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

Excipients: lactose monohydrate 27.4 mg, povidone (polyvinylpyrrolidone low molecular weight) 14.5 mg, corn starch 10.5 mg, croscarmellose sodium 6.4 mg, talc 6.4 mg, calcium stearate 3.2 mg, polysorbate 80 1.6 mg, hard gelatine capsules: titanium dioxide 2.0%, gelatin up to 100%.

Description:

Hard gelatin capsules № 0 of white color.

The contents of the capsules are a powder or compacted mass of white or white with a yellowish tint of color, disintegrating when pressed with a glass rod.

Pharmacotherapeutic group:Antibiotic-macrolide

ATX: & nbsp

J.01.F.A.09 Clarithromycin

Pharmacodynamics:

Clarithromycin is a semisynthetic antibiotic of the macrolide group and has an antibacterial effect, interacting with 50S ribosomal subunit and suppressing the synthesis of protein bacteria, sensitive to it.

Clarithromycin is highly effective in vitro for both standard laboratory strains of bacteria and those isolated from patients in clinical practice. It is highly active against a wide range of aerobic and anaerobic, gram-positive and gram-negative microorganisms.The minimum inhibitory concentrations (MPC) of clarithromycin for most pathogens are less than the erythromycin MPC on average per log2 breeding.

Has a bactericidal effect against Helicobacter pylori, this activity of clarithromycin is higher at neutral pH than with acid.

In addition, data in vitro and in vivo indicate that clarithromycin acts on clinically significant species of mycobacteria.

In studies in vitro shown, that clarithromycin highly active in relation to Legionella pneumophila and Mycoplasma pneumoniae. but Enterobacteriaceae, Pseudomonas spp. and other non-fermenting lactose, gram-negative microorganisms are not susceptible to the action of clarithromycin.

The activity of clarithromycin against most strains of the microorganisms listed below has been proven in vitro, and in clinical practice for the 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);

- mycobacteria: Mycobacterium avium complex (MAC): Mycobacterium avium, Mycobacterium intracellulare; Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum.

Products of beta-lactamase do not render influences on the activity of clarithromycin.Most strains of staphylococcus aureus resistant to methicillin and oxacillin are resistant to clarithromycin.

Helicobacter pylori

Sensitivity N. pylori to clarithromycin was studied on isolates N. pylori, isolated from 104 patients prior to initiation of drug therapy. In 4 patients, strains resistant to clarithromycin were isolated N. pylori, in 2 cases - strains with moderate resistance, in the remaining 98 patients, isolates N. pylori were sensitive to clarithromycin.

Clarithromycin exerts its action in vitro and for most strains of the following microorganisms (however, the safety and efficacy of clarithromycin in clinical practice have not been confirmed by clinical studies, and practical significance remains unclear):

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

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

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

- anaerobic gram-negative microorganisms: Bacteroides melaninogenicus;

- spirochetes: Borrelia burgdorferi, Treponema pallidum;

- Campylobacteria: Campylobacter jejuni.

The main metabolite of clarithromycin in the human body is the microbiologically active metabolite 14-hydroxyclarithromycin.The microbiological activity of the metabolite is the same as that of clarithromycin, or 1-2 times weaker in respect of most microorganisms. The exception is N. influenzae, in respect of which the efficiency of the metabolite is twice as high.

Clarithromycin and its metabolite in combination can have both additive and synergistic effects on N. influenzae in vitro and in vivo, depending on the strain of bacteria.

Pharmacokinetics:

Suction

The drug is rapidly absorbed in the gastrointestinal tract. The absolute bioavailability of clarithromycin is about 50%. Eating directly before taking the drug increases the bioavailability of clarithromycin by an average of 25%. Clarithromycin can be applied before meals or during meals.

Distribution, metabolism and excretion

Clarithromycin is metabolized in the cytochrome P450 system (CYP3A) of the liver. When taking repeated doses of the preparation, cumulation was practically not detected, and the character of metabolism in the human body did not change.

Research in vitro showed that on average about 70% of clarithromycin binds to human plasma proteins at drug concentrations of 0.45-4.5 μg / ml.At a concentration of 45 μg / ml, binding is reduced to 41%, probably as a result of saturation of the binding sites. This phenomenon was observed only at drug concentrations that are significantly higher than therapeutic concentrations.

Research in vivo Mr.and animals showed that clarithromycin is present in all tissues, with the exception of the central nervous system, in concentrations several times higher than plasma. The highest concentrations (10-20 times higher than plasma concentrations) were found in the liver and lungs.

In healthy volunteers, when using clarithromycin at a dose of 250 mg 2 times a day, the maximum concentrations (C_mOh) of clarithromycin and 14-hydroxyclarithromycin in blood plasma were achieved after 2-3 days and were 1 μg / ml and 0.6 μg / ml, respectively. The half-life (T_1/2) of the initial drug and its main metabolite were 3-4 hours and 5-6 hours, respectively.

When using clarithromycin in a dose of 500 mg twice a day C_mOh clarithromycin and 14-hydroxyclarithromycin in the blood plasma were achieved after taking the 5th dose and averaged 2.7-2.9 μg / ml and 0.83-0.88 μg / ml, respectively. T_1/2of the initial drug and its main metabolite were 4.5-4.8 hours and 6.9-8.7 hours, respectively. FROM_mOh 14-hydroxyclarithromycin did not increase in proportion to the dose of clarithromycin, while T_1/2 both clarithromycin and its hydroxylated metabolite, tended to increase with increasing doses. Such nonlinear pharmacokinetics of clarithromycin in combination with a decrease in the formation of 14-hydroxyclarithromycin and N-detylated metabolite at high doses indicates a non-linear metabolism of clarithromycin, which becomes more pronounced at high doses.

The kidneys excreted about 37.9% after oral administration of clarithromycin at a dose of 250 mg and 46% after taking clarithromycin at a dose of 1200 mg; intestine is withdrawn about 40.2% and 29.1% respectively,

Patients clarithromycin and 14-hydroxyclorithromitations quickly penetrate into tissues and body fluids. There is limited evidence that the concentration of clarithromycin in the cerebrospinal fluid is insignificant when taken orally (1-2% of the concentration in the blood plasma at normal blood-brain barrier permeability). Concentration in tissues is usually several times higher than in plasma. The table gives examples of tissue and plasma concentrations:

Examples of tissue and plasma concentrations

Concentrations (250 mg every 12 hours)
Type of fabric	Tissue (μg / g)	Plasma (μg / ml)
Tonsils	1,6	0,8
Lungs	8,8	1,7

Pharmacokinetics in specific patient groups

Patients with hepatic impairment

In patients with moderate to severe hepatic impairment, but with preserved renal function, correction of the dose of clarithromycin is not required. Equilibrium concentration in blood plasma and systemic clearance of clarithromycin do not differ in patients of this group and in healthy volunteers. The equilibrium concentration of 14-hydroxyclarithromycin in patients with impaired liver function is lower than in healthy individuals.

Patients with impaired renal function

When the renal function is impaired, the minimum concentration increases (C_min) and C_mOhclarithromycin in blood plasma, T_1/2, area under the pharmacokinetic curve "concentration-time" (AUC) of clarithromycin and its metabolite 14-hydroxyclarithromycin. The elimination constant and deducing by nights decrease. The degree of changes in these parameters depends on the degree of renal dysfunction.

Elderly patients

In elderly patients, the concentration of clarithromycin and its metabolite 14-hydroxyclarithromycin in the blood was higher, and excretion was slower than in the group of young people.However, after correction for renal clearance of creatinine (CC), there was no difference in both groups. Thus, the main effect on the pharmacokinetic parameters of clarithromycin is the function of the kidneys, not age.

Patients with mycobacterial infections

The equilibrium concentrations of clarithromycin and 14-hydroxyclarithromycin in patients with HIV infection who received clarithromycin in usual doses (500 mg twice a day) were similar to those in healthy people. However, when using clarithromycin at higher doses that may be required for the treatment of mycobacterial infections, antibiotic concentrations can be significantly higher than usual. In patients with HIV infection who took clarithromycin in a dose of 1000 mg per day and 2000 mg per day in 2 divided doses, the equilibrium values of C_mOh usually 2-4 μg / ml and 5-10 μg / ml, respectively. When using the drug at higher doses, an increase in T_1/2 compared with that of healthy people who received clarithromycin in usual doses. Increase in plasma concentrations and lengthening T_1/2when using clarithromycin at higher doses is consistent with the known non-linear pharmacokinetics of the drug.

Combined treatment with omeprazole

Clarithromycin 500 mg 3 times a day in combination with omeprazole at a dose of 40 mg / day contributes to an increase in T_1/2 and AUC omeprazole. In all patients receiving combination therapy, compared with patients receiving one omeprazole, an increase of 89% AUC and 34% T_1/2omeprazole. In clarithromycin FROM_mOh, FROM_min and AUC increased by 10%, 27% and 15%, respectively, compared with the data when only clarithromycin without omeprazole. In the equilibrium state, the concentrations of clarithromycin in the gastric mucosa 6 hours after admission in the group receiving the combination were 25 times greater than those in the group of patients receiving one clarithromycin. The concentrations of clarithromycin in the stomach tissues 6 hours after taking 2 drugs were 2 times higher than the data obtained in the group of patients receiving only clarithromycin.

Indications:

Infectious-inflammatory diseases caused by microorganisms sensitive to clarithromycin:

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

- infections of the upper respiratory tract and ENT organs (such as pharyngitis, sinusitis);

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

- disseminated or localized mycobacterial infections caused by Mycobacterium avium and Mycobacterium intracellulare;

- localized infections caused by Mycobacterium chelonae, Mycobacterium fortuitum and Mycobacterium kansasii;

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

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

- odontogenic infections.

Contraindications:

- Hypersensitivity to clarithromycin, other components of the drug and other macrolides;

- interval lengthening QT, ventricular arrhythmia or ventricular tachycardia of the "pirouette" type and anamnesis;

- hypokalemia (risk of lengthening the interval QT);

- simultaneous reception of clarithromycin with ticagrelor or ranolazine;

- simultaneous reception of clarithromycin with astemizole, cisapride, pimozide, terfenadine (see section "Interaction with other drugs");

- simultaneous reception of clarithromycin with ergot alkaloids, for example, ergotamine, dihydroergotamine (see.section "Interaction with other drugs");

- simultaneous reception of clarithromycin with midazolam for oral administration (see section "Interaction with other drugs");

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

- simultaneous reception of clarithromycin with colchicine (see section "Interaction with other drugs");

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

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

- the period of breastfeeding;

- children under 12 years of age (efficacy and safety not established);

- porphyria;

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

Carefully:

- Renal failure of moderate to severe severity;

- hepatic failure of moderate to severe severity;

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

- simultaneous reception of clarithromycin with other ototoxic drugs, especially aminoglycosides (see section "Interaction with other drugs");

- simultaneous reception with drugs that are metabolized by isoenzyme CYP3A, eg, carbamazepine, cilostazol, ciclosporin, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants (for example, warfarin), quinidine, rifabutin, sildenafil, tacrolimus, vinblastine (see the section "Interaction with other drugs");

- simultaneous reception with drugs that induce isoenzyme CYP3A4, for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St John's wort (see "Interaction with other medicines");

- simultaneous reception of clarithromycin with statins independent of isoenzyme metabolism CYP3A (eg, fluvastatin) (see the section "Interaction with other drugs");

- simultaneous reception with blockers of "slow" calcium channels, which are metabolized by isoenzyme CYP3A4 (e.g., verapamil, amlodipine, diltiazem);

- patients with coronary heart disease (CHD), severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats per minute), as well as patients taking antiarrhythmic drugs simultaneously IA class (quinidine, procainamide) and III class (dofetilide, amiodarone, sotalol);

- Pregnancy.

Pregnancy and lactation:

The safety of the use of clarithromycin during pregnancy and lactation has not been established.

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

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

Clarithromycin is excreted along with breast milk. If you need to take clarithromycin, breastfeeding should be discontinued.

Dosing and Administration:

Inside, regardless of food intake.

The usual recommended dose of clarithromycin for adults and children over 12 years of age and a body weight of more than 33 kg is 250 mg twice a day. In more severe cases, the dose is increased to 500 mg twice a day.

Usually the duration of treatment is from 5 to 14 days, with community-acquired pneumonia and sinusitis - from 6 to 14 days.

For the treatment of mycobacterial infections, except tuberculosis, recommended a dose of clarithromycin 500 mg 2 times a day.

Treatment of disseminated MAC infections in patients with HIV infection should continue as long as there is clinical and microbiological efficacy. Clarithromycin should be used in combination with other antimicrobial agents active against these pathogens.

The duration of treatment of other non-tuberculosis mycobacterial infections is determined by the doctor.

For the prevention of infections caused by MAC, the recommended dose of clarithromycin for adults is 500 mg 2 times a day.

For the treatment of odontogenic infections The dose of clarithromycin is 250 mg twice a day for 5 days.

To eradicate N. pylori in patients with peptic ulcer caused by H. pylori, clarithromycin can be administered 500 mg twice a day in combination with other antimicrobial agents and proton pump inhibitors for 7-14 days, in accordance with national and international recommendations for the treatment of infection N. pylori.

Patients with renal insufficiency

Patients with CC less than 30 ml / min are prescribed half of the usual dose of clarithromycin, that is 250 mg once a day or, for more severe infections, 250 mg twice a day. The maximum daily dose is 500 mg. Treatment of such patients continues no more than 14 days.

Side effects:

Classification of the incidence of side effects according to the recommendations of the World Health Organization (WHO): very often> 1/10; often from> 1/100 to <1/10; infrequently from> 1/1000 to <1/100; rarely from> 1/10000 to <1/1000; very rarely <1/10000, including individual messages; the frequency is unknown - it is not possible to establish the frequency of occurrence from the available data.

Allergic reactions: often - a rash; infrequently anaphylactoid reaction¹, hypersensitivity, dermatitis bullous¹, itching, urticaria, maculopapular rash³; frequency unknown - anaphylactic reaction, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis,drug rash with eosinophilia and systemic symptoms (DRESS-syndrome).

From the nervous system: often - headache, insomnia; infrequently - loss of consciousness¹, dyskinesia¹, dizziness, drowsiness, tremor, anxiety, increased excitability³; frequency is unknown - convulsions, psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, dreaming ("nightmarish" dreams), paresthesia, mania.

From the skin: often - intense sweating; infrequently - acne, hemorrhages.

From the urinary system: frequency unknown - renal failure, interstitial nephritis.

From the side of metabolism and nutrition: infrequently - anorexia, a decrease in appetite.

From the side of the musculoskeletal system: infrequently - muscle spasm³, musculoskeletal stiffness¹, myalgia²; frequency unknown - rhabdomyolysis²*, myopathy.

From the digestive system: often - diarrhea, vomiting, dyspepsia, nausea, pain in the abdomen; infrequently - esophagitis¹, gastroesophageal reflux disease², gastritis, proctalgia², stomatitis, glossitis, bloating⁴, constipation, dry mouth, eructations, flatulence, cholestasis⁴, hepatitis, including cholestatic and hepatocellular; frequency unknown - acute pancreatitis, discoloration of the tongue and teeth, hepatic insufficiency, cholestatic jaundice.

From the respiratory system: infrequently - asthma¹, nose bleed², pulmonary embolism¹.

From the sense organs: often - dysgeusia, perversion of taste; infrequently - vertigo, hearing impairment, ringing in the ears; frequency is unknown - deafness, agevzia (loss of taste sensations), parosmia, anosmia.

From the cardiovascular system: often - vasodilation¹; infrequent - atrial flutter, lengthening of the interval QT on an electrocardiogram, atrial fibrillation, extrasystole¹, cardiac arrest; The frequency is unknown - ventricular tachycardia, including the "pirouette" type.

Laboratory indicators: often - a deviation in the hepatic test; infrequent increase in creatinine concentration¹, increased urea concentration¹, change in the ratio of albumin-globulin¹, leukopenia, peitropenia⁴, eosinophilia⁴, thrombocythemia³, increased activity in the blood: alanine aminotransferase (ALT), aspartate aminotransferase (ACT), gamma glutamyl transferase (GGT)⁴, alkaline phosphatase (AFP)⁴, lactate dehydrogenase (LDH)¹; frequency unknown - agranulocytosis, thrombocytopenia, increase in the value of the international normalized ratio (INR), prolongation of prothrombin time, change in urine color, hyperbilirubinemia.

General disorders: infrequent - malaise⁴, hyperthermia³, asthenia, chest pain⁴, chills⁴, fatigue⁴.

Infectious and parasitic diseases: infrequently - cellulite¹, candidiasis, gastroenteritis², secondary infections³ (including vaginal); frequency unknown - pseudomembranous colitis, erysipelas.

Patients with depressed immunity

In patients with HIV infection 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.

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

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

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

These adverse reactions were reported only when clarithromycin was used in the form of a lyophilizate to prepare a solution for infusion.

²These adverse reactions were reported only when clarithromycin was used in the form of a sustained-release tablet, coated with a film coat.

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

⁴Reports of these adverse reactions were obtained only when clarithromycin is used in the form of a tablet coated with film.

Overdose:

Symptoms

Taking a large dose of clarithromycin can cause symptoms of disorders from the gastrointestinal tract. In one patient with a history of bipolar disorder, after receiving 8 g of clarithromycin, changes in the mental state, paranoid behavior, hypokalemia and hypoxia were described.

Treatment

In case of overdose, remove the unabsorbed preparation from the gastrointestinal grant (gastric lavage, activated charcoal, etc.) and perform symptomatic therapy. Hemodialysis and peritoneal dialysis do not have a significant effect on the concentration of clarithromycin in the blood plasma, which is typical for other drugs of the macrolide group.

Interaction:

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

Cisapride, pimozide, terfenadine and astemizole

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

Alkaloids of ergot

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

HMG Inhibitors-CoA reductase (statins)

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

Clarithromycin should be used with caution in combination therapy with other statins. It is recommended to use statins that do not depend on the isoenzyme metabolism CYP3A (eg, fluvastatin). In case of need for joint intake, it is recommended to take the lowest dose of statin. It should monitor the development of signs and symptoms of myopathy.

The effect of other drugs on clarithromycin

Preparations that are inducers of isoenzyme CYP3A (eg, rifampicin, rifabutin, phenytoin, carbamazepine, phenobarbital, St. John's wort pitted), can induce the metabolism of clarithromycin. This can lead to a subtherapeutic concentration of clarithromycin, which leads to a decrease in its effectiveness.In addition, it is necessary to observe the concentration of the isoenzyme inducer CYP3A In blood plasma, which can increase due to inhibition of the isoenzyme CYP3A clarithromycin. With the combined use of rifabutin and clarithromycin, an increase in the plasma concentration of rifabutin and a decrease in the plasma concentration of clarithromycin with an increased risk of uveitis have been observed.

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

Efavirenz, nevirapine, rifampicin, rifabutin and rifapentin

Strong inductors of the cytochrome P450 system, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentin can accelerate the metabolism of clarithromycin and thus reduce the concentration of clarithromycin in the plasma and weaken the therapeutic effect, and at the same time increase the concentration of 14-hydroxycylarithromycin metabolite, also being microbiologically active. Since the microbiological activity of clarithromycin and 14-hydroxyclarithromycin is different for different bacteria,The therapeutic effect can be reduced by 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-hydroxyclarithromycin increases. Since 14-hydroxyclarithromycin has a low activity against infections Mycobacterium avium complex (MAC), the overall activity against these pathogens may change, therefore alternative treatment should be considered for MAC treatment.

Fluconazole

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

Ritonavir

A pharmacokinetic study showed that a joint intake of ritonavir at a dose of 200 mg every eight hours and clarithromycin at a dose of 500 mg every 12 hours led to a marked suppression of the metabolism of clarithromycin. With the joint administration of ritonavir C_mOh clarithromycin increased by 31%, C_min increased by 182% and AUC increased by 77%. A complete inhibition of the formation of 14-hydroxyclarithromycin was noted. Due to the wide range of clarithromycin, a decrease in its dose in patients with normal renal function is not required. In patients with renal insufficiency it is advisable to consider the following options for dose adjustment: with a QC of 30-60 ml / min, the dose of clarithromycin should be reduced by 50%; with QC less than 30 ml / min, the dose of clarithromycin should be reduced by 75%. Ritonavir should not be taken together with clarithromycin in doses exceeding 1 g / day.

Effects of clarithromycin on other drugs

Antiarrhythmic drugs (quinidine and disopyramide)

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

In post-marketing applications, cases of hypoglycemia were reported with the combined use of clarithromycin and disopyramide.It is necessary to monitor the concentration of glucose in the blood with the simultaneous use of clarithromycin and disopyramide.

Oral hypoglycemic agents / insulin

With the combined use of clarithromycin and oral hypoglycemic agents (eg, sulfonylureas) and / or insulin, pronounced hypoglycemia can be observed. Simultaneous use of clarithromycin with some hypoglycemic drugs (for example, nateglinide, pioglitazone, repaglinide and rosiglitazone) can lead to inhibition of the isoenzyme CYP3A clarithromycin, resulting in the development of hypoglycemia. Careful monitoring of glucose concentration is recommended.

Interactions due to the isoenzyme CYP3A

Joint reception of clarithromycin, which is known to inhibit isoenzyme CYP3A, and drugs, primarily metabolized by isoenzyme CYP3A, can be associated with a mutual increase in their concentrations, which can enhance or prolong both the therapeutic and side effects. Clarithromycin should be used with caution for patients receiving drugs that are substrates of isoenzyme CYP3A, especially if these drugs have a narrow therapeutic range (for example, carbamazepine), and / or are extensively metabolized by this enzyme. In case of need, correction of the dose of the drug taken together with clarithromycin should be carried out, and joint administration of some drugs is contraindicated (see section "Contraindications"). Also, if possible, monitoring of plasma concentrations of drugs primarily metabolized by isoenzyme CYP3A.

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

Indirect anticoagulants

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

Omeprazole

Clarithromycin (500 mg every 8 hours) was tested in healthy adult volunteers in combination with omeprazole (40 mg daily). With the combined use of clarithromycin and omeprazole, the equilibrium concentrations of omeprazole were increased (C_mOh, AUC and T_1/2increased by 30%, 89% and 34% respectively). The average pH in the stomach for 24 hours was 5.2 with only omeprazole and 5.7 with omeprazole together with clarithromycin.

Sildenafil, tadalafil and vardenafil

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

Theophylline, carbamazepine

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

Tolterodin

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

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

When combined with midazolam and clarithromycin (500 mg twice daily), there was an increase AUC midazolam: 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 be applied to other benzodiazepines, which are metabolized by the isoenzyme CYP3A, including triazolam and alprazolam. For benzodiazepines, the excretion of which does not depend on the isoenzyme CYP3A (temazepam, nitrazepam, lorazepam), clinically significant interaction with clarithromycin is unlikely.

With the combined use of clarithromycin and triazolam, the central nervous system (CNS) may be affected, for example, drowsiness and confusion. In this regard, in the case of joint application, it is recommended to follow the symptoms of the CNS disorder.

Interaction with other drugs

Aminoglycosides

With simultaneous reception of clarithromycin with other ototoxic drugs, especially aminoglycosides,care must be taken to monitor the functions of the vestibular and hearing aids both during therapy and after its termination.

Colchicine

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

Digoxin

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

Zidovudine

Simultaneous oral administration of clarithromycin tablets of conventional release and zidovudine by adult HIV-infected patients may lead to a decrease in the equilibrium concentration of zidovudine. Because the clarithromycin influences the absorption of zidovudine when taken orally, interactions can be largely avoided by taking clarithromycin and zidovudine with an interval of 4 hours. Such an interaction was not observed in HIV-infected children who took a children's suspension of clarithromycin with zidovudine or dideoxyinosine. Because the clarithromycin may interfere with the absorption of zidovudine when administered simultaneously in adults in adults,Such interaction is hardly possible with the use of clarithromycin intravenously.

Phenytoin and valproic acid

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

Bi-directional drug interaction

Atazanavir

Clarithromycin and atazanavir are both substrates and isoenzyme inhibitors CYP3A. There is evidence of bi-directional interaction of these drugs. The combined use of clarithromycin (500 mg twice daily) and atazanavir (400 mg once daily) can lead to a twofold increase in the effect of clarithromycin and a decrease in the effect of 14-hydroxycylarithromycin by 70%, with an increase AUC atazanavir by 28%. 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 moderate renal insufficiency (KK 30-60 ml / min), the dose of clarithromycin should be reduced by 50%; in patients with SC 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 is metabolized by the isoenzyme CYP3A4 (e.g., verapamil, amlodipine, diltiazem), you should be careful, since there is a risk of arterial hypotension. Plasma concentrations of clarithromycin, as well as blockers of "slow" calcium channels, can increase with simultaneous application. Arterial hypotension, bradyarrhythmia and lactic acidosis are possible with concurrent administration of clarithromycin and verapamil.

Itraconazole

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

Saquinavir

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

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 clarithromycin was used, cases of hepatic dysfunction were reported (increased hepatic enzyme activity in the blood plasma, 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 regularly monitor the activity of plasma 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. Antibacterial drugs can change the normal intestinal microflora, which can lead to an increase in C. difficile. Pseudomembranous colitis caused by Clostridium difficile, it is necessary to suspect in all patients experiencing the appearance of 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 after 2 months after taking antibiotics were described.

Clarithromycin should be used with caution in patients with ischemic heart disease, severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats / min), and with simultaneous use with antiarrhythmic drugs 1A class (quinidine, procainamide) and III class (dofetilide, amiodarone, sotalol).With these conditions and with simultaneous reception of clarithromycin with these drugs, the electrocardiogram should be monitored regularly to increase the interval QT. 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 growing resistance Streptococcus pneumoniae to antibiotics of the macrolide group, it is important to conduct sensitivity testing for the appointment 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 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 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 symptoms (DRESS-syndrome), you must immediately stop taking clarithromycin and begin the appropriate therapy,

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

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

Data on the effect of clarithromycin on the ability to drive vehicles and mechanisms are not available.

Care should be taken when driving vehicles and mechanisms, taking into account the potential for dizziness, vertigo, confusion and disorientation that may occur when using this drug.

When there are undesirable phenomena from the central nervous system should refrain from performing these activities.

Form release / dosage:

Capsules, 250 mg.

Packaging:

7, 10 or 14 capsules in a planar cell packaging made of a polyvinylchloride film and aluminum foil.

2 or 4 contour packs of 7 capsules, 1 or 2 contour packs of 14 capsules.

1, 2 or 3 contourcell packs of 10 capsules together with instructions for use in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:P N002496 / 01

Date of registration:21.07.2009 / 29.06.2015

Expiration Date:Unlimited

The owner of the registration certificate:VERTEKS, AO VERTEKS, AO Russia

Manufacturer: & nbsp

VERTEKS, AO Russia

Representation: & nbspVERTEKS CJSC VERTEKS CJSC Russia

Information update date: & nbsp24.01.2018

Illustrated instructions

Instructions

Clarithromycin (Clarithromycin)