Clarithromycin prolonged pills 500mg, 7pcs

Composition

Active ingredient: clarithromycin-500.00 mg.

Auxiliary substances:

hypromellose (hydroxypropylmethylcellulose 6 sPz) – 13.57 mg,

hypromellose (hydroxypropylmethylcellulose 100 sPz) – 266.48 mg,

lactose monohydrate-176.36 mg,

colloidal silicon dioxide-4.84 mg,

magnesium stearate-7.75 mg.

Shell: Aquarius Preferred HSP BPP314073 Yellow (Aquarius Preferred HSP BPP314073 Yellow) [hypromellose (hydroxypropyl methylcellulose 6 SDR) – 5,225 mg copovidon – 3,990 mg, Polydextrose – 2,660 mg, macrogol-3350 (peg-3350) – 1,805 mg, triglycerides medium-chain – 0,570 mg, titanium dioxide – 3,665 mg, dye quinoline yellow lacquer – 1,064 mg, dye iron oxide yellow – 0,019 mg, lacquer aluminum blue (FD & C Blue No. 1 Aluminum Lake (11-13%) – 0.002 mg] – 19,00 mg.

Pharmacological action

Semisynthetic antibiotic of the macrolide group. It has an antibacterial effect by interacting with the 50S ribosomal subunit of bacteria and suppressing protein synthesis in the microbial cell.

Clarithromycin showed high activity in vitro against standard and isolated bacterial cultures. Highly effective against many aerobic and anaerobic, gram-positive and gram-negative microorganisms. In addition, in vivo and in vitro data indicate that clarithromycin acts on clinically significant mycobacterium 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 following microorganisms has been proven in in vitro studies and in clinical practice in diseases listed in the section “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.

Beta-lactamase production does not affect the activity of clarithromycin. Most strains of staphylococci that are resistant to methicillin and oxacillin are also resistant to clarithromycin.

Clarithromycin also has an in vitro effect on most strains of the microorganisms listed below (however, the safety and efficacy of clarithromycin in clinical practice has not been confirmed by clinical studies, and the practical significance remains unclear):  

aerobic gram-positive microorganisms: Streptococcus agalactiae, streptococci (groups C, F, G), streptococci of the Viridans group;

aerobic gram-negative microorganisms: Bordeteila pertussis, Pasteurella multocida;

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

anaerobic gram-negative microorganisms: 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. 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 Hemophilus influenzae, for which the effectiveness of the metabolite is 2 times higher. The parent substance and its main metabolite have either an additive or synergistic effect against Haemophilus influenzae in vitro and in vivo, depending on the bacterial strain.

Pharmacokinetics

Suction and distribution

When taken orally, clarithromycin is rapidly and actively absorbed in the gastrointestinal tract. Absolute bioavailability is 50%. Food slows down absorption without significantly affecting bioavailability. With repeated use of the drug dose, no accumulation was detected, and the nature of metabolism in the human body did not change.

Clarithromycin in therapeutic concentrations accumulates in the skin, lungs and soft tissues (in them concentrations are 10 times higher than plasma).

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

Clarithromycin and 14-hydroxyclarithromycin are well distributed in all tissues and body fluids. After oral use of clarithromycin, its content in the cerebrospinal fluid remains low (with normal BBB permeability of 1-2% of the blood serum level). The content in tissues is usually several times higher than its content in blood serum.

Metabolism and elimination

Clarithromycin is metabolized in the cytochrome P 450 system with the participation of CYP3A4, CYP3A5, and CYP3A7 isoenzymes to form the main microbiologically active metabolite 14-hydroxyclarithromycin.

When taking a single dose of 500 mg, the half-lives (T1 / 2) of the initial drug and its main metabolite for the long-acting dosage form at a dose of 500 mg were 5.3 hours and 7.7 hours, respectively; at a dose of 1000 mg – 5.8 and 8.9 hours, respectively.

The time of onset of the maximum concentration (TMAX) when taking both 500 mg and 1000 mg is approximately 6 hours. At steady state, the Cmax of 14-hydroxyclarithromycin does not increase in proportion to the dose of clarithromycin, while the half-lives of both clarithromycin and its main metabolite increase with increasing dose. The non-linear nature of clarithromycin pharmacokinetics is associated with a decrease in the formation of 14-hydroxylated and N-demethylated metabolites at higher doses, which indicates a non-linear metabolism of clarithromycin at high doses.

It is excreted by the kidneys and intestines (20-30% in unchanged form, the rest in the form of metabolites).

Pharmacokinetics in special clinical cases

of liver disease

In patients with moderate to severe hepatic impairment, but with preserved renal function, no dose adjustment of clarithromycin is required, and the steady-state concentrations (Sss) and systemic clearance of clarithromycin do not differ from these indicators in healthy patients. The Csss of 14-hydroxyclarithromycin in people with impaired liver function is lower than in healthy people.

Kidney diseases

In patients with impaired renal function, Cmax and Cmin in blood plasma, T 1/2, the area under the concentration-time curve (AUC) of clarithromycin and 14-hydroxyclarithromycin increases. The elimination constant and urinary excretion are reduced. The degree of changes in these parameters depends on the degree of impaired renal function.

Elderly patients

In elderly patients, the concentration of clarithromycin and 14-hydroxyclarithromycin in the blood was higher, and excretion was slower than in young people. It is believed that changes in pharmacokinetics in elderly patients are primarily associated with changes in creatinine clearance and renal function, and not with the age of patients.

HIV infection

The steady-state concentrations of clarithromycin and 14-hydroxyclarithromycin in HIV-infected patients treated with clarithromycin at normal doses (500 mg 1 time per day) were similar to those in healthy people. However, when using clarithromycin in higher doses, the antibiotic concentrations may significantly exceed the usual ones. In patients with HIV infection who received clarithromycin at a dose of 1 g/day and 2 g/day in 2 doses, Cmax was usually 2-4 mcg / ml and 5-10 mcg/ml, respectively. When using the drug in higher doses, there was an elongation of T 1/2 compared to that in healthy people who received clarithromycin in normal doses. The increase in plasma concentrations and the duration of the elimination half-life when clarithromycin is administered at higher doses is consistent with the known non-linearity of the drug’s pharmacokinetics..

Indications

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

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

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

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

Use during pregnancy and lactation

The safety of clarithromycin use in pregnant and lactating women has not been established.The use of the drug during pregnancy (especially in the First trimester) is possible only if there are clear indications and only if the intended 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 period of use of the drug, the patient should be warned about possible risks to the fetus. It is known that clarithromycin penetrates into breast milk, so if it is necessary to use it during lactation, the question of discontinuing breastfeeding should be decided.

Contraindications

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

– concomitant use of clarithromycin with the following drugs: astemizole, cisapride, pimozide, terfenadine, ergot alkaloids (eg, ergotamine, dihydroergotamine), midazolam for oral use (see “Interaction with other medicines”);

– concomitant use of clarithromycin with inhibitors of HMG-COA reductase (statins), which are largely metabolized by CYP3A4 (lovastatin, simvastatin), in connection with the increased risk of myopathy, including rhabdomyolysis;

– concomitant use of colchicine in patients with impaired liver function and/or kidney;

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

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

– severe renal insufficiency (creatinine clearance less than 30 ml/min), concomitant use of clarithromycin with ticagrelor or ranolazine;

– severe liver failure, occurring simultaneously with renal insufficiency;

– cholestatic jaundice/hepatitis encountered in the application of clarithromycin (in the anamnesis);

– porphyria;

– hypokalaemia (risk of QT interval prolongation);

– lactation period (breastfeeding);

– children’s age up to 12 years (effectiveness and safety not established);

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

With caution

– moderate renal failure; 

– moderate to severe liver failure; 

– IHD, severe heart failure, severe bradycardia (less than 50 beats / min);

– concomitant use of clarithromycin with other ototoxic drugs, especially aminoglycosides; 

– concomitant use of clarithromycin with statins, independent of the isoenzyme CYP3A metabolism (e. g. fluvastatin);

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

– simultaneous use of drugs that are metabolized by CYP3A4, such as, carbamazepine, Cilostazol, cyclosporine, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants (e. g. warfarin), quinidine, rifabutin, sildenafil, tacrolimus, vinblastine;

– simultaneous use of drugs that induce CYP3A4 (e. g. rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort);

– simultaneous reception of blockers “slow” calcium channels, which are metabolized by CYP3A4 (e. g. verapamil, amlodipine, diltiazem);

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

– hypomagnesemia;

– pregnancy.

Side effects

Side effects are presented depending on the effect on organs and organ systems.

The following adverse events reported with clarithromycin are classified according to the frequency of occurrence according to the following gradation: very common (≥ 1/10), common (≥ 1/100 to 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare ( 

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

Infectious and parasitic diseases: infrequently-candidiasis, gastroenteritis; unspecified frequency-erysipelas, erythrasma, pseudomembranous colitis. As with other antibacterial drugs, secondary infections ( including vaginal infections) are also possible.

From the blood and lymphatic system: rarely-leukopenia, eosinophilia, neutropenia; unspecified frequency-agranulocytosis, thrombocytopenia.

From the immune system: infrequently-allergic reactions (urticaria, pruritus, maculopapular rash, skin hyperemia); unspecified frequency – anaphylactic reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis – Lyell’s syndrome (potentially life-threatening), drug rash with eosinophilia and systemic symptoms (DRESS-syndrome).

Mental disorders: infrequently-anxiety, drowsiness; unspecified frequency-confusion, depersonalization, depression, disorientation, hallucinations, psychotic disorders, “nightmare” dreams, mania.

From the nervous system: often-headache, insomnia; infrequently-dizziness, tremor; unspecified frequency-paresthesia, convulsions.

From the sensory organs: often-dysgeusia (perversion of taste); infrequently-vertigo, hearing impairment, tinnitus; unspecified frequency-hearing loss that passes after discontinuation of the drug, avgesia, parosmia, anosmia.

From the cardiovascular system: often-vasodilation; infrequently-prolongation of the QT interval on the ECG (as with other macrolides), atrial flutter; unspecified frequency-ventricular tachycardia, including the “pirouette” type (“torsade de pointes”).

Respiratory, thoracic and mediastinal disorders: infrequently-asthma, pulmonary embolism, nosebleeds.

From the gastrointestinal tract: often – nausea, abdominal pain, dyspepsia; infrequently-vomiting, diarrhea, glossitis, stomatitis, bloating, constipation, belching, flatulence, dry mouth, gastroesophageal reflux disease, gastritis, proctalgia; unspecified frequency-acute pancreatitis, discoloration of teeth and tongue.

From the liver and biliary tract: infrequently-cholestasis, hepatocellular and cholestatic hepatitis; very rarely-in isolated cases, deaths from liver failure were recorded, which were usually observed in the presence of serious concomitant diseases and/or the simultaneous use of other medications; unspecified frequency – cholestatic jaundice.

From the skin and subcutaneous tissues: often-intense sweating; unspecified frequency-acne, hemorrhages.

Musculoskeletal and connective tissue disorders: infrequently-myalgia, muscle spasm; unspecified frequency-myopathy.

From the side of the kidneys and urinary tract: unspecified frequency – renal failure, interstitial nephritis.

From the side of metabolism and nutrition: infrequently – anorexia, decreased appetite.

Laboratory parameters: often-increased activity of “liver” enzymes; infrequently-increased creatinine concentration, hypoglycemia (including with simultaneous use of hypoglycemic drugs), increased activity of alkaline phosphatase, unspecified frequency-increased value of the international normalized ratio, prolongation of prothrombin time, increased bilirubin.

Common disorders: infrequently-asthenia, chest pain, chills, fatigue, malaise, hyperthermia.

Patients with suppressed immunity

In patients with AIDS and other immunodeficiency disorders who receive clarithromycin in 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 common 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 activity of “liver” enzymes in the blood. There were also cases of adverse events with a low frequency of occurrence, such as shortness of breath, insomnia and dry mouth.

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

Interaction

Concomitant use of clarithromycin increases the blood concentration of drugs metabolized in the liver by cytochrome P450 (CYP3A) isoenzymes, which may lead to a mutual increase in their concentrations, which may increase or prolong both therapeutic and side effects. Concomitant use 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”).

Cisapride and pimozide

When used together, it is possible: an increase in the concentration of cisapride, an increase in the QT interval, the appearance of cardiac arrhythmias, including ventricular tachycardia, including the “pirouette” type, ventricular fibrillation.

Terfenadine and astemizole

When used together, it is possible: an increase in the concentration of terfenadine/ astemizole in the blood, the occurrence of cardiac arrhythmias, an increase in the QT interval, 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.

Effect of other medications on clarithromycin

Drugs that are inducers of the CYP3A isoenzyme (for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort) can induce the metabolism of clarithromycin. This can lead to a sub-therapeutic concentration of clarithromycin, which leads to a decrease in its effectiveness. In addition, it is necessary to monitor the concentration of the inducer of the CYP3A isoenzyme in blood plasma, which may increase due to inhibition of the inducer of the CYP3A isoenzyme by clarithromycin. With the combined use of rifabutin and clarithromycin, an increase in plasma concentrations and a decrease in serum clarithromycin concentrations were observed with an increased risk of uveitis.

The following drugs have a proven or suspected effect on the concentration of clarithromycin in blood plasma; if they are used together with clarithromycin, dose adjustment or switching to alternative treatment may be required.

Efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine

Strong inducers of cytochrome P-450, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine may accelerate the metabolism of clarithromycin and thus lower the concentration of clarithromycin in plasma and weaken its therapeutic effect, and to increase the concentration of 14-Oh-clarithromycin – metabolite that is also microbiologically active. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin differs with respect to different bacteria, the therapeutic effect may be reduced with the combined use of clarithromycin and enzyme inducers.

Etravirine

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

Fluconazole

Concomitant use of fluconazole 200 mg daily and clarithromycin 500 mg twice daily in 21 adult volunteers resulted in an increase in the minimum mean steady-state clarithromycin concentration (Ss) and AUC by 33% and 18%, respectively. At the same time, co-use did not significantly affect the average steady-state concentration of the active metabolite 14-OH-clarithromycin. Clarithromycin dose adjustment is not required for concomitant use of fluconazole.

Ritonavir

Concomitant use of ritonavir at 600 mg / day and clarithromycin 1 g / day may reduce the metabolism of clarithromycin (an increase in Cmax by 31%, Cmin by 182% and AUC by 77%), complete suppression of the formation of 14-hydroxyclarithromycin. Due to the wide therapeutic range, no dosage reduction is required in patients with normal renal function. In patients with renal insufficiency, it is advisable to consider the following dose adjustment options: with a creatinine clearance of 30-60 ml / min, the dose of clarithromycin should be reduced by 50%. Ritonavir should not be co-administered with clarithromycin in doses exceeding 1 g per day.

Oral hypoglycemic agents / Insulin

Concomitant use of clarithromycin and oral hypoglycemic drugs and / or insulin may lead to severe hypoglycemia. Hypoglycemia may occur when clarithromycin is co-administered with certain oral hypoglycemic drugs, such as nateglinide, pioglitazone, repaglinide, rosiglitazone due to inhibition of the CYP3A isoenzyme by clarithromycin. Careful monitoring of blood glucose levels is recommended.

Effect of clarithromycin on other medicinal products

Antiarrhythmic drugs (quinidine and disopyramide) 

When combined with quinidine or disopyramide, ventricular tachycardia of the “pirouette” type may occur. When clarithromycin is co-administered with these drugs, an electrocardiogram should be regularly monitored for an increase in the QT interval, and serum concentrations of these drugs should also be monitored.

Interactions due to CYP3A4

Concomitant use 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 increase or prolong both therapeutic and side effects. Clarithromycin should be used with caution in patients receiving drugs that are substrates of the CYP3A isoenzyme, especially if these drugs have a narrow therapeutic range (for example: carbamazepine), and/or are intensively metabolized by this enzyme. If necessary, the dose of the drug taken together with clarithromycin should be adjusted. Serum concentrations of drugs primarily metabolized by the CYP3A isoenzyme should also be monitored whenever possible.

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

HMG-CoA reductase inhibitors

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

Clarithromycin should be used with caution in combination therapy with statins. If co-use is necessary, it is recommended to take the lowest dose of statin. It is necessary to use statins that do not depend on the metabolism of the CYP3A isoenzyme (for example: fluvastatin).

Oral anticoagulants

There is a risk of serious bleeding and a significant increase in prothrombin time with the simultaneous use of clarithromycin and warfarin. If patients are receiving clarithromycin and oral anticoagulants at the same time, prothrombin time and INR should be carefully monitored.

Omeprazole

When clarithromycin and omeprazole are co-administered, the steady-state plasma concentrations of omeprazole may increase (Cmax, AUC0-24, T 1/2 by 30%,89%, and 34%, respectively).

Sildenafil, tadalafil and vardenafil 

Each of these phosphodiesterase inhibitors is metabolized at least partially by CYP3A. At the same time, the CYP3A isoenzyme can be inhibited in the presence of clarithromycin. Concomitant use of clarithromycin with sildenafil, tadalafil, or vardenafil may increase the inhibitory effect on phosphodiesterase. When prescribing these drugs together, you should consider reducing the dose of sildenafil, tadalafil and vardenafil.

Theophylline, carbamazepine

It is possible to increase the concentration of theophylline or carbamazepine in the systemic circulation.

Tolterodine

Tolterodine is primarily metabolized via the 2D6 isoform of cytochrome P450 (CYP2D6). However, in the part of the population lacking the CYP2D6 isoenzyme, metabolism occurs via CYP3A. In this population, suppression of the CYP3A isoenzyme leads to significantly higher serum tolterodine concentrations. In a population with a low level of metabolism via the CYP2D6 isoenzyme, it may be necessary to reduce the dose of tolterodine in the presence of inhibitors of the CYP3A isoenzyme, such as clarithromycin.

Triazolobenzodiazepines (for example: alprazolam, midazolam, triazolam) 

With the combined use of clarithromycin (500 mg twice daily), the AUC of midazolam may increase: 7 times after oral use and 2.7 times after intravenous use. Concomitant oral use of midazolam and clarithromycin should be avoided. If an intravenous form of midazolam is used together with clarithromycin, the patient’s condition should be carefully 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 elimination is independent of CYP3A (temazepam, nitrazepam, lorazepam), a clinically significant interaction with clarithromycin is unlikely.

With the combined use of clarithromycin and triazolam, effects on the central nervous system (CNS) may occur, for example, drowsiness and confusion. In this regard, in the case of combined use, it is recommended to monitor the symptoms of CNS disorders.

Interaction with other drugs

Colchicine

Colchicine is a substrate of both CYP3A and the P-glycoprotein (Pgp) transporter protein responsible for drug elimination. Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are co-administered, inhibition of Pgp and / or CYP3A may lead to increased colchicine action. It is necessary to monitor the possible development of clinical symptoms of colchicine intoxication, especially in elderly patients and patients with chronic renal failure (fatal cases have been reported). In patients with normal renal and hepatic function, it is necessary to reduce the dose of colchicine when used simultaneously with clarithromycin.

Concomitant use of clarithromycin and colchicine is contraindicated in patients with impaired liver or kidney function (see section “Contraindications”).

Digoxin

Digoxin is assumed to be a Pgp substrate. Clarithromycin is known to inhibit Pgp. When digoxin and clarithromycin are co-administered, inhibition of Pgp by clarithromycin may lead to increased digoxin action. Concomitant use of digoxin and clarithromycin may also lead to an increase in serum digoxin concentrations. Some patients experienced significant clinical symptoms of digoxin poisoning, including potentially fatal arrhythmias. When taking clarithromycin and digoxin together, the concentration of digoxin in the blood serum should be carefully monitored.

Zidovudine

Concomitant oral use of clarithromycin and zidovudine in adult HIV-infected patients may lead to a decrease in the steady-state concentration of zidovudine.

Since clarithromycin affects the absorption of zidovudine when taken orally, interactions can be largely avoided by taking clarithromycin and zidovudine at 4-hour intervals.

This type of interaction does not occur in HIV-infected children receiving clarithromycin suspension together with zidovudine or dideoxyinosine. Since clarithromycin may interfere with the absorption of zidovudine when taken concomitantly by mouth in adult patients, such an interaction is unlikely to occur when clarithromycin is used intravenously.

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, it is recommended to determine their serum concentrations, as there are reports of their increase.

Bidirectional drug interaction 

Atazanavir

Clarithromycin and atazanavir are both substrates and inhibitors of CYP3A. There is evidence of a bidirectional interaction between these drugs. Co-use of clarithromycin (500 mg twice daily) and atazanavir (400 mg once daily) may result in a twofold increase in clarithromycin exposure and a 70% decrease in 14-OH-clarithromycin, with a 28% increase in atazanavir AUC. Due to the wide therapeutic range of clarithromycin, no dose reduction is required in patients with normal renal function. 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 dosage form of clarithromycin. Clarithromycin in doses exceeding 1000 mg per day should not be administered together with protease inhibitors.

Slow Calcium Channel Blockers

Caution should be exercised when concomitantly using clarithromycin and slow calcium channel blockers that are metabolized by the CYP3A4 isoenzyme (for example: verapamil, amlodipine, diltiazem), since there is a risk of hypotension. Plasma concentrations of clarithromycin, as well as “slow” calcium channel blockers, may increase with simultaneous use. Hypotension, bradyarrhythmia, and lactic acidosis may occur with concomitant use of clarithromycin and verapamil.

When co-administered with clarithromycin, it is possible to reduce blood pressure, bradyarrhythmia and lactic acidosis.

Itraconazole

Clarithromycin and itraconazole are substrates and inhibitors of the CYP3A isoenzyme, which determines the bidirectional interaction of 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 evaluated for symptoms of increased or prolonged pharmacological effects of these drugs.

Saquinavir

Clarithromycin and saquinavir are substrates and inhibitors of the CYP3A isoenzyme, which determines the bidirectional interaction of drugs. Concomitant use of clarithromycin (500 mg twice daily) and saquinavir (in soft gelatin capsules,1200 mg 3 times daily) may increase the AUC and Ss of saquinavir by 177% and 187%, and clarithromycin-by 40%. When these two drugs are used together for a limited time and in the doses/formulations indicated above, no dose adjustment is required. The results of drug interaction studies with saquinavir monotherapy may not correspond to the effects observed with saquinavir/ritonavir therapy. When taking saquinavir in combination with ritonavir, the potential effect of ritonavir on clarithromycin should be considered.

Darunavir

In patients with creatinine clearance less than 30 ml/min, the dose of clarithromycin should be reduced by 75%, using the appropriate dosage form of clarithromycin.

How to take, course of use and dosage

Tablets should be taken orally with meals. Tablets should not be broken or chewed, they must be swallowed whole.

Adults and children over 12 years of age – 1 tablet (500 mg) 1 time a day with meals. 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. The exceptions are community-acquired pneumonia and sinusitis, which require treatment for 6 to 14 days.

Overdose

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

Treatment: gastric lavage, symptomatic therapy. Hemodialysis and peritoneal dialysis do not significantly affect the concentration of clarithromycin in serum, which is typical for other drugs of the macrolide group.

Description

Yellow film-coated tablets, oblong, biconvex. The cut is white or almost white in color.

Special instructions

Most strains of staphylococci that are resistant to methicillin and oxacillin are resistant to clarithomycin. Long-term use of antibiotics can lead to the formation of colonies with an increased number of insensitive bacteria and fungi. In case of superinfection, appropriate therapy should be prescribed.

Cases of hepatic dysfunction (increased blood concentrations of liver enzymes, hepatocellular and/or cholestatic hepatitis with or without jaundice) have been reported with clarithromycin. Hepatic dysfunction can be severe, but is usually reversible. There are cases of liver failure with a fatal outcome, mainly associated with the presence of serious concomitant diseases and/or the simultaneous use of other medications. If signs and symptoms of hepatitis appear, such as anorexia, jaundice, dark urine, itching, abdominal pain on palpation, clarithromycin therapy should be stopped immediately.

In the presence of chronic liver diseases, it is necessary to conduct regular monitoring of serum enzymes.

Cases of pseudomembranous colitis, the severity of which can range from mild to life-threatening, have been reported with virtually all antibacterial agents, including clarithromycin. Antibacterial drugs can alter the normal intestinal microflora, which can lead to the growth of Clostridium difficile. Pseudomembranous colitis caused by Clostridium difficile should be suspected in all patients experiencing diarrhea after the use of antibacterial agents. After the course of antibiotic therapy, careful medical supervision of the patient is necessary. Cases of pseudomembranous colitis were described 2 months after taking antibiotics.

Clarithromycin should be used with caution in patients with CHD, severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats / min), as well as when used simultaneously with Class IA antiarrhythmic drugs (quinidine, procainamide) and Class III antiarrhythmic drugs (dofetilide, amiodarone, sotalol). In these conditions and when taking the drug simultaneously with these drugs, the ECG should be regularly monitored for an increase in the QT interval.

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

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

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

With prolonged or repeated use of the drug, superinfection may develop (the growth of insensitive bacteria and fungi). If a secondary infection occurs, adequate therapy should be prescribed.

Macrolides can be used for infections caused by Corynebacterium minutissimum (erythrasma), acne vulgaris and erysipelas, as well as 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), it is necessary to immediately stop taking clarithromycin and start appropriate therapy.

When co-administered with warfarin or other indirect anticoagulants, MHO and prothrombin time should be monitored (see section “Interaction with other drugs”).

When clarithromycin is co-administered with oral hypoglycemic agents, careful monitoring of glucose levels is recommended.

Influence on the ability to drive vehicles and mechanisms

Caution should be exercised when driving vehicles and engaging in other potentially dangerous activities, as some of the side effects of clarithromycin, such as dizziness, drowsiness, may adversely affect the ability to drive a vehicle and perform potentially dangerous activities that require increased concentration and speed of psychomotor reactions. If the described adverse events occur, you should refrain from performing these types of activities.

Storage conditions

At a temperature not exceeding 25 °C. Keep out of reach of children.

Shelf

life is 2 years.

Active ingredient

Clarithromycin

Conditions of release from pharmacies

By prescription

Dosage form

long-acting tablets

Purpose

Children as prescribed by a doctor, Pregnant women as prescribed by a doctor, Adults as prescribed by a doctor, Children over 12 years of age

Indications

Stomach and Duodenal Ulcers, Colds, Bronchitis, Otitis Media, Tonsillitis, Respiratory Tract Infections, Sore Throat, Skin Infections