Pharmacy No. 84. Delivery of medicines to your home and office.

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Klacid, 1 piece, 70.7 g, 250 mg/5 ml, powder for suspension for oral administration

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 vitro studies

the binding of clarithromycin to plasma proteins averaged about 70% at clinically significant concentrations from 0.45 to 4.5 μg/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

Fabrics	Concentrations
Fabrics	Tissue, µg/g	Serum, mcg/ml
Tonsils	1,6	0,8
Lungs	8,8	1,7

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.

Instructions for use KLACID granules

Combinations are contraindicated due to the possible development of severe consequences of drug interactions

An increase in plasma concentrations of cisapride, pimozide and terfenadine in the blood serum was observed when they were used together with clarithromycin, which can lead to a prolongation of the QT interval and the occurrence of arrhythmias, incl. ventricular tachycardia, ventricular fibrillation and ventricular ari. Similar effects were observed with the combined use of astemizole and other macrolides.

Concomitant use of clarithromycin and ergotamine or dihydroergotamine has been associated with symptoms of acute ergotism, such as vasospasm and ischemia of the limbs and other tissues, including the central nervous system.

Effect of other drugs on the pharmacokinetics of clarithromycin

The effect of these drugs on clarithromycin blood concentrations is known or suspected, and dosage adjustments or alternative therapy may be necessary.

Potent inducers of the cytochrome P450 isoenzyme system, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentine, can accelerate the metabolism of clarithromycin, reducing its concentration in the blood plasma, but increasing the concentration of 14-OH-clarithromycin, a microbiologically active metabolite. Because The microbiological activity of clarithromycin and 14-OH-clarithromycin is different in relation to different bacteria; the expected therapeutic effect may not be achieved due to the combined use of clarithromycin and inducers of isoenzymes of the cytochrome P450 system.

Css of the active metabolite 14-OH-clarithromycin did not change significantly when combined with fluconazole. No clarithromycin dose change is required.

The use of ritonavir and clarithromycin led to a significant inhibition of clarithromycin metabolism. Cmax of clarithromycin increased by 31%. Cmin - by 182%, AUC increased by 77%. There was complete inhibition of the formation of 14-OH-clarithromycin. Due to the large therapeutic range, a dose reduction of clarithromycin is not required in patients with normal renal function. For patients with renal failure, dose adjustment is necessary:

with CC 30-60 ml/min, the dose of clarithromycin should be reduced by 50%, with CC <30 ml/min - by 75%. Clarithromycin in doses exceeding 1 g/day should not be used together with ritonavir.

Effect of clarithromycin on the pharmacokinetics of other drugs

There are post-marketing reports of the development of ventricular tachycardia of the torsade de pointes type that occurred with the simultaneous use of clarithromycin with quinidine or disopyramide. It is recommended to carry out ECG monitoring for timely detection of QT interval prolongation. Serum concentrations of these drugs should be monitored during clarithromycin therapy.

Concomitant use of clarithromycin, a known inhibitor of the CYP3A isoenzyme, and a drug primarily metabolized by this isoenzyme, may cause an increase in the concentration of this drug in the blood plasma, which, in turn, may enhance or prolong its therapeutic effect and the risk of adverse reactions.

Caution should be exercised when using clarithromycin in patients receiving drugs that are CYP3A substrates, especially if they have a narrow therapeutic index (eg, carbamazepine) and/or are extensively metabolized by this isoenzyme.

In patients receiving clarithromycin, dose adjustments and, if possible, close monitoring of plasma concentrations of a drug metabolized by CYP3A may be necessary.

Such drugs or groups of drugs are metabolized by the same isoenzyme CYP3A:

alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (eg, warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfen adin, triazolam and vinblastine . A similar mechanism of interaction has been noted with the use of phenytoin. theophylline and valproate, metabolized by another isoenzyme of the cytochrome P450 system.

Like other macrolides, clarithromycin led to increased concentrations of HMG-CoA reductase inhibitors such as lovastatin and simvastatin. Rarely, rhabdomyolysis has been reported in patients when co-administered with these drugs.

The use of clarithromycin in combination with omeprazole in healthy adult volunteers resulted in an increase in the Css of omeprazole. When omeprazole was used alone, the average pH value of gastric juice when measured over 24 hours was 5.2, when omeprazole was used together with clarithromycin - 5.7.

The combined use of clarithromycin and oral anticoagulants may potentiate the effect of the latter, which requires careful monitoring of prothrombin time.

There is a possibility of increased plasma concentrations of PDE inhibitors (sildenafil, tadalfil and vardenafil) when used together with clarithromycin, which may require a reduction in the dose of PDE inhibitors.

The results of clinical studies have shown that there is a slight but statistically significant increase in plasma concentrations of theophylline or carbamazepine when used concomitantly with clarithromycin.

A dose reduction of tolterodine may be necessary when used with clarithromycin.

The combined use of oral midazolam and clarithromycin should be avoided. When administering midazolam intravenously with clarithromycin, the patient should be carefully monitored for timely dose adjustment. The same precautions should be taken when using other triazolebenzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination does not depend on CYP3A (temazepam, nitrazepam, lorazepam), the development of a clinically significant interaction with clarithromycin is unlikely.

There are post-marketing reports of drug interactions and the development of adverse reactions from the central nervous system (such as drowsiness and confusion) with the combined use of clarithromycin and triazolam. The patient should be monitored for the possibility of increased pharmacological effects on the central nervous system.

Other types of interaction

Colchicine is a substrate of CYP3A and P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are used concomitantly, inhibition of Pgp and/or CYP3A by clarithromycin may result in increased colchicine exposure. Patients should be monitored for clinical signs of colchicine toxicity.

During post-marketing surveillance, increased serum digoxin concentrations have been reported in patients receiving clarithromycin concomitantly with digoxin. Some patients developed signs of glycoside intoxication, incl. life-threatening arrhythmias. Serum digoxin concentrations in patients should be carefully monitored when administered with clarithromycin.

Concomitant use of clarithromycin immediate-release tablets and zidovudine in HIV-infected patients may cause a decrease in serum Css of zidovudine. This can be avoided by maintaining an interval between doses of clarithromycin and zidovudine. This interaction has not been reported with clarithromycin suspension and zidovudine or dideoxynosine in children.

Bidirectional drug interactions between clarithromycin and atazanavir, itraconazole, and saquinavir are also possible.

The development of arterial hypotension, bradyarrhythmia and lactic acidosis has been reported with the combined use of clarithromycin and verapamil.

KLATSID

Interaction

The following drugs are contraindicated in combination with clarithromycin due to the potential for serious side effects:
Cisapride, pimozide, terfenadine and astemizole

When clarithromycin was co-administered with cisapride, pimozide, terfenadine or astemizole, increased plasma concentrations of the latter were reported, which could lead to QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and torsade de pointes (TdP) (see section "Contraindications")

Ergot alkaloids

Post-marketing studies show that when clarithromycin is used together with ergotamine or dihydroergotamine, the following effects associated with acute poisoning with ergotamine drugs are possible: vascular spasm, ischemia of the limbs and other tissues, including the central nervous system. Concomitant use of clarithromycin with ergot alkaloids is contraindicated (see section “Contraindications”).

HMG-CoA reductase inhibitors (statins)

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 combined use with clarithromycin increases their serum concentrations, which leads to an increased risk of developing myopathy, including Rhabdomyolysis Cases of rhabdomyolysis have been reported in patients taking clarithromycin concomitantly with these drugs. If clarithromycin is necessary, lovastatin or simvastatin should be discontinued during therapy.

Clarithromycin should be used with caution in combination therapy with other statins. It is recommended to use statins that are independent of the metabolism of the CYP3A isoenzyme (for example, fluvastatin). If coadministration is necessary, it is recommended to take the lowest dose of statin. The development of signs and symptoms of myopathy should be monitored.

Effect of other drugs on clarithromycin

Drugs that are inducers of the CYP3A isoenzyme

(for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) may induce the metabolism of clarithromycin. This may result in subtherapeutic concentrations of clarithromycin, resulting in reduced effectiveness. In addition, it is necessary to monitor the concentration of the CYP3A inducer in the blood plasma, which may increase due to the inhibition of the CYP3A isoenzyme by clarithromycin. When rifabutin and clarithromycin were used together, an increase in plasma concentrations of rifabutin and a decrease in serum concentrations of clarithromycin were observed with an increased risk of developing uveitis.

The following drugs have a proven or suspected effect on clarithromycin plasma concentrations; if used together with clarithromycin, dosage adjustments or switching to alternative treatment may be required

Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine

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

Etravirine

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

Fluconazole

Coadministration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily in 21 healthy volunteers resulted in an increase in the mean clarithromycin minimum steady-state concentration (Cmin) and AUC by 33% and 18%, respectively. However, co-administration did not significantly affect the average steady-state concentration of the active metabolite 14-OH-clarithromycin. No dose adjustment of clarithromycin is required when taking fluconazole concomitantly.

Ritonavir

A pharmacokinetic study showed that coadministration of ritonavir 200 mg every eight hours and clarithromycin 500 mg every 12 hours resulted in a marked suppression of the metabolism of clarithromycin. When co-administered with ritonavir, clarithromycin Cmax increased by 31%, Cmin increased by 182% and AUC increased by 77%. Complete suppression of the formation of 14-OH-clarithromycin was noted. Due to the wide therapeutic range of clarithromycin, dose reduction is not required in patients with normal renal function. In patients with renal failure, it is advisable to consider the following dose adjustment options: with CC 30-60 ml/min, the dose of clarithromycin should be reduced by 50%; with CC less than 30 ml/min, the dose of clarithromycin should be reduced by 75%. Ritonavir should not be co-administered with clarithromycin in doses exceeding 1 g/day.

Effect of clarithromycin on other drugs

Antiarrhythmic drugs (quinidine and disopyramide)

Ventricular tachycardia of the “pirouette” type may occur with the combined use of clarithromycin and quinidine or disopyramide. When clarithromycin is coadministered with these drugs, the electrocardiogram should be regularly monitored for prolongation of the QT interval, and serum concentrations of these drugs should also be monitored.

During post-marketing use, cases of hypoglycemia have been reported during co-administration of clarithromycin and disopyramide. It is necessary to monitor the concentration of glucose in the blood while using clarithromycin and disopyramide.

Oral hypoglycemic agents/insulin

When clarithromycin is used together with oral hypoglycemic agents (for example, sulfonylureas) and/or insulin, severe hypoglycemia may occur. Concomitant use of clarithromycin with certain hypoglycemic drugs (for example, nateglinide, pioglitazone, repaglinide and rosiglitazone) may lead to inhibition of the CYP3A isoenzyme by clarithromycin, which may result in hypoglycemia. Careful monitoring of glucose concentrations is recommended.

Interactions due to CYP3A isoenzyme

Co-administration of clarithromycin, which is known to inhibit the CYP3A isoenzyme, 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 index (for example, carbamazepine) and/or are extensively metabolized by this enzyme. If necessary, the dose of the drug taken together with clarithromycin should be adjusted. Also, whenever possible, serum concentrations of drugs primarily metabolized by the CYP3A isoenzyme should be monitored.

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 (eg, warfarin), quinidine, rifabutin, sildenafil, tacrolimus, triazolam and vinblastine. Also, agonists of the CYP3A isoenzyme include the following drugs that are contraindicated for combined use 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 cytochrome P450 systems include phenytoin, theophylline and valproic acid.

Indirect anticoagulants

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

Omeprazole

Clarithromycin (500 mg every 8 hours) was studied in healthy adult volunteers in combination with omeprazole (40 mg daily). When clarithromycin and omeprazole were co-administered, steady-state plasma concentrations of omeprazole were increased (Cmax, AUC0-24 and T1/2 increased by 30%, 89% and 34%, respectively). The mean 24-hour gastric pH was 5.2 when omeprazole was taken alone and 5.7 when omeprazole was taken with clarithromycin.

Sildenafil, tadalafil and vardenafil

Each of these phosphodiesterase inhibitors is metabolized, at least in part, by the CYP3A isoenzyme. 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 result in increased phosphodiesterase inhibitory effects. When using these drugs together with clarithromycin, consider reducing the dose of sildenafil, tadalafil and vardenafil.

Theophylline, carbamazepine

When clarithromycin and theophylline or carbamazepine are used together, the concentration of these drugs in the systemic circulation may increase.

Tolterodine

The primary metabolism of tolterodine occurs through the 2D6 isoform of cytochrome P450 (CYP2D6). However, in part of the population lacking the CYP2D6 isoenzyme, metabolism occurs through the CYP3A isoenzyme. In this population, inhibition of CYP3A results in significantly higher serum tolterodine concentrations. In populations that are poor metabolizers of CYP2D6, a dose reduction of tolterodine may be required in the presence of CYP3A inhibitors such as clarithromycin.

Benzodiazepines (eg, alprazolam, midazolam, triazolam)

When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC increased by 2.7 times after intravenous midazolam and 7 times after oral administration. Concomitant use of clarithromycin with oral midazolam is contraindicated. If intravenous midazolam is used concomitantly 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 CYP3A, including triazolam and alprazolam. For benzodiazepines whose elimination is not dependent on the CYP3A isoenzyme (temazepam, nitrazepam, lorazepam), a clinically significant interaction with clarithromycin is unlikely.

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

Interactions with other drugs

Aminoglycosides

When taking clarithromycin concomitantly with other ototoxic drugs, especially aminoglycosides, caution should be exercised and the functions of the vestibular and auditory systems should be monitored both during and after therapy.

Colchicine

Colchicine is a substrate of both CYP3A and the P-glycoprotein (Pgp) transporter protein. It is known that clarithromycin and other macrolides are inhibitors of the CYP3A and Pgp isoenzymes. When clarithromycin and colchicine are taken together, inhibition of Pgp and/or CYP3A may result in increased effects of colchicine. The development of clinical symptoms of colchicine poisoning should be monitored. There have been post-marketing reports of cases of colchicine poisoning when taken concomitantly with clarithromycin, most often in elderly patients.

Some of the reported cases occurred in patients suffering from kidney failure. Some cases were reported to be fatal.

The simultaneous use of clarithromycin and colchicine is contraindicated (see section “Contraindications”).

Digoxin

Digoxin is suspected to be a Pgp substrate. Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may result in increased effects of digoxin. Coadministration of digoxin and clarithromycin may also result in increased serum concentrations of digoxin. Some patients have experienced clinical symptoms of digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored when clarithromycin and digoxin are coadministered.

Zidovudine

Concomitant use of clarithromycin tablets and oral zidovudine by adult HIV-infected patients may result in decreased steady-state zidovudine concentrations.

Because clarithromycin interferes with the oral absorption of zidovudine, the interaction can be largely avoided by taking clarithromycin and zidovudine 4 hours apart.

This interaction was not observed in HIV-infected children taking clarithromycin pediatric suspension with zidovudine or dideoxyinosine. Since clarithromycin may interfere with the absorption of zidovudine when administered concomitantly orally in adult patients, such an interaction is unlikely to occur when clarithromycin is used intravenously.

Phenytoin and valproic acid

There is evidence of interactions between CYP3A inhibitors (including clarithromycin) and drugs that are not metabolized by CYP3A (phenytoin and valproic acid). For these drugs, when used together with clarithromycin, it is recommended to determine their serum concentrations, as there are reports of their increase.

Bidirectional drug interactions

Atazanavir

Clarithromycin and atazanavir are both substrates and inhibitors of the CYP3A isoenzyme. There is evidence of a bidirectional interaction between these drugs.

Coadministration 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 exposure, with a 28% increase in atazanavir AUC. Due to the wide therapeutic range of clarithromycin, dose reduction is not required in patients with normal renal function. In patients with moderate renal failure (creatinine clearance 30-60 ml/min), the dose of clarithromycin should be reduced by 50%. In patients with CC 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 used in conjunction with protease inhibitors.

Blockers of "slow" calcium channels

When using clarithromycin simultaneously with blockers of “slow” calcium channels that are metabolized by the CYP3A4 isoenzyme (for example, verapamil, amlodipine, diltiazem), caution should be exercised as there is a risk of arterial hypotension. Plasma concentrations of clarithromycin, as well as slow calcium channel blockers, may increase with simultaneous use. Arterial hypotension, bradyarrhythmia and lactic acidosis are possible when taking clarithromycin and verapamil simultaneously.

Itraconazole

Clarithromycin and itraconazole are substrates and inhibitors of the CYP3A isoenzyme, which determines the bidirectional interaction of the drugs. Clarithromycin may increase plasma concentrations of itraconazole, while itraconazole may increase plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be closely monitored 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 the drugs. Concomitant administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily) in 12 healthy volunteers increased the AUC and Cmax of saquinavir by 177% and 187%, respectively, compared with saquinavir administration alone. separately. The AUC and Cmax values of clarithromycin were approximately 40% higher than with clarithromycin monotherapy. When these two drugs are used together for a limited time at the doses/formulations indicated above, no dose adjustment is required. Results from drug interaction studies using saquinavir soft gelatin capsules may not be consistent with the effects observed with saquinavir hard gelatin capsules. The results of drug interaction studies with saquinavir monotherapy may not be consistent with the effects observed with saquinarine/ritonavir therapy. When taking saquinavir with ritonavir, consider the potential effect of ritonavir on clarithromycin.

Klacid 250 mg 10 pcs. film-coated tablets

pharmachologic effect

Antibacterial, bacteriostatic.

Composition and release form Klacid 250 mg 10 pcs. film-coated tablets

Film-coated tablets - 1 tablet:

Active ingredients: clarithromycin - 2500 mg;
Excipients: croscarmellose sodium - 35 mg, microcrystalline cellulose - 85 mg, pregelatinized starch - 65 mg, silicon dioxide - 7.2 mg, povidone - 20 mg, stearic acid - 12.5 mg, magnesium stearate - 7.5 mg, talc - 17.5 mg, quinoline yellow (E104) - 0.3 mg;
Film shell composition: hypromellose - 13 mg, hydroxypropylcellulose (hyprolose) - 1 mg, propylene glycol - 8.6 mg, sorbitan monooleate - 1 mg, titanium dioxide - 3 mg, sorbic acid - 0.55 mg, vanillin - 0.55 mg, quinoline yellow (E104) - 0.8 mg.

7, 10 or 14 pcs. - blisters (1, 2, 3) - cardboard packs.

Description of the dosage form

Light yellow, oval, biconvex film-coated tablets.

Directions for use and doses

Inside, regardless of food intake.

Typically, adults are prescribed 250 mg of clarithromycin 2 times a day. In more severe cases, the dose is increased to 500 mg 2 times a day. Typically, the duration of treatment is from 5–6 to 14 days.

Patients with creatinine Cl less than 30 ml/min are prescribed half the usual dose of clarithromycin, i.e. 250 mg 1 time per day, or for more severe infections - 250 mg 2 times per day. Treatment of such patients continues for no more than 14 days.

For mycobacterial infections, 500 mg of the drug is prescribed 2 times a day.

For common MAC infections in patients with AIDS: Treatment should be continued as long as there is clinical and microbiological evidence of benefit. Clarithromycin should be prescribed in combination with other antimicrobial drugs.

For infectious diseases caused by mycobacteria, except tuberculosis: the duration of treatment 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 odontogenic infections, the dose of clarithromycin is 250 mg 2 times a day for 5 days.

For eradication of H. pylori

Combination treatment with three drugs

Clarithromycin at a dose of 500 mg 2 times a day in combination with lansoprazole at a dose of 30 mg 2 times a day and amoxicillin at a dose of 1000 mg 2 times a day for 10 days.

Clarithromycin at a dose of 500 mg 2 times a day in combination with amoxicillin at a dose of 1000 mg 2 times a day and omeprazole at a dose of 20 mg/day for 7–10 days.

Combination treatment with two drugs

Clarithromycin at a dose of 500 mg 3 times a day in combination with omeprazole at a dose of 40 mg/day for 14 days, followed by omeprazole at a dose of 20–40 mg/day for the next 14 days.

Clarithromycin at a dose of 500 mg 3 times a day in combination with lansoprazole at a dose of 60 mg/day for 14 days. For complete healing of the ulcer, additional reduction in the acidity of gastric juice may be required.

Pharmacodynamics

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

Clarithromycin has demonstrated high in vitro activity against standard and isolated bacterial cultures. Highly effective against many aerobic and anaerobic, gram-positive and gram-negative microorganisms.

Clarithromycin is highly effective in vitro against Legionella pneumophila, Mycoplasma pneumoniae and Helicobacter (Campilobacter) pylori. Enterobacteriaceae and Pseudomonas, as well as other non-lactose-degrading gram-negative bacteria, are not sensitive to clarithromycin.

Clarithromycin has been shown to have an antibacterial effect against the following pathogens: aerobic gram-positive microorganisms - Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes; aerobic gram-negative microorganisms: Haemophilus influenzae, Haemophilus parainftuenzae, Moraxella catarrhalis, Legionella pneumophila, Neisseria gonorrhoeae; other microorganisms - Mycoplasma pneumoniae, Chlamydia pneumoniae (TWAR), Chlamydia trachomatis; mycobacteria - Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum; Mycobacterium avium complex (MAC) - a complex including: Mycobacterium avium, Mycobacterium intracellulare.

The production of beta-lactamase does not affect the activity of clarithromycin.

Most strains of staphylococci resistant to methicillin and oxacillin are also resistant to clarithromycin.

Helicobacter pylori. The sensitivity of H. pylori to clarithromycin was studied on H. pylori isolates isolated from 104 patients before starting drug therapy. In 4 patients, strains of H. pylori were isolated that were resistant to clarithromycin, in 2, strains with intermediate resistance were isolated, and in the remaining 98 patients, H. pylori isolates were sensitive to clarithromycin. Clarithromycin is effective in vitro and against most strains of the following microorganisms (however, the safety and effectiveness of the use 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), 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;
campylobacter - Campylobacter jejuni.

The main metabolite of clarithromycin in the human body is the microbiologically active metabolite - 14-hydroxyclarithromycin (14-OH-clarithromycin). 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 H.influenzae, for which the effectiveness of the metabolite is 2 times higher. The parent substance and its major metabolite have either additive or synergistic effects against H. influenzae in vitro and in vivo, depending on the bacterial culture.

Sensitivity studies

Quantitative methods that require measuring the diameter of the growth inhibition zone of microorganisms provide the most accurate estimates of the sensitivity of bacteria to antimicrobial agents.

One recommended susceptibility testing procedure uses discs soaked in 15 μg of clarithromycin (Kirby-Bauer diffusion test); the test results are interpreted depending on the diameter of the zone of growth inhibition of the microorganism and the MIC value of clarithromycin. The MIC value is determined by diluting the medium or diffusion into agar.

Laboratory tests give one of 3 results:

resistant - we can assume that the infection cannot be treated with this drug;
moderately sensitive - the therapeutic effect is ambiguous, and possibly increasing the dosage may lead to sensitivity;
sensitive - the infection can be considered treatable with clarithromycin.

Pharmacokinetics

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 in vitro studies, the binding of clarithromycin to plasma proteins was 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)

Fabrics	Concentrations
Fabrics	Tissue, µg/g	Serum, mcg/ml
Tonsils	1,6	0,8
Lungs	8,8	1,7

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.

Indications for use Klacid 250 mg 10 pcs. film-coated tablets

lower respiratory tract infections (such as bronchitis, pneumonia);
upper respiratory tract infections (such as pharyngitis, sinusitis);
infections of the skin and soft tissues (such as folliculitis, inflammation of the subcutaneous tissue, erysipelas);
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 Mycobacterium avium complex (MAC). HIV-infected patients with a CD4 lymphocyte count (T-helper lymphocytes) of no more than 100 per 1 mm3;
to eliminate H. pylori and reduce the frequency of relapses of duodenal ulcers;
odontogenic infections.

Contraindications

hypersensitivity to macrolide drugs;
simultaneous use of clarithromycin with the following drugs: astemizole, cisapride, pimozide, terfenadine, ergotamine, dihydroergotamine;
porphyria;
pregnancy;
lactation period;
children under 3 years of age.

With caution: impaired liver and kidney function.

Clarithromycin is eliminated primarily by the liver. In this regard, caution should be exercised when prescribing antibiotics to patients with impaired liver function. Caution should be exercised when treating patients with moderate to severe renal failure with clarithromycin. In clinical practice, cases of toxicity of colchicine when combined with clarithromycin have been described, especially in elderly people. Some of them were observed in patients with renal failure; Several deaths have been reported in similar patients. The possibility of cross-resistance between clarithromycin and other macrolide drugs, as well as lincomycin and clindamycin, must be considered.

Application Klacid 250 mg 10 pcs. film-coated tablets during pregnancy and breastfeeding

The safety of clarithromycin in pregnant and lactating women has not been studied. Clarithromycin is known to be excreted in breast milk. Therefore, the use of clarithromycin during pregnancy and lactation is recommended only in cases where there is no safer alternative, and the risk associated with the disease itself outweighs the possible harm to the mother and fetus.

special instructions

In the presence of chronic liver diseases, it is necessary to regularly monitor serum enzymes.

Prescribe with caution against drugs metabolized by the liver.

In case of co-administration with warfarin or other indirect anticoagulants, PT must be monitored.

In children, it is preferable to use Klacid in powder dosage form for the preparation of an oral suspension of 125 mg/5 ml and 250 mg/5 ml.

Overdose

Symptoms: Taking a large dose of clarithromycin may cause symptoms of gastrointestinal disorders. In one patient with a history of bipolar disorder, changes in mental status, paranoid behavior, hypokalemia, and hypoxemia were described after taking 8 g of clarithromycin.

Treatment: in case of overdose, the unabsorbed drug should be removed from the gastrointestinal tract and symptomatic therapy should be carried out. Hemodialysis and peritoneal dialysis do not have a significant effect on clarithromycin serum levels, which is also typical for other macrolide drugs.

Side effects Klacid 250 mg 10 pcs. film-coated tablets

The most common adverse events were from the gastrointestinal tract, incl. diarrhea, vomiting, abdominal pain and nausea. Other adverse reactions included headache, taste disturbances, and transient increases in liver enzymes.

Post-marketing experience

During treatment with clarithromycin, liver dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported infrequently. Hepatic dysfunction can be severe and is usually reversible. In very rare cases, deaths from liver failure have been reported, which were usually observed in the presence of serious concomitant diseases and/or concomitant use of other drugs.

Isolated cases of increased serum creatinine levels have been described, but their connection with the drug has not been established.

Allergic reactions have been reported with oral administration of clarithromycin, ranging from urticaria and minor rashes to anaphylaxis and Stevens-Johnson syndrome/toxic epidermal necrolysis.

There have been reports of transient CNS effects including dizziness, anxiety, insomnia, nightmares, tinnitus, confusion, disorientation, hallucinations, psychosis and depersonalization; their cause-and-effect relationship with the drug has not been established.

Cases of hearing loss have been reported during treatment with clarithromycin; after cessation of treatment, hearing was usually restored. There are also cases of disturbances in the sense of smell, which are usually combined with a perversion of taste.

Glossitis, stomatitis, oral thrush and discoloration of the tongue have been described during treatment with clarithromycin. There are known cases of tooth discoloration in patients treated with clarithromycin. These changes are usually reversible and can be corrected by your dentist.

Rare cases of hypoglycemia have been described, some of which were observed in patients receiving oral hypoglycemic agents or insulin.

Isolated cases of leukopenia and thrombocytopenia have been reported.

When treating with clarithromycin, as with other macrolides, prolongation of the QT interval, ventricular tachycardia and torsade de pointes (TdP) have been observed in rare cases.

Rare cases of pancreatitis and seizures have been described.

There are reports of the development of interstitial nephritis during treatment with clarithromycin.

In clinical practice, cases of toxicity of colchicine when combined with clarithromycin have been described, especially in elderly people. Some of them were observed in patients with renal failure; Several deaths have been reported in similar patients.

Children with suppressed immune systems

In patients with AIDS and other immunodeficiencies receiving clarithromycin in higher doses over a long period of time for the treatment of mycobacterial infections, it is often difficult to differentiate the undesirable effects of the drug from symptoms of HIV infection or intercurrent illnesses.

The main adverse events in patients taking clarithromycin orally at a dose of 1 g were nausea, vomiting, taste disturbance, abdominal pain, diarrhea, rash, bloating, headache, hearing loss, constipation, increased AST and ALT levels. Dyspnea, insomnia, and dry mouth were also reported less frequently.

In this group of patients with suppressed immunity, significant deviations of laboratory parameters from normative values in specific tests (sharp increase or decrease) were recorded. Based on this, approximately 2–3% of patients taking clarithromycin orally at a dose of 1 g/day had significant laboratory abnormalities, such as increased AST, ALT levels and decreased white blood cell and platelet counts. Fewer patients also experienced elevated blood urea nitrogen levels.

Drug interactions

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, there was a small but statistically significant (p) difference when combining theophylline or carbamazepine with clarithromycin.

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.

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 torsade de pointes (TdP).

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