When co-administered with clarithromycin and digoxin, inhibition Pgp clarithromycin may lead to an increase in the action of digoxin. The combined administration of digoxin and clarithromycin may also lead to an increase in plasma digoxin concentrations. Some patients experienced significant clinical symptoms of digoxin poisoning, including potentially fatal arrhythmias. With the simultaneous administration of clarithromycin and digoxin, the concentration of digoxin in the blood plasma should be carefully monitored.

Zidovudine

Simultaneous oral administration of tablets clarithromycin and zidovudine by adult HIV-infected patients may lead to a decrease in the equilibrium concentration of 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. Such an interaction was not observed in HIV-infected children taking a children's suspension of clarithromycin, with zidovudine or dideoxyinosine. Because the clarithromycin may interfere with the absorption of zidovudine when administered simultaneously in adults in adults, this interaction is hardly possible with the use of clarithromycin intravenously.

Phenytoin and valproic acid

There are data on the interactions of isoenzyme inhibitors CYP3A (including clarithromycin) with drugs that are not metabolized by isoenzyme CYP3A (phenytoin and valproic acid). For these drugs, when combined with clarithromycin, it is recommended to determine their plasma concentrations, since there are reports of their increase.

Bi-directional drug interactions

Atazanavir

Clarithromycin and atazanavir are both substrates and isoenzyme inhibitors CYP3A. There is evidence of bi-directional interaction of these drugs. The combined use of clarithromycin (500 mg twice daily) and atazanavir (400 mg once a day) can lead to a twofold increase in the effect of clarithromycin and a reduction in the effect of 14- (R) -claritromycin by 70%, with an increase AUC atazanavir by 28%. Due to the wide therapeutic range of clarithromycin, reducing its dose in patients with normal renal function is not required. In patients with moderate renal failure (CK 30-60 ml / min), the dose of clarithromycin should be reduced by 50%. In patients with QC less than 30 ml / min, the dose of clarithromycin should be reduced by 75% using the appropriate dosage form of clarithromycin. Clarithromycin in doses exceeding 1000 mg per day, can not be used in conjunction with protease inhibitors.

Blocks of "slow" calcium channels

With the simultaneous use of clarithromycin and blockers of "slow" calcium channels, which is metabolized by the isoenzyme CYP3A4 (e.g., verapamil, amlodipine, diltiazem), you should be careful, since there is a risk of arterial hypotension.Plasma concentrations of clarithromycin, as well as blockers of "slow" calcium channels, can increase with simultaneous application. Arterial hypotension, bradyarrhythmia and lactic acidosis are possible with concurrent administration of clarithromycin and verapamil.

Itraconazole

Clarithromycin and itraconazole are substrates and inhibitors of the isoenzyme CYP3A, which determines the bi-directional interaction of drugs. Clarithromycin can increase the concentration of itraconazole in the plasma, while itraconazole can increase the plasma concentration of clarithromycin. Patients simultaneously taking itraconazole and clarithromycin, should be carefully examined for signs of increased or prolonged pharmacological effects of these drugs.

Saquinavir

Clarithromycin and saquinavir are substrates and inhibitors of the isoenzyme CYP3A, which determines the bi-directional interaction of drugs. Simultaneous use of clarithromycin (500 mg twice daily) and saquinavir (in soft gelatin capsules, 1200 mg three times a day) in 12 healthy volunteers caused an increase AUC and C_mOh saquinavir by 177% and 187%, respectively, compared with the administration of saquinavir alone. Values AUC and C_mOh clarithromycin were approximately 40% higher than with monotherapy with clarithromycin. When these two drugs are used together for a limited time in the doses / formulations mentioned above, dose adjustment is not required. The results of a study of drug interactions using saquinavir in soft gelatin capsules may not correspond to the effects observed with saquinavir in hard gelatin capsules. The results of the study of drug interactions with saquinavir monotherapy may not correspond to the effects observed with saquinarine / ritonavir therapy. When taking saquinavir together with ritonavir, the potential effect of ritonavir on clarithromycin.

Special instructions:

When applying clarithromycin, hepatic dysfunction was reported (increased hepatic enzyme concentrations in the blood, hepatocellular and / or cholestatic hepatitis with or without jaundice).

Hepatic dysfunction can be severe, but is usually reversible.There are cases of hepatic insufficiency with a fatal outcome, mainly associated with the presence of serious concomitant diseases and / or with the simultaneous use of other medicines. When signs and symptoms of hepatitis such as anorexia, jaundice, darkening of the urine, itching, tenderness of the abdomen during palpation, it is necessary to immediately 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.

In the case of combined use with warfarin or other indirect anticoagulants, prothrombin time and INR should be monitored.

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

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

Possible worsening of myasthenia gravis symptoms gravis.

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.

With caution apply the drug to patients with a predisposition to lengthen the interval QT. With these conditions, the electrocardiogram should be monitored regularly to increase the interval QT.

In case of acute hypersensitivity reactions, such as anaphylactic reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylactic reactions, rash with eosinophilia and systemic symptoms, purpura Shenlaine-Henoch, it is necessary to immediately stop taking clarithromycin and begin appropriate therapy.

Given the growing resistance Streptococcus pneumoniae to macrolides, it is important to conduct sensitivity testing in the appointment of clarithromycin.

It is possible to develop cross-resistance to clarithromycin and other antibiotics of the macrolide group.

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

During the period of treatment, care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions. Consideration should be given to the potential for the development of side effects such as dizziness, vertigo, confusion and disorientation.When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:

Tablets, film-coated, 250 mg, 500 mg.

Packaging:

Dosage of 250 mg: 7, 10 or 12 tablets in a contour cell box made of a polyvinylchloride film and aluminum foil printed lacquered.

For 1 or 2 contour packs with instructions for medical use in a cardboard box.

Dosage 500 mg: for 5, 7 or 10 tablets in a contour cell box made of a polyvinylchloride film and aluminum foil printed lacquered.

For 1 or 2 contour packs with instructions for medical use in a cardboard box.

Storage conditions:

In a dry, protected from light place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002497

Date of registration:16.06.2014 / 22.12.2015

Expiration Date:16.06.2019

The owner of the registration certificate:RAFARMA, CJSC RAFARMA, CJSC Russia

Manufacturer: & nbsp

RAFARMA, JSC Russia

Information update date: & nbsp24.01.2018

Illustrated instructions

Instructions

Clarithromycin (Clarithromycin)