Klacid film-coated tablets 500 mg 14 pcs. in Moscow

Klacid film-coated tablets 500 mg 14 pcs. in Moscow

Interaction with cytochrome P450. Clarithromycin is metabolized in the liver by the cytochrome P4503A isoenzyme (CYP3A). This mechanism determines many interactions with other drugs. Clarithromycin may inhibit the biotransformation of other drugs by this system, which may lead to increased serum levels. The following drugs or classes are known or suspected to be metabolized by the same CYP3A isoenzyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin), pimozide , quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam and vinblastine. Similar mechanisms of interaction, which are mediated by other cytochrome P450 isoenzymes, are characteristic of phenytoin, theophylline and valproic acid. In clinical studies, when theophylline or carbamazepine was combined with clarithromycin, there was a small but statistically significant (p<0.05) increase in serum theophylline and carbamazepine levels.

In clinical practice, the following CYP3A-mediated interactions have been reported with the use of erythromycin and/or clarithromycin.

When clarithromycin was combined with HMG-CoA reductase inhibitors, such as lovastatin and simvastatin, rhabdomyolysis developed in rare cases.

With simultaneous use of clarithromycin with cisapride, an increase in the levels of the latter was observed. This may lead to prolongation of the QT interval and the development of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsade de pointes (TdP). Similar effects have been reported in patients receiving clarithromycin with pimozide (see "Contraindications").

Macrolides caused disruption of the metabolism of terfenadine, which led to an increase in its plasma levels and was sometimes associated with the development of arrhythmias, incl. prolongation of the QT interval, ventricular tachycardia, ventricular fibrillation and ventricular tachycardia of the “pirouette” type (see “Contraindications”).

In one study of 14 healthy volunteers, the combined use of clarithromycin tablets and terfenadine resulted in a 2- to 3-fold increase in serum levels of the acid metabolite terfenadine and a prolongation of the QT interval, which was not associated with any clinical effects. In clinical practice, cases of ventricular tachycardia of the “pirouette” type have been reported when clarithromycin is combined with quinidine or disopyramide. Serum levels of these drugs should be monitored during treatment with clarithromycin.

Ergotamine/dihydroergotamine. In clinical practice, when clarithromycin was combined with ergotamine or dihydroergotamine, cases of acute toxicity of the latter, which is characterized by vasospasm and ischemia of the limbs and other tissues, including the central nervous system, were recorded.

Interaction with other drugs. In patients receiving clarithromycin tablets in combination with digoxin, an increase in serum concentrations of the latter was observed. Monitoring serum digoxin levels is advisable.

Colchicine. It is a substrate for CYP3A and P-glycoprotein. Clarithromycin and other macrolides are inhibitors of CYP3A and P-glycoprotein. When colchicine and clarithromycin are coadministered, inhibition of P-glycoprotein and/or CYP3A may result in increased effects of colchicine. Patients should be closely monitored for symptoms of colchicine toxicity.

Interaction with antiretroviral drugs. Concomitant oral administration of clarithromycin tablets with zidovudine in HIV-infected adults may result in a decrease in the Css of zidovudine. This interaction was not observed in HIV-infected children taking clarithromycin pediatric suspension with zidovudine or dideoxyinosine. In a pharmacokinetic study, the combined use of ritonavir at a dose of 200 mg every 8 hours and clarithromycin at a dose of 500 mg every 12 hours resulted in a significant suppression of the metabolism of clarithromycin. Cmax of clarithromycin when combined with ritonavir increased by 31%, Cmin by 182%, AUC by 77%.

Virtually complete inhibition of the formation of 14-hydroxyclarithromycin was observed. Given the high therapeutic index of clarithromycin, a dose reduction is not required in patients with normal renal function. However, in patients with impaired renal function, dose adjustment is advisable. In patients with Cl creatinine 30-60 ml/min, the dose of clarithromycin is reduced by 50%, and in patients with Cl creatinine <30 ml/min - by 75%. At doses greater than 1 g/day, clarithromycin should not be used in combination with ritonavir.

Klacid, 125 mg/5 ml, powder for the preparation of suspension for oral administration, 42.3 g, 1 pc.

The first data on pharmacokinetics were obtained from the study of clarithromycin tablets. The drug is quickly absorbed into the gastrointestinal tract. The absolute bioavailability of clarithromycin 50 mg tablets is approximately 50%. Food slightly delayed the onset of absorption and the formation of the active metabolite of 14-OH-clarithromycin, but did not affect the bioavailability of the drug.

In vitro

In in vitro studies, clarithromycin binding to plasma proteins averaged approximately 70% at clinically relevant concentrations ranging from 0.45 to 4.5 mcg/ml.

Healthy

The bioavailability and pharmacokinetics of clarithromycin suspension were studied in healthy adults and children. When administered once in adults, the bioavailability of the suspension was equivalent to or slightly greater than that of the tablets (both 250 mg dose). As with tablets, food slightly delayed the absorption of clarithromycin suspension but did not affect the overall bioavailability of the drug. Cmax, AUC and T1/2 of clarithromycin when taking the pediatric suspension (after meals) were 0.95 mcg/ml, 6.5 mcg h/ml and 3.7 hours, respectively, and when taking a 250 mg tablet on an empty stomach - 1.1 µg/ml; 6.3 µg·h/ml and 3.3 h.

When clarithromycin suspension was administered at a dose of 250 mg every 12 hours in adults, steady-state blood levels were practically achieved by the fifth dose. In this case, the pharmacokinetic parameters were as follows: Cmax - 1.98 μg/ml, AUC - 11.5 μg h/ml, Tmax - 2.8 hours and T1/2 - 3.2 hours - for clarithromycin and, accordingly, 0. 67; 5.33; 2.9 and 4.9 for 14-OH-clarithromycin. In healthy subjects, serum concentrations peaked within 2 hours after oral administration. Css of the main metabolite - 14-OH-clarithromycin - is about 0.6 μg/ml, and T1/2 when using the drug at a dose of 250 mg every 12 hours is 5-6 hours. When prescribing clarithromycin at a dose of 500 mg every 12 hours, Css 14-OH-clarithromycin is slightly higher (up to 1 μg/ml), and T1/2 is about 7 hours. When using both doses, equilibrium concentrations of the metabolite are usually achieved within 2–3 days. When clarithromycin is prescribed at a dose of 250 mg every 12 hours, approximately 20% of the dose is excreted unchanged by the kidneys. When used at a dose of 500 mg every 12 hours, approximately 30% of the dose is excreted unchanged by the kidneys. The renal clearance of clarithromycin is not significantly dose-dependent and approaches the normal glomerular filtration rate. The main metabolite found in urine is 14-OH-clarithromycin, which accounts for 10–15% of the dose (250 or 500 mg every 12 hours).

Sick

Clarithromycin and its 14-OH metabolite are well distributed into tissues and body fluids. Tissue concentrations are usually several times higher than serum concentrations. Table 1 provides examples of tissue and serum concentrations.

Table 1

Concentrations when administered at a dose of 250 mg every 12 hours

In children requiring oral antibiotic treatment, clarithromycin has high bioavailability. Moreover, its pharmacokinetic profile was similar to those in adults taking the same suspension. The drug is quickly and well absorbed in children. Food slightly delays the absorption of clarithromycin, but does not significantly affect its bioavailability or pharmacokinetic properties.

The steady-state parameters of clarithromycin pharmacokinetics achieved after 5 days (ninth dose) were as follows: Cmax - 4.6 μg/ml, AUC - 15.7 μg·h/ml and Tmax - 2.8 hours; corresponding values ​​for 14-OH metabolite: 1.64 μg/ml; 6.69 mcg h/ml and 2.7 hours. Estimated T1/2 of clarithromycin and its metabolite are 2.2 and 4.3 hours, respectively.

In patients with otitis, 2.5 hours after taking the fifth dose (7.5 mg/kg 2 times a day), the average concentrations of clarithromycin and 14-OH metabolite in the middle ear were 2.53 and 1.27 μg/g. Concentrations of the drug and its metabolite were 2 times higher than their serum levels.

Liver dysfunction

Steady-state concentrations of clarithromycin in patients with impaired liver function did not differ from those in healthy subjects, while levels of 14-OH-clarithromycin were lower. The decrease in the formation of 14-OH-clarithromycin in patients with impaired liver function was, at least partially, offset by an increase in the renal clearance of clarithromycin compared with that in healthy subjects.

Renal dysfunction

The pharmacokinetics of clarithromycin also changed in patients with impaired renal function who received the drug orally at a dose of 500 mg repeatedly. In such patients, plasma levels, T1/2, Cmax, Cmin and AUC of clarithromycin and its 14-OH metabolite were higher than in healthy people. Deviations in these parameters correlated with the degree of renal failure: with more severe renal dysfunction, the differences were more significant (see “Dosage and Administration”).

Aged people

In a comparative study in elderly healthy subjects receiving repeat oral clarithromycin 500 mg, plasma levels of the drug were increased and elimination was slower compared with those in younger healthy subjects. However, there was no difference between the two groups when adjustment was made for creatinine Cl. It was concluded that changes in the pharmacokinetics of clarithromycin reflect renal function and not the age of the patient.

Patients with mycobacterial infections

Css of clarithromycin and 14-OH-clarithromycin in patients with HIV infection who received clarithromycin in usual doses in the form of tablets in adults and suspension in children were similar to those in healthy people. However, when clarithromycin is used in higher doses, which may be required to treat mycobacterial infections, antibiotic concentrations may be significantly higher than usual.

In children with HIV infection receiving clarithromycin at a dose of 15–30 mg/kg/day in 2 divided doses, steady-state Cmax values ​​typically ranged from 8 to 20 mcg/ml. However, in children with HIV infection who received a clarithromycin suspension at a dose of 30 mg/kg/day in 2 divided doses, Cmax reached 23 mcg/ml.

When using the drug in higher doses, a prolongation of T1/2 was observed compared with that in healthy people receiving clarithromycin in usual doses. The increase in plasma concentrations and T1/2 duration when clarithromycin is prescribed at higher doses is consistent with the known nonlinearity of the pharmacokinetics of the drug.

Klacid, 14 pcs., 500 mg, film-coated tablets

The drug is quickly absorbed into the gastrointestinal tract. Absolute bioavailability is about 50%. With repeated doses of the drug, no accumulation was detected, and the nature of metabolism in the human body did not change. Eating immediately before taking the drug increased the bioavailability of the drug by an average of 25%.

Clarithromycin can be taken before or with meals.

In vitro

in vitro studies

binding of clarithromycin to plasma proteins by 70% at concentrations from 0.45 to 4.5 μg/ml. At a concentration of 45 μg/ml, binding decreases to 41%, probably as a result of saturation of binding sites. This is observed only at concentrations many times higher than the therapeutic value.

Healthy

When clarithromycin was prescribed at a dose of 250 mg 2 times a day, the maximum Css of clarithromycin and 14-hydroxyclarithromycin in plasma were reached after 2–3 days and were 1 and 0.6 μg/ml, respectively. T1/2 of the parent drug and its main metabolite were 3–4 and 5–6 hours, respectively. When clarithromycin was prescribed at a dose of 500 mg 2 times a day, the maximum Css of clarithromycin and 14-hydroxyclarithromycin in plasma were achieved after taking the 5th dose and amounted to on average 2.7–2.9 and 0.88–0.83 μg/ml, respectively. T1/2 of the parent drug and its main metabolite were 4.5–4.8 hours and 6.9–8.7 hours, respectively.

At steady state, the level of 14-hydroxyclarithromycin does not increase in proportion to clarithromycin doses, and T1/2 of clarithromycin and its main metabolite increase with increasing dose. The nonlinear nature of the pharmacokinetics of clarithromycin is associated with a decrease in the formation of 14-OH- and N-demethylated metabolites when using higher doses, which indicates the nonlinearity of the metabolism of clarithromycin when taking high doses. About 37.9% are excreted in the urine after taking 250 mg and 46% after taking 1200 mg of clarithromycin, and through the intestines - about 40.2 and 29.1%, respectively.

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

The table provides examples of tissue and serum concentrations.

Concentrations (250 mg every 12 hours)

Liver dysfunction

In patients with moderate to severe impairment of liver function, but with preserved renal function, no dose adjustment of clarithromycin is required. Css in blood plasma and systemic clearance of clarithromycin do not differ between patients in this group and healthy patients. Css of 14-hydroxyclarithromycin in people with impaired liver function is lower than in healthy people.

Renal dysfunction

If renal function is impaired, the minimum and maximum levels of clarithromycin in the blood plasma, T1/2, AUC of clarithromycin and 14-OH metabolite increase. The elimination constant and urinary excretion decrease. The degree of changes in these parameters depends on the degree of renal dysfunction.

Elderly patients

In elderly patients, the level of clarithromycin and its 14-OH metabolite in the blood was higher, and elimination was slower than in the group of young people. It is believed that changes in pharmacokinetics in elderly patients are associated primarily with changes in creatinine clearance and renal function, and not with the age of the patients.

Patients with mycobacterial infections

Css of clarithromycin and 14-OH-clarithromycin in patients with HIV infection who received clarithromycin in usual doses (500 mg 2 times a day) were similar to those in healthy people. However, when clarithromycin is used in higher doses, which may be required to treat mycobacterial infections, antibiotic concentrations may be significantly higher than usual.

In patients with HIV infection taking clarithromycin at a dose of 1000 and 2000 mg/day in 2 divided doses, Css were usually 2–4 and 5–10 μg/ml, respectively. When using the drug in higher doses, a prolongation of T1/2 was observed compared with that in healthy people receiving clarithromycin in usual doses. The increase in plasma concentrations and T1/2 duration when clarithromycin is prescribed at higher doses is consistent with the known nonlinearity of the pharmacokinetics of the drug.

Combination treatment with omeprazole

Clarithromycin 500 mg 3 times a day in combination with omeprazole at a dose of 40 mg/day increases T1/2 and AUC0-24 of omeprazole. In all patients receiving combination therapy, compared with those receiving omeprazole alone, there was an 89% increase in AUC0-24 and a 34% increase in T1/2 of omeprazole. For clarithromycin, Cmax, Cmin and AUC0-8 increased by 10, 27 and 15%, respectively, compared with data when clarithromycin alone was used without omeprazole. At steady state, clarithromycin concentrations in the gastric mucosa 6 hours after dosing in the group receiving the combination were 25 times higher than those in those receiving clarithromycin alone. Concentrations of clarithromycin in gastric tissue 6 hours after taking 2 drugs were 2 times higher than the data obtained in the group of patients receiving only clarithromycin.