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

Excipients: pregelatinized starch 130.00 mg Microcrystalline cellulose 170.00 mg Colloidal silica 14.40 mg, 70 mg croscarmellose sodium, povidone 40.00 mg magnesium stearate 15.00 mg 25.00 mg stearic acid;

film sheath: Hypromellose 25.60 mg macrogol 6000 4.72 mg Talc 20.36 mg Titanium dioxide 7.92 mg Dimethicone 0.12 mg, 0.88 mg of vanillin.

Description:

Oval biconvex tablets, film-coated, white, or almost white, with a transverse notch on either side of dividing the tablet into two equal halves.

Pharmacotherapeutic group:antibiotic-macrolide

ATX: & nbsp

J.01.F.A.09 Clarithromycin

Pharmacodynamics:

Semisynthetic, macrolide antibiotic of broad spectrum of action. Disrupts the synthesis of the protein of microorganisms (binds to 50S subunit of the ribosome membrane of a 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;

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

- other microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae;

- Mycobacterium: Mycobacterium avium complex (MAC), a 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, Streptococcus spp. groups 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 chelonae;

- Campylobacteria: Campylobacter jejuni.

Microbiologically active metabolite of clarithromycin - 14 (R) -hydroxyclamirithromycin, is twice as active as the parent 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 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. Food slows down absorption, without significantly affecting bioavailability. Bioavailability is approximately 50%. Food slightly delays both the process of absorption of clarithromycin, and the formation of its active metabolite, which has an antimicrobial effect, 14- (R) -hydroxyclarithromycin, however, it does not affect the degree of bioavailability. The connection with plasma proteins is 65-75%. After a single dose, 2 peaks of the maximum concentration are recorded - C_mOh. 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 the maximum concentration (TC_mOh) - 2-3 hours.

After oral administration, 20-30% of the dose is rapidly hydroxylated in the liver by cytochrome P450 isoenzymes: CYP3A4, CYP3A5 and CYP3A7 with formation of the main metabolite - 14 (R) -hydroxyclamirithromycin, 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 (1/2 tablet), the equilibrium concentration (Css) of the unchanged drug and its main metabolite in the blood serum is 1 and 0.6 μg / ml, respectively; half-life (T1/2) - 3-4 hours 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; T_1/2 - 4.8-5 and 6.9-8.7 hours, respectively.

In therapeutic concentrations, it accumulates in the lungs, skin and soft tissues (concentrations 10 times higher than serum).

It is excreted by the kidneys and intestines (20-30% - in unchanged form, the rest - in the form of metabolites). With a single admission of 250 and 1000 mg of kidneys, 37.9 and 46% are removed, the intestines - 40.2 and 29.1%, respectively.

With chronic renal failure, the time to reach the maximum concentration (TC_mOh), directly the maximum concentration (C_mOh) and the area under the curve "concentration-time" (AUC) clarithromycin and its metabolite.

Indications:

Clarithromycin is indicated for the treatment of infectious and inflammatory diseases caused by microorganisms sensitive to it. In particular, clarithromycin appoint with the following diseases:

Adults: pharyngitis, tonsillitis, acute sinusitis, exacerbation of chronic bronchitis, community-acquired pneumonia, uncomplicated infections of the skin and subcutaneous tissue; prevention and treatment of disseminated infection caused by Mycobacterium avium and Mycobacterium intracellulare. In combination with amoxicillin and omeprazole / lansoprazole in the form of triple therapy for infections caused by Helicobacter pylori, including duodenal ulcer. In combination with omeprazole or ranitidine, bismuth citrate in the form of dual therapy for the treatment of duodenal ulcers caused by Helicobacter pylori.

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, to the components of the drug and other macrolides;

- simultaneous reception of clarithromycin with the following drugs: astemizole, cisapride, pimozide, terfenadine (see section "Interaction with other medicinal products").

- simultaneous reception of clarithromycin with ergot alkaloids, for example, ergotamine and dihydroergotamine, and other ergot alkaloids (cf.section "Interaction with other medicinal products");

- simultaneous reception of clarithromycin with benzodiazepines, such as midazolam for oral administration (see section "Interaction with other medicinal products");

- Patients with a history of prolonged QT interval, ventricular arrhythmia or ventricular pirouette tachycardia;

- Patients with hypokalemia (risk of prolonging the QT interval);

- Patients with severe hepatic insufficiency occurring concomitantly with renal insufficiency;

- simultaneous reception of clarithromycin with inhibitors of HMG-CoA reductase (statins), which are largely metabolized by the isoenzyme CYP3A4 (lovastatin, simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see "Interaction with Other Drugs");

- simultaneous reception of clarithromycin with colchicine in patients with impaired liver or kidney function, taking P-glycoprotein inhibitors or potent inhibitors of the CYP3A4 isoenzyme;

- Patients with cholestatic jaundice / hepatitis in history, developed with the use of clarithromycin (see section "Special instructions");

- porphyria;

- the period of breastfeeding;

- Children under 12 years of age (efficacy and safety not established).

Carefully:

Renal failure of moderate to severe severity;

- hepatic insufficiency of moderate and severe severity;

- Myasthenia gravis (possibly increased symptoms);

- simultaneous reception of clarithromycin with benzodiazepines, such as alprazolam, triazolam, midazolam for intravenous use (see section "Interaction with other medicinal products");

- simultaneous reception with drugs that are metabolized by the isoenzyme CYP3A4, for example, carbamazepine, cilostazol, ciclosporin, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants (for example, warfarin), quinidine, rifabutin, sildenafil, tacrolimus, vinblastine (see the section "Interaction with other medicinal products");

- simultaneous administration with drugs inducing isoenzyme CYP3A4, for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St John's wort (see "Interaction with other medicinal products");

- simultaneous reception with blockers of "slow" calcium channels, which are metabolized by the isoenzyme CYP3A4 (for example, verapamil, amlodipine, diltiazem);

- Patients with coronary heart disease, severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats / min), and patients taking antiarrhythmic drugs of the IA class simultaneously (quinidine, procainamide) and III class (dofetilide, amiodarone, sotalol);

- Pregnancy.

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 potential risk to the fetus and / or there is no safer therapy with alternative drugs.

If pregnancy occurs during the use of the drug, the patient should be warned about possible risks to the fetus.

It is known that clarithromycin is excreted in breast milk. During lactation, the question of abolishing breastfeeding should be addressed.

Dosing and Administration:

Inside, the tablets are taken regardless of food intake.

Adults and children over 12 years of age or with a body weight of more than 33 kg:

- with pharyngitis and tonsillitis caused by Streptococcus pyogenes - 250 mg (1/2 tablet each) for 10 days every 12 hours, with acute sinusitis - 500 mg (1 tablet) for 14 days every 12 hours;

- with exacerbation of chronic bronchitis caused by Haemophilus influenzae - 500 mg (1 tablet) for 7-14 days every 12 hours;

caused by Haemophilus parainfluenzae - 500 mg (1 tablet) for 7 days every 12 hours; caused by Moraxella catarrhalis, Streptococcus pneumoniae - 250 mg (1/2 tablet each) for 7-14 days every 12 hours;

- with community-acquired pneumonia caused by Haemophilus influenzae - 250 mg (1/2 tablet each) for 7 days every 12 hours; caused by Streptococcus pneumoniae, Chlamydia pneumoniae, Mycoplasma pneumoniae - no 250 mg (no 1/2 tablet) for 7-14 days every 12 hours;

- with uncomplicated infections of the skin and subcutaneous tissue caused by Staphylococcns aureus, Streptococcus pyogenes - 250 mg (1/2 tablet each) for 7-14 days every 12 hours.

Adults with the purpose of eradication Helicobacter pylori in combination with other medicines: clarithromycin - 500 mg (1 tablet), lansoprazole - 30 mg and amoxicillin - 1000 mg, all medicines 2 times a day for 10-14 days; clarithromycin - 500 mg (1 tablet), omeprazole - 20 mg and amoxicillin - 1000 mg, all medicines 2 times a day for 10 days; clarithromycin - 500 mg (1 tablet) 3 times a day, omeprazole - 40 mg per day for 14 days, with the appointment of omeprazole for the next 14 days at a dose of 20 mg per day.

In the treatment of infections caused by Mycobacterium avium, appoint or nominate inside on 500 mg (on 1 tablet) 2 times a day. The maximum daily dose is 1000 mg. Duration of treatment - 6 months. and more.

In patients with chronic renal insufficiency (creatinine clearance less than 30 ml / min or a serum creatinine concentration of more than 3.3 mg / 100 ml), the dose is reduced by a factor of 2 or increases the interval by a factor of 2. The maximum duration of treatment in patients of this group is 14 days.

While maintaining normal kidney function patients with moderate or severe hepatic impairment dosage adjustment is not required.

Side effects:

The incidence of side effects listed below was determined according to the following (classification of the World Health Organization): very often (more than 10%), often (more than 1% and less than 10%), infrequently (more than 0.1% and less than 1%), rarely (more than 0.01% and less than 0.1%), very rarely (less than 0.01%), including individual messages, the frequency is unknown (can not be estimated using available data).

Allergic reactions:

Often: skin rash.

Infrequent: hypersensitivity, itching, hives.

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

From the nervous system:

Often: headache, insomnia.

Infrequent: dizziness, drowsiness, tremors, anxiety.

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

From the skin:

Often: intense sweating.

Unknown: acne, purple Shenlaine-Genocha, hemorrhage.

From the urinary system:

Unknown: renal failure, interstitial nephritis.

From the side of metabolism and nutrition:

Infrequent: anorexia, poor appetite.

From the musculoskeletal system:

Unknown: myopathy, increased symptoms of myasthenia gravis.

From the digestive system:

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

Infrequent: gastritis, stomatitis, glossitis, bloating, flatulence, constipation, dry mouth, belching, cholestasis, hepatocellular and cholestatic hepatitis.

Unknown: acute pancreatitis, discoloration of the tongue and teeth, cholestatic jaundice,liver failure.

From the sense organs:

Often: a change in taste (dysgeusia), a taste perversion.

Infrequently: vertigo, hearing impairment, noise and ringing in the ears.

Unknown: hearing loss, agevzia (loss of taste sensations), parosmia (perversion of smell), anosmia (loss of smell).

From the cardiovascular system:

Infrequent: increased QT interval on ECG, atrial flutter. It is unknown: ventricular tachycardia, including "pirouette" type.

Laboratory indicators:

Often: deviation in the hepatic test.

Infrequent: leukopenia, neutropenia, eosinophilia, increased activity in the blood: alanine aminotransferase, aspartate aminotransferase, gamma glutamyltransferase, alkaline phosphatase, lactate dehydrogenase. Unknown: agranulocytosis, thrombocytosis, thrombocytopenia, hypoglycemia, increased INR (international normalized ratio), prolonged prothrombin time, change in urine color, increased bilirubin concentration in the blood.

Infectious and parasitic diseases:

Infrequently: candidiasis.

Unknown: pseudomembranous colitis, erysipelas, erythrasma.

General disorders:

Infrequently: malaise, asthenia, pain in the chest, chills, fatigue.

Patients with depressed immunity

In patients with AIDS and other immunodeficiency 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.

Overdose:

Symptoms: abdominal pain, nausea, vomiting, diarrhea.

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

Interaction:

Simultaneous use of clarithromycin and the following drugs is contraindicated in connection with the possibility of developing serious side effects

Cisapride, pimozide, terfenadine and astemizole

With the joint administration of clarithromycin with cisapride, pimozide, terfenadine, astemisole reported increased plasma concentrations of the latter, which may lead to an increase in the QT interval and the occurrence of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and ventricular pirouette tachycardia (see Contraindications).

Alkaloids of ergot

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 section "Contraindications").

The effect of other drugs on clarithromycin

Preparations that are inducers of CYP3A (for example, 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 monitor the concentration of the SURCA inductor in the blood plasma, which may increase due to the inhibition of CYP3A by clarithromycin. With the combined use of rifabutin and clarithromycin, there was an increase in plasma rifabutin concentration and a decrease in serum concentration of clarithromycin with an increased risk of uveitis. The following drugs have a proven or suspected effect on the concentration of clarithromycinin 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 reduce the concentration of clarithromycin in the plasma and weaken the therapeutic effect, and at the same time increase the concentration of the 14-OH-clarithromycin metabolite, which is also microbiologically active. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin differs with respect to different bacteria, the therapeutic effect may decrease with the combined use of clarithromycin and enzyme inducers.

Etravirine

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

Fluconazole

With the simultaneous administration of fluconazole at a dose of 200 mg daily and clarithromycin at a dose of 1 g / day is possible an increase in Css and AUC of clarithromycin by 33% and 18%, respectively. At the same time, the combined administration did not significantly affect the average equilibrium concentration of the active metabolite of 14-OH-clarithromycin. Correction of the dose of clarithromycin in the case of concurrent administration of fluconazole is not required.

Ritonavir

Joint reception of ritonavir in 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 CmClarithromycin increased by 31%, Css increased by 182% and AUC increased by 77%. A complete suppression of the formation of 14-OH-clarithromycin was noted. 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: in case of creatinine clearance of 30-60 ml / min, the dose of clarithromycin should be reduced by 50%; when creatinine clearance is less than 30 ml / min, the dose of clarithromycin should be reduced by 75%. Ritonavir should not be taken together with clarithromycin in doses exceeding 1 g / day.

Oral hypoglycemic agents and 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 CYP3A isoenzyme with 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. With the simultaneous use of clarithromycin with these drugs, the electrocardiogram should be monitored regularly to increase the QT interval, and the serum concentrations of these drugs should be monitored.

Interactions caused by the isoenzyme CYP3A

The combined use of clarithromycin, which is known to inhibit the CYP3A isoenzyme, and drugs primarily metabolized by the CYP3A isoenzyme, can be associated with a mutual increase in their concentrations, which may enhance or prolong both the therapeutic and side effects. Clarithromycin should be used with caution in patients receiving drugs that are substrates of the 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 serum concentrations of drugs, primarily metabolized by 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 CYP3A agonists are the following drugs that are 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 use of clarithromycin with lovastatin or simvastatin is contraindicated (see "Contraindications") because these statins are heavily metabolized by the CYP3A4 isoenzyme and co-administration with clarithromycin increases their serum concentrations, leading 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 are independent of the metabolism of CYP3A (for example, fluvastatin).

Indirect anticoagulants

With the joint administration of warfarin and clarithromycin, bleeding, a pronounced increase in the international normalized ratio (MNO) and prothrombin time are possible. In the case of combined use with warfarin or other indirect anticoagulants, it is necessary to monitor INR and prothrombin time.

Omeprazole

With the combined use of clarithromycin and omeprazole, an increase in the equilibrium plasma concentration of omeprazole (C_max 5 AUC_0-24 and T_1/2increased 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-5 inhibitors is metabolized, at least in part, by CYP3A. At the same time, 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

The primary metabolism of tolterodine is via the 2D6 cytochrome P450 isoform (CYP2D6). However, in the part of the population devoid of the isoenzyme CYP2D6, the metabolism occurs via CYP3A. In this population group, suppression of CYP3A results in significantly higher serum concentrations of tolterodine. In a population with a low level of metabolism via CYP2D6, a dose reduction of tolterodine in the presence of CYP3A inhibitors, such as clarithromycin.

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

When combined with midazolam and clarithromycin tablets (500 mg twice daily), augmentation of midazolam AUC was noted: 2.7 times after intravenous administration of midazolam and 7 times after oral administration. It is necessary to avoid 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 also apply to other benzodiazepines that are metabolized of CYP3A, including triazolam and alprazolam. For benzodiazepines, the excretion of which does not depend on CYP3A (temazepam, nitrazepam, lorazepam), clinically significant interaction with clarithromycin is unlikely.

When used together, clarithromycin and triazolam possible effects on the central nervous system (CNS), such as 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 for both CYP3A, and transporter proteins, P-glycoprotein (Pgp). It is known that clarithromycin and other macrolides inhibit CYP3A and Pgp. When co-administered clarithromycin and colchicine inhibition of Pgp and / or CYP3A can lead to increased action of colchicine. Clinical symptoms of colchicine poisoning should be monitored, especially in elderly patients and patients with chronic renal failure (fatal cases reported).

In patients with normal renal and hepatic function, a dose of colchicine should be lowered with simultaneous use with clarithromycin. Simultaneous use of clarithromycin and colchicine is contraindicated in patients with impaired liver or kidney function (see section "Contraindications").

Digoxin

It is assumed that digoxin is the substrate of Pgp. It is known that clarithromycin inhibits Pgp. When co-administered with clarithromycin and digoxin, inhibition of Pgp with clarithromycin may lead to an increase in the action of digoxin. The combined use of digoxin and clarithromycin can also lead to an increase in serum digoxin concentration. With the combined use of clarithromycin and digoxin, the concentration of digoxin in the blood serum should be carefully monitored (possibly the development of potentially fatal arrhythmias).

Zidovudine

Simultaneous oral administration of clarithromycin and zidovudine tablets 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.

Phenytoin and valproic acid

There are data on the interactions 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 their increase.

Bi-directional drug interactions

Atazanavir

Clarithromycin and atazanavir are both substrates and inhibitors of 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-OH-clarithromycin by 70%, with an increase in Atazanavir AUC 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 insufficiency (creatinine clearance 30 - 60 ml / min), the dose of clarithromycin should be reduced by 50%.In patients with creatinine clearance less than 30 ml / min, the dose of clarithromycin should be reduced by 75% using the appropriate 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 are metabolized by the isoenzyme CYP3A4 (for example, 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 CYP3A, which determines bi-directional drug interactions. 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 CYP3A, which determines bi-directional drug interactions. With the combined use of clarithromycin (500 mg twice daily) 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, compared with the administration of saquinavir alone. The AUC and Css values of clarithromycin were approximately 40% higher than with clarithromycin monotherapy. When these two drugs are used together for a limited time in the doses / dosage forms mentioned above, dose adjustment is not required.

Special instructions:

Long-term use of antibiotics can lead to the formation of colonies with an increased number of insensitive bacteria and fungi. When superinfection is necessary to appoint appropriate therapy.

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 simultaneous use of other medications. 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 diseases it is necessary to carry out regular monitoring of serum enzymes.

In the treatment of nearly all antibacterial agents, including clarithromycin, described cases of pseudomembranous colitis, the severity of which can range from mild to life-threatening. Antibiotic drugs can change the normal intestinal microflora, which can lead to the growth of C. difficile. Pseudomembranous colitis caused by Clostridium difficile should be suspected in all patients experiencing the appearance of diarrhea after using antibacterial agents. After the course of antibiotic therapy, careful medical supervision of the patient is necessary.Cases of pseudomembranous colitis after 2 months after taking antibiotics were described.

Clarithromycin should be used with caution in patients with coronary heart disease (CHD), severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats / min), and with simultaneous use with antiarrhythmic drugs IA class (quinidine, procainamide) and III class (dofetilide, amiodarone, sotalol). With these conditions and with the simultaneous administration of clarithromycin with these drugs, the electrocardiogram should be monitored regularly to increase the QT interval.

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

Given the increasing resistance of Streptococcus pneumoniae to macrolides, it is important to conduct sensitivity testing in the administration of clarithromycin to patients with community-acquired pneumonia. With hospital pneumonia clarithromycin should be used in combination with appropriate antibiotics. Infections of the skin and soft tissues of mild and moderate severity are most often caused by Staphylococcus aureus and Streptococcus pyogenes.In this case, both pathogens can be resistant to macrolides. Therefore, it is important to carry out a sensitivity test.

Macrolides can be used for infections caused by Corynebacterium minutissimum (erythrasma), diseases acne vulgaris and erysipelas, as well as in those situations where penicillin can not be used.

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-Genoh, immediately stop taking clarithromycin and begin appropriate therapy.

In patients receiving clarithromycin, reported on worsening of myasthenia gravis symptoms.

In the case of joint use with warfarin or other indirect anticoagulants, it is necessary to monitor INR and prothrombin time (see the section "Interaction with other drugs").

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

During the treatment period it is necessary to refrain from driving motor vehicles and practicing potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Tablets, film-coated, 500 mg.

Packaging:

On 7 tablets in a blister of PVC / PVDC film and foil of aluminum printed lacquered, two blisters are placed in a cardboard box together with instructions for use.

Storage conditions:

In a dry, the dark 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:PL-000839

Date of registration:10.10.2011

The owner of the registration certificate:REPLEK FARM Skopje, OOOREPLEK FARM Skopje, OOO Macedonia

Manufacturer: & nbsp

REPLEKPHARM, AD Macedonia

Representation: & nbspREPLECK FARM LTD SCOPJEREPLECK FARM LTD SCOPJERussia

Information update date: & nbsp22.10.2014

Illustrated instructions

Instructions

Clarithromycin (Clarithromycin)