Clarithromycin, 500 mg 7 pcs

A semi-synthetic antibiotic of macrolide group. It has antibacterial effect by interacting with 50S ribosomal subunit of bacteria and inhibiting protein synthesis in the microbial cell.

Clarithromycin has demonstrated high in vitro activity against standard and isolated cultures of bacteria. It is highly effective against many aerobic and anaerobic, Gram-positive and Gram-negative microorganisms. In addition, in vivo and in vitro data indicate that clarithromycin is effective against clinically relevant mycobacterial species. In vitro studies confirm the high efficacy of clarithromycin against Legionella pneumophila, Mycoplasma pneumoniae and Helicobacter pylori. However, Enterobacteriaceae, Pseudomonas spp. and other non-lactose-fermenting Gram-negative microorganisms are immune to clarithromycin.

The activity of clarithromycin against most strains of the microorganisms listed below has been proven in in vitro studies and in clinical practice for the conditions listed under “Indications for use”:

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

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

other microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae (TWAR), Chlamydia trachomatis;

Mycobacteria: Mycobacterium avium complex (MAC): Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum.

The production of β-lactamase has no effect on clarithromycin activity. Most staphylococcal strains resistant to methicillin and oxacillin are also resistant to clarithromycin.

Clarithromycin also has activity in vitro against most strains of the microorganisms listed below (but the safety and efficacy of clarithromycin in clinical practice has not been confirmed in clinical studies, and the practical significance remains unclear):

Aerobic Gram-positive microorganisms: Streptococcus agalactiae, Streptococci (groups C, F, G), Streptococci group Viridans;

Aerobic Gram-negative microorganisms: Bordeteila pertussis, Pasteurella multocida;

anaerobic gram-positive microorganisms: Clostridium perfringens, Peptococcus niger, Propionibacterium acnes;

anaerobic gram-negative microorganisms: Bacteroides melaninogenicus;

spirochetes: Borrelia burgdorferi, Treponema pallidum; Campylobacter: Campylobacter jejuni.

The main metabolite of clarithromycin in humans is the microbiologically active metabolite 14-hydroxyclarithromycin. The microbiological activity of the metabolite is the same as that of the parent substance, or 1-2 times weaker against most microorganisms. The exception is Naemophilus influenzae, against which the effectiveness of the metabolite is 2 times higher. The starting substance and its main metabolite have either additive or synergistic effect against Naemophilus influenzae under in vitro and in vivo conditions depending on the bacterial strain.

Pharmacokinetics

Intake and distribution

In oral administration, clarithromycin is rapidly and actively absorbed in the gastrointestinal tract. Absolute bioavailability is 50%. Food slows down absorption without significantly affecting bioavailability. No cumulation was found when multiple doses of the drug were administered, and the pattern of metabolism in the human body was not altered.

Therapeutic concentrations of Clarithromycin are accumulated in the skin, lungs and soft tissues (where concentrations are 10 times higher than plasma concentrations).

Clarithromycin binds to plasma proteins 70% at concentrations from 0.45 to 4.5 µg/ml. When prolonged-acting clarithromycin is taken orally in dose of 500 mg daily, equilibrium maximum concentrations (Cmax) of clarithromycin and 14-hydroxyclarithromycin in plasma are 1.3 and 0.48 µg/ml, respectively. At a dose of 1000 mg, the Cmax of clarithromycin and 14-hydroxyclarithromycin reached 2.4 µg/ml and 0.67 µg/ml, respectively. The time to reach maximum plasma concentration (TCmax) when taking the prolonged-acting dosage form is 6 hours.

Clarithromycin and 14-hydroxyclarithromycin are well distributed to all tissues and body fluids. After oral administration of clarithromycin, its content in cerebrospinal fluid remains low (with normal HEB permeability 1-2% of serum levels). Its content in tissues is usually several times higher than its content in serum.

Metabolism and excretion

Clarithromycin is metabolized in cytochrome P450 system with participation of CYP3A4, CYP3A5, CYP3A7 isoenzymes to form the main microbiologically active metabolite 14-hydroxyclarithromycin.

In a single dose of 500 mg, the half-lives (T1/2) of the original drug and its main metabolite for the sustained release dosage form of 500 mg were 5.3 hours and 7.7 hours, respectively; in a dose of 1000 mg – 5.8 and 8.9 hours, respectively.

The time of onset of maximum concentration (TCmax) with both 500 mg and 1000 mg doses is approximately 6 hours. At equilibrium, the Cmax of 14-hydroxyclarithromycin does not increase in proportion to clarithromycin doses, whereas the elimination half-lives of both clarithromycin and its main metabolite increase with increasing dose. The nonlinear nature of clarithromycin pharmacokinetics is associated with decreased formation of 14-hydroxylated and N-demethylated metabolites at higher doses, indicating nonlinear metabolism of clarithromycin at high doses.

Extracted by the kidneys and intestines (20-30% unchanged, the rest as metabolites).

Pharmacokinetics in special clinical cases

Hepatic disorders

. In patients with moderate to severe hepatic impairment but with preserved renal function, no adjustment of clarithromycin dose is required; the equilibrium concentrations (Csas) and systemic clearance of clarithromycin do not differ from those of healthy patients. The Cs of 14-hydroxyclarithromycin is lower in people with hepatic impairment than in healthy subjects.

Kidney disease

In patients with impaired renal function, plasma Cmax and Cmin, T1/2, area under the concentration-time curve (AUC) of clarithromycin and 14-hydroxyclarithromycin are increased. The elimination constant and urinary excretion decreases. The degree of change in these parameters depends on the degree of renal impairment.

Elderly patients

In elderly patients, blood concentrations of clarithromycin and 14-hydroxyclarithromycin were higher and excretion slower than in younger adults. Changes in pharmacokinetics in elderly patients are thought to be primarily related to changes in creatinine clearance and renal function rather than to patient age.

HIV infection

The equilibrium concentrations of clarithromycin and 14-hydroxyclarithromycin in patients with HIV infection who received clarithromycin in usual doses (500 mg once daily) were similar to those in healthy subjects. However, when clarithromycin is used in higher doses, concentrations of the antibiotic may be significantly higher than usual. In HIV-infected patients taking clarithromycin at a dose of 1 g/day and 2 g/day in 2 doses, Cmax was typically 2-4 mcg/ml and 5-10 mcg/ml, respectively. When using the drug in higher doses, a prolongation of the T1/2 was observed compared to that in healthy subjects receiving clarithromycin in usual doses. The increased plasma concentrations and longer half-life with higher doses of clarithromycin are consistent with the known non-linearity of the drug’s pharmacokinetics.

Indications

Infectious and inflammatory diseases caused by microorganisms sensitive to the drug:

– infections of the upper respiratory tract and ENT organs (pharyngitis, sinusitis);

– lower respiratory tract infections (bronchitis, community-acquired pneumonia);

– skin and soft tissue infections (such as folliculitis, inflammation of the subcutaneous tissue, rust).

Active ingredient

Composition

Active ingredient: clarithromycin – 500.00 mg.

Excipients:

Hypromellose (hydroxypropyl methylcellulose 6 cPs) – 13.57 mg,

hypromellose (hydroxypropyl methylcellulose 100 cPs) – 266.48 mg,

Lactose monohydrate – 176.36 mg,

Colloidal silicon dioxide – 4.84 mg,

Magnesium stearate – 7.75 mg.

The shell: Aquarius Preferred HSP BPP314073 Yellow [hypromellose (hydroxypropyl methylcellulose 6 cPs) – 5.225 mg, copovidone – 3.990 mg, polydextrose – 2.660 mg, macrogol-3350 (polyethylene glycol-3350) – 1,805 mg, medium-chain triglycerides – 0.570 mg, titanium dioxide – 3.665 mg, quinoline yellow dye – 1.064 mg, iron oxide yellow dye – 0.019 mg, aluminum blue dye (FD&C Blue No. 1 Aluminum Lake (11-13%) – 0.002 mg] – 19.00 mg.

How to take, the dosage

The tablets should be taken orally with meals. The tablets should not be crushed or chewed, they should be swallowed whole.

Adults and children over 12 years of age: 1 tablet (500 mg) once daily with a meal. In severe cases the dose is increased to 2 tablets (1000 mg) once a day with meals. The duration of treatment is usually 5-14 days. Exceptions are community-acquired pneumonia and sinusitis, which require 6 to 14 days of treatment.

Interaction

Concomitant administration of clarithromycin increases blood concentrations of drugs metabolized in the liver by cytochrome P450 isoenzymes (CYP3A), their concentrations may increase mutually, which may increase or prolong both therapeutic and side effects. Co-administration with such drugs as astemizole, cisapride, pimozide, terfenadine, ergotamine, dihydroergotamine, alprazolam, midazolam, triazolam (oral dosage forms), simvastatin, lovastatin is contraindicated due to the possibility of serious side effects (see “Contraindications”).

Cyzapride and pimozide

When used concomitantly the following is possible: increase in cisapride concentration, prolongation of QT interval, occurrence of cardiac arrhythmias, including ventricular tachycardia, including pirouette type, ventricular fibrillation.

Terfenadine and astemizole

When used concomitantly the following is possible: increase in terfenadine/astemizole blood concentration, occurrence of cardiac arrhythmias, QT interval prolongation, ventricular tachycardia, ventricular fibrillation and pirouette tachycardia.

Ergotamine/dihydroergotamine

When used together, the following effects associated with acute poisoning with drugs of the ergotamine group are possible: vascular spasm, ischemia of the extremities and other tissues, including the central nervous system.

The effect of other drugs on clarithromycin

Drugs that are inducers of the CYP3A isoenzyme (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort) may induce the metabolism of clarithromycin. This can lead to subtherapeutic concentrations of clarithromycin, resulting in decreased efficacy. In addition, plasma concentration of CYP3A isoenzyme inducer should be monitored, which may increase due to inhibition of CYP3A isoenzyme inducer by clarithromycin. When rifabutin and clarithromycin were used together, there was an increase in plasma concentrations and a decrease in serum concentrations of clarithromycin with an increased risk of uveitis.

The following drugs have proven or suspected effects on plasma concentrations of clarithromycin; doses may need to be adjusted or alternative treatment may be necessary if they are used with clarithromycin.

Efavirenz, nevirapine, rifampicin, rifabutin and rifapentin

. Strong cytochrome P450 inducers such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentine can accelerate the metabolism of clarithromycin and thus decrease the plasma concentration of clarithromycin and weaken its therapeutic effect, and at the same time increase the concentration of 14-OH clarithromycin, a metabolite that is also microbiologically active. Since microbiological activity of clarithromycin and 14-OH clarithromycin differs in respect to different bacteria, the therapeutic effect may be reduced when clarithromycin and enzyme inducers are used together.

Etravirine

The concentration of clarithromycin is decreased with etravirine, but the concentration of the active metabolite 14-OH-clarithromycin is increased. Because 14-OH clarithromycin has low activity against Mycobacterium avium complex (MAC) infections, the overall activity against their pathogens may change, so alternative treatments should be considered for MAC treatment.

Fluconazole

The co-administration of fluconazole at a dose of 200 mg daily and clarithromycin at a dose of 500 mg twice daily in 21 adult volunteers resulted in a 33% and 18% increase in the minimum average equilibrium concentration (Csas) and AUC of clarithromycin, respectively. However, co-administration had no significant effect on the mean equilibrium concentration of the active metabolite 14-OH clarithromycin. Dose adjustment of clarithromycin in case of concomitant administration of fluconazole is not required.

Ritonavir

The co-administration of ritonavir 600 mg/day and clarithromycin 1 g/day may decrease the metabolism of clarithromycin (increase Cmax by 31 %, Cmin by 182 % and AUC by 77 %), complete inhibition of 14-hydroxyclarithromycin formation. Due to the wide therapeutic range, no dosage reduction is required in patients with normal renal function. In patients with renal impairment, it is reasonable to consider the following dose adjustments: if creatinine clearance is 30-60 ml/min, the dose of clarithromycin should be reduced by 50%. Ritonavir should not be coadministered with clarithromycin in doses greater than 1 g per day.

Peroral antidiabetic agents/insulin

The concomitant use of clarithromycin and oral antidiabetic agents and/or insulin may lead to severe hypoglycemia. Concomitant use of clarithromycin with some oral antidiabetic drugs such as nateglinide, pioglitazone, repaglinide, rosiglitazone due to inhibition of CYP3A isoenzyme by clarithromycin may cause hypoglycemia. Close monitoring of blood glucose concentrations is recommended.

The effect of clarithromycin on other drugs

Antirhythmic drugs (quinidine and disopyramide)

Ventricular pirouette tachycardia may occur when combined with quinidine or disopyramide. If clarithromycin is concomitantly used with these drugs, the electrocardiogram should be monitored regularly to determine whether the QT interval is prolonged, and the serum concentrations of these drugs should be monitored.

CYP3A4 interactions

The co-administration of clarithromycin, which is known to inhibit the CYP3A enzyme, and drugs primarily metabolized by the CYP3A isoenzyme may be associated with a mutual increase in their concentrations, which may enhance or prolong both therapeutic and adverse effects. Clarithromycin should be used with caution in patients receiving drugs that are substrates of CYP3A isoenzyme, especially if these drugs have a narrow therapeutic range (for example: carbamazepine), and/or are extensively metabolized by this enzyme. Dose adjustments should be made if necessary for drugs taken together with clarithromycin. The serum concentrations of drugs primarily metabolized by CYP3A isoenzyme should also be monitored if possible.

. The following drugs/classes are metabolized by the same CYP3A isoenzyme as clarithromycin, such as alprazolam, carbamazepine, cilostazol, cyclosporine, disopyramide, methylprednisolone, midazolam, omeprazole, indirect anticoagulants (e.g., warfarin), quinidine, rifabutin, sildenafil, tacrolimus, triazolam and vinblastine. CYP3A agonists also include the following drugs that are contraindicated for co-administration with clarithromycin: astemizole, cisapride, pimozide, terfenadine, lovastatin, simvastatin and ergot alkaloids (see section “Contraindications”). Drugs that interact similarly through other isoenzymes within the cytochrome P450 system include phenytoin, theophylline and valproic acid.

HMG-CoA reductase inhibitors

The co-administration of clarithromycin with lovastatin or simvastatin is contraindicated (see “Contraindications.

Co-administration of lovastatin or simvastatin is contraindicated (see section “Contraindications”) due to the fact that these statins are significantly metabolized by CYP3A4 isoenzyme and co-administration with clarithromycin increases their serum concentrations, which leads to increased risk of myopathy, including rhabdomyolysis. Rare cases of rhabdomyolysis have been reported in patients taking these drugs together. If clarithromycin is required, lovastatin or simvastatin should be discontinued during therapy.

Clarithromycin should be used with caution when combined therapy with statins. If co-administration is necessary, it is recommended to take the lowest dose of statin. Statins that are not dependent on CYP3A isoenzyme metabolism (e.g.: fluvastatin) should be used.

Peroral anticoagulants

There is a risk of serious bleeding and significantly increased prothrombin time when clarithromycin and warfarin are used concomitantly. If patients receive clarithromycin and oral anticoagulants concomitantly, prothrombin time and INR should be monitored closely.

Omeprazole

The co-administration of clarithromycin and omeprazole may increase equilibrium plasma concentrations of omeprazole (Cmax, AUC0-24, T1/2 by 30%, 89%, and 34%, respectively).

Sildenafil, tadalafil and vardenafil

Each of these phosphodiesterase inhibitors is metabolized at least in part with CYP3A. At the same time, the CYP3A isoenzyme may be inhibited in the presence of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil may lead to increased inhibitory effects on phosphodiesterase. A reduction in the dose of sildenafil, tadalafil, and vardenafil should be considered when prescribing these drugs together.

Theophylline, carbamazepine

Theophylline or carbamazepine may increase concentration in systemic blood flow.

Tolterodine

The primary metabolism of tolterodine is through the 2D6 isoform of cytochrome P450 (CYP2D6). However, in a portion of the population lacking the CYP2D6 isoenzyme, metabolism occurs via CYP3A. In this population, suppression of the CYP3A isoenzyme leads to significantly higher serum concentrations of tolterodine. In a population with low levels of metabolism via the CYP2D6 isoenzyme, a dose reduction of tolterodine in the presence of CYP3A isoenzyme inhibitors such as clarithromycin may be required.

Triazolobenzodiazepines (e.g.: alprazolam, midazolam, triazolam)

The co-administration of clarithromycin (500 mg twice daily) may increase the AUC of midazolam: 7-fold after oral administration and 2.7-fold after intravenous administration. Co-administration of midazolam and clarithromycin should be avoided. If intravenous form of midazolam is used together with clarithromycin, the patient’s condition should be closely monitored for possible dose adjustment. The same precautions should be applied to other benzodiazepines that are metabolized by the CYP3A isoenzyme, including triazolam and alprazolam. For benzodiazepines whose excretion is not dependent on CYP3A (temazepam, nitrazepam, lorazepam), a clinically significant interaction with clarithromycin is unlikely.

When clarithromycin and triazolam are used together, central nervous system (CNS) effects such as drowsiness and confusion are possible. Therefore, it is recommended to monitor for CNS disturbance symptoms if used together.

Interaction with other drugs

Colchicine

Colchicine is a substrate of both CYP3A and the carrier protein responsible for drug excretion, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. If clarithromycin and colchicine are coadministered, inhibition of Pgp and/or CYP3A may enhance the effects of colchicine. It is necessary to control the possible development of clinical symptoms of colchicine intoxication, especially in elderly patients and patients with chronic renal failure (fatal cases have been reported). In patients with normal renal and hepatic function, the dose of colchicine should be reduced when used concomitantly with clarithromycin.

The concomitant use of clarithromycin and colchicine is contraindicated in patients with impaired hepatic or renal function (see section “Contraindications”).

Digoxin

Digoxin is believed to be a substrate of Pgp. Clarithromycin is known to inhibit Pgp. When digoxin and clarithromycin are coadministered, the inhibition of Pgp by clarithromycin may enhance the effects of digoxin. Concomitant administration of digoxin and clarithromycin may also result in increased serum concentrations of digoxin. Significant clinical symptoms of digoxin poisoning, including potentially fatal arrhythmias, have been reported in some patients. Serum digoxin concentrations should be closely monitored when clarithromycin and digoxin are coadministered.

Zidovudine

The concomitant oral administration of clarithromycin and zidovudine in HIV-infected adults may decrease the equilibrium concentration of zidovudine.

Because clarithromycin affects oral absorption of zidovudine, interactions can be largely avoided by taking clarithromycin and zidovudine 4 hours apart.

This type of interaction does not occur in HIV-infected children receiving clarithromycin in suspension form with zidovudine or dideoxynosine. Because clarithromycin can interfere with the absorption of zidovudine when taken orally at the same time in adult patients, this interaction is unlikely to occur with intravenous clarithromycin.

Phenytoin and valproic acid

There are data on interactions of CYP3A inhibitors (including clarithromycin) with drugs that are not metabolized by CYP3A (phenytoin and valproic acid). For these drugs, when combined with clarithromycin, determination of their serum concentrations is recommended, since there are reports of elevated concentrations.

Bidirectional drug interactions

Atazanavir

Clarithromycin and atazanavir are both CYP3A substrates and inhibitors. There is evidence of a bidirectional interaction between these drugs. Co-administration of clarithromycin (500 mg twice daily) and atazanavir (400 mg once daily) may result in a two-fold increase in exposure of clarithromycin and a 70% decrease in 14-OH clarithromycin, with a 28% increase in AUC of atazanavir. Due to the wide therapeutic range of clarithromycin, no dose reduction is required in patients with normal renal function. In patients with moderate renal impairment (creatinine clearance 30-60 ml/min) the dose of clarithromycin should be reduced by 50%. In patients with CKR less than 30 ml/min, the clarithromycin dose should be reduced by 75% using an appropriate clarithromycin dosage form. Clarithromycin in doses greater than 1000 mg per day should not be coadministered with protease inhibitors.

Slow calcium channel blockers

Care should be taken with clarithromycin and slow calcium channel blockers that are metabolized by CYP3A4 (e.g.: verapamil, amlodipine, diltiazem) simultaneously because of the risk of arterial hypotension. Plasma concentrations of clarithromycin, as well as of “slow” calcium channel blockers may increase with concomitant use. Arterial hypotension, bradyarrhythmia and lactoacidosis are possible with concomitant use of clarithromycin and verapamil.

The co-administration of clarithromycin may cause decreased blood pressure, bradyarrhythmia, and lactic acidosis.

Itraconazole

Clarithromycin and itraconazole are substrates and inhibitors of CYP3A isoenzyme, which determines the bidirectional interaction of the drugs. Clarithromycin may increase the plasma concentration of itraconazole, while itraconazole may increase the plasma concentration of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be carefully examined for symptoms of increased or prolonged duration of pharmacological effects of these drugs.

Saquinavir

Clarithromycin and saquinavir are substrates and inhibitors of CYP3A isoenzyme, which determines the bidirectional interaction of the drugs. Co-administration of clarithromycin (500 mg 2 times daily) and saquinavir (in soft gelatin capsules, 1200 mg 3 times daily) may increase AUC and Cs of saquinavir by 177 and 187%, and of clarithromycin – by 40%. No dose adjustments are required when these two drugs are used together for a limited time and in the doses/compounds indicated above. The results of drug interaction studies with saquinavir monotherapy may not correspond to the effects observed with saquinavir/ritonavir therapy. The potential effects of ritonavir on clarithromycin should be considered when taking saquinavir together with ritonavir.

Darunavir

In patients with a CKR less than 30 mL/min, the dose of clarithromycin should be reduced by 75% using an appropriate form of clarithromycin.

Special Instructions

Most strains of staphylococci resistant to methicillin and oxacillin are resistant to clarithomycin. Prolonged use of antibiotics can lead to colonies with increased numbers of insensitive bacteria and fungi. Appropriate therapy should be administered if superinfection occurs.

When using clarithromycin, cases of liver dysfunction (increased concentration of hepatic enzymes in the blood, hepatocellular and/or cholestatic hepatitis with or without jaundice) have been reported. Liver dysfunction can be severe, but is usually reversible. There are cases of hepatic failure with fatal outcome, mainly associated with the presence of serious comorbidities and/or concomitant use of other drugs. In case of signs and symptoms of hepatitis, such as anorexia, jaundice, darkened urine, itching, abdominal pain on palpation, clarithromycin therapy should be stopped immediately.

In the presence of chronic liver disease, serum enzymes should be monitored regularly.

When treated with almost all antibacterial agents, including clarithromycin, there have been described cases of pseudomembranous colitis, the severity of which may vary from mild to life-threatening. Antibacterials can alter the normal gut flora, which can lead to growth of Clostridium difficile. Pseudomembranous colitis caused by Clostridium difficile should be suspected in all patients who experience diarrhea after antibiotic use. After a course of antibiotic therapy, careful medical follow-up of the patient is necessary. Cases of pseudomembranous colitis have been described 2 months after antibiotic treatment.

Clarithromycin should be used with caution in patients with CHD, severe heart failure, hypomagnesemia, severe bradycardia (less than 50 bpm), and concomitant use with antiarrhythmic drugs of class IA (quinidine, procainamide) and class III (dofetilide, amiodarone, sotalol). In these conditions and when concomitant use of the drug with these drugs, ECG monitoring for QT interval prolongation should be performed regularly.

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

In view of the increasing resistance of Streptococcus pneumoniae to macrolides, it is important to perform sensitivity testing when prescribing clarithromycin to patients with community-acquired pneumonia. In hospital pneumonia, clarithromycin should be used in combination with appropriate antibiotics.

Mild to moderate skin and soft tissue infections are most commonly caused by Staphylococcus aureus and Streptococcus pyogenes. Both pathogens may be resistant to macrolides. Therefore, it is important to test for sensitivity.

In long-term or repeated use of the drug it is possible to develop superinfection (growth of insensitive bacteria and fungi). If secondary infection occurs, adequate therapy should be prescribed.

Macrolides can be used in infections caused by Corynebacterium minutissimum (erythrazma), common acne and rye, and in situations where penicillin cannot be used.

In case of acute hypersensitivity reactions such as anaphylactic reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), clarithromycin should be stopped immediately and appropriate therapy should be started.

In case of concomitant use with warfarin or other indirect anticoagulants, MHO and prothrombin time should be monitored (see section “Interaction with other medicinal products”).

When using clarithromycin concomitantly with oral antidiabetic drugs, close monitoring of glucose levels is recommended.

Influence on driving and operating ability

Perhaps caution should be exercised when driving vehicles and engaging in other potentially dangerous activities, as some of clarithromycin side effects, such as dizziness, somnolence, may adversely affect the ability to drive and perform potentially dangerous activities that require increased concentration and rapid psychomotor reactions. In case of occurrence of the described adverse effects one should refrain from performing the specified activities.

Synopsis

Contraindications

– hypersensitivity to clarithromycin and other components of the drug, as well as hypersensitivity to other antibiotics of the macrolide group;

– concomitant use of clarithromycin with the following drugs: astemizole, cisapride, pimozide, terfenadine, ergot alkaloids (e.g., ergotamine, dihydroergotamine), oral midazolam (see “

– concomitant administration of clarithromycin with HMG-CoA reductase inhibitors (statins) that are largely metabolized by the CYP3A4 isoenzyme (lovastatin, simvastatin), due to an increased risk of myopathy, including rhabdomyolysis;

– concomitant use of colchicine in patients with hepatic and/or renal dysfunction;

– concomitant use of P-glycoprotein inhibitors or potent inhibitors of CYP3A4 isoenzyme;

– patients with a history of QT interval prolongation or ventricular arrhythmias, including polymorphic ventricular tachycardia (“torsade de pointes”);

p> – severe renal impairment (creatinine clearance less than 30 mL/min), concomitant use of clarithromycin with ticagrelor or ranolazine;

– severe hepatic impairment concomitant with renal impairment;

– cholestatic jaundice/hepatitis with clarithromycin (history);

– porphyria;

– hypokalemia (risk of QT interval prolongation);

– lactation (breastfeeding) period;

– Children under 12 years of age (efficacy and safety not established);

– lactose intolerance, lactase deficiency, glucose-galactose malabsorption.

With caution

– moderate renal failure;

– moderate to severe hepatic failure;

– CHD, severe heart failure, significant bradycardia (less than 50 bpm);

– concomitant administration of clarithromycin with other ototoxic agents, particularly aminoglycosides;

– concomitant administration of clarithromycin with statins that are independent of CYP3A isoenzyme metabolism (e.g., fluvastatin);

– concomitant administration with benzodiazepines such as alprazolam, triazolam, midazolam for intravenous use;

– concomitant administration with drugs that are metabolized by the CYP3A4 isoenzyme, such as carbamazepine, cilostazol, cyclosporine, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants (eg: warfarin), quinidine, rifabutin, sildenafil, tacrolimus, vinblastine;

– concomitant administration with drugs that induce the CYP3A4 isoenzyme (e.g: rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort);

– concomitant administration with “slow” calcium channel blockers that are metabolized by CYP3A4 isoenzyme (e.g: verapamil, amlodipine, diltiazem);

– simultaneous use of antiarrhythmic drugs of class IA (quinidine, procainamide) and class III (dofetilide, amiodarone, sotalol);

– hypomagnesemia;

– pregnancy.

Side effects

The adverse effects are presented according to the effects on organs and systems.

The adverse events reported with clarithromycin listed below are distributed according to the frequency of occurrence according to the following gradation: Very common (≥ 1/10), common (≥ 1/100 to 1/10), infrequent (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), unspecified frequency (cannot be calculated from available data).

In each group, adverse effects are presented in decreasing order of severity.

Infectious and parasitic diseases: infrequent – candidiasis, gastroenteritis; unspecified frequency – rye, erythrasm, pseudomembranous colitis. As with the use of other antibacterial drugs, secondary infections (including vaginal) are also possible.

The blood and lymphatic system: rare – leukopenia, eosinophilia, neutropenia; unspecified frequency – agranulocytosis, thrombocytopenia.

Intrinsic system disorders: infrequent – allergic reactions (urticaria, skin itching, maculopapular rash, skin hyperemia); unspecified frequency – anaphylactic reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis – Lyell syndrome (potentially life-threatening), drug rash with eosinophilia and systemic symptomatology (DRESS syndrome).

Mental disorders: infrequent – anxiety, somnolence; unspecified frequency – confusion, depersonalization, depression, disorientation, hallucinations, psychotic disorders, “nightmare” dreams, mania.

Nervous system disorders: frequently – headache, insomnia; infrequently – dizziness, tremor; unspecified frequency – paresthesias, seizures.

Senses: frequently – dysgeusia (perversion of taste); infrequently – vertigo, hearing loss, tinnitus; unspecified frequency – hearing loss that resolves after discontinuation of the drug, avgasia, parosmia, anosmia.

Cardiovascular system: common: vasodilation; infrequent: prolongation of QT interval on ECG (as with other macrolides), atrial flutter; unspecified frequency: ventricular tachycardia, including “torsade de pointes” type.

Respiratory system, thorax and mediastinum: infrequent – asthma, pulmonary embolism, nasal bleeding.

Gastro-intestinal tract disorders: frequent – nausea, abdominal pain, dyspepsia; infrequent – vomiting, diarrhea, glossitis, stomatitis, bloating, constipation, belching, flatulence, dry oral mucosa, gastroesophageal reflux disease, gastritis, proctalgia; unspecified frequency – acute pancreatitis, discolored teeth and tongue.

Hepatic and biliary tract disorders: infrequent – cholestasis, hepatocellular and cholestatic hepatitis; very rare – in single cases there were registered facts of death from liver failure, which were usually observed in presence of serious concomitant diseases and/or concurrent use of other medicines; unspecified frequency – cholestatic jaundice.

Skin and subcutaneous tissue: often – intense sweating; unspecified frequency – acne, hemorrhages.

Muscular system and connective tissue: infrequent – myalgia, muscle spasm; unspecified frequency – myopathy.

Renal and urinary tract disorders: unspecified frequency – renal failure, interstitial nephritis.

Metabolism and nutrition: infrequent – anorexia, decreased appetite.

Laboratory measures: frequent – increase of “liver” enzymes activity; infrequent – increase of creatinine concentration, hypoglycemia (including in concurrent use of hypoglycemic agents), increase of alkaline phosphatase activity; unspecified frequency – increase of International normalized ratio value, prolongation of prothrombin time, increase of bilirubin.

General disorders: infrequent – asthenia, chest pain, chills, fatigue, malaise, hyperthermia.

Patients with suppressed immunity

In patients with AIDS and other immunodeficiencies who receive clarithromycin at higher doses for long term treatment of mycobacterial infections, it is often difficult to distinguish adverse effects of the drug from symptoms of HIV infection or a concomitant disease.

The most common adverse events in patients taking a daily dose of clarithromycin equal to 1000 mg were: nausea, vomiting, perversion of taste, abdominal pain, diarrhea, rash, flatulence, headache, constipation, hearing disorders, and increased activity of “liver” enzymes in blood. There have also been cases of adverse events with low frequency of occurrence, such as dyspnea, insomnia, and dry mouth.

In patients with suppressed immunity, laboratory parameters were evaluated by analyzing their significant deviations from the norm (sharp increase or decrease). Based on this criterion, 2-3% of patients who received clarithromycin at a dose of 1000 mg daily registered a significant increase in blood ALT and AST activity, as well as a decrease in leukocyte and platelet counts. A small number of patients also registered an increase in residual urea nitrogen concentration.

Overdose

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

Treatment: gastric lavage, symptomatic therapy. Hemodialysis and peritoneal dialysis have no significant effect on serum concentrations of clarithromycin, as is common with other macrolide drugs.

Pregnancy use

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