Clacid, 125 mg/5 ml 70.7 g

Pharmacotherapeutic group: Antibiotic, macrolide

Pharmacological action

Semi-synthetic antibiotic of macrolide group. It has antibacterial action, interacting with 50S ribosomal subunit of bacteria and inhibiting protein synthesis of bacteria sensitive to it.

Clarithromycin has shown high in vitro activity against both standard laboratory strains of bacteria and those isolated from patients in clinical practice. It shows high activity against many aerobic and anaerobic gram-positive and gram-negative microorganisms. Minimum inhibitory concentrations (MIC) of clarithromycin for most pathogens are lower than MIC of erythromycin on average per log₂ dilution.

Clarithromycin in vitro is highly active against Legionella pneumophila and Mycoplasma pneumoniae. It has a bactericidal effect against Helicobacter pylori; this activity of clarithromycin is higher at neutral pH than at acidic pH. In addition, in vitro and in vivo data indicate that clarithromycin acts on clinically relevant mycobacterial species. Enterobacteriaceae and Pseudomonas spp. as well as other non-lactose-fermenting Gram-negative bacteria are not sensitive to clarithromycin.

The activity of clarithromycin against most strains of the microorganisms listed below has been demonstrated both in vitro and in clinical practice for the diseases listed under “Indications”.

Aerobic Gram-positive microorganisms: Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes; aerobic gram-negative microorganisms: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Legionella pneumophila; other microorganisms: Mycoplasma pneumoniae, Chlamydia pneumoniae (TWAR), Mycobacteria: Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium avium complex (MAC) – complex including Mycobacterium avium, Mycobacterium intracellulare.

The production of β-lactamase has no effect on clarithromycin activity.

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

Helicobacter pylori

Sensitivity of Helicobacter pylori to clarithromycin was studied in Helicobacter pylori isolates isolated from 104 patients before initiation of therapy with the drug. Clarithromycin-resistant Helicobacter pylori strains were isolated in 4 patients, 2 patients had moderate resistance strains, and the remaining 98 patients’ Helicobacter pylori isolates were sensitive to clarithromycin.

Clarithromycin has action in vitro against most strains of the microorganisms listed below, but the safety and efficacy of clarithromycin in clinical practice has not been confirmed by clinical studies, and the practical value remains unclear.

Aerobic Gram-positive microorganisms: Streptococcus agalactiae, Streptococci (groups C, F, G), Streptococci group Viridans; 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 humans 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 Haemophilus influenzae, against which the effectiveness of the metabolite is 2 times higher. The parent compound and its main metabolite have either additive or synergistic effect against Naemophilus influenzae under in vitro and in vivo conditions depending on the bacterial strain.

Sensitivity test

Quantitative methods that require measurement of the diameter of the growth suppression zone provide the most accurate estimates of bacterial sensitivity to antimicrobial agents. One recommended technique for sensitivity testing uses discs impregnated with 15 µg of clarithromycin (Kirby-Bauer disc-diffusion method); in interpreting the test, zona diameters of growth suppression correlate with the IPC values of clarithromycin. IPC values are determined by dilution in broth or agar.

When using these techniques, a report from the laboratory that the strain is “sensitive” indicates that the infectious agent is likely to respond to treatment. A “resistant” response indicates that the pathogen will probably not respond to treatment. A response of “intermediate resistance” suggests that the therapeutic effect of the drug may be ambiguous or the microorganism may be sensitive when higher doses of the drug are used (“intermediate resistance” is also called “moderate resistance”).

Pharmacokinetics

Intake

The first pharmacokinetic data were obtained when clarithromycin tablets were studied. The drug is rapidly absorbed from the gastrointestinal tract. The absolute bioavailability of clarithromycin tablets of 250 mg is approximately 50%. Food slightly delayed the onset of absorption and formation of the active metabolite 14-OH clarithromycin, but did not affect the bioavailability of the drug.

Distribution, metabolism and excretion

In in vitro studies, the plasma protein binding of clarithromycin averaged about 70% at clinically relevant concentrations of 0.45 to 4.5 µg/mL.

Healthy. The bioavailability and pharmacokinetics of clarithromycin suspension were studied in healthy adults and children. When administered as a single dose in adults, the overall bioavailability of the suspension was equivalent to that of the tablets (in both cases the dose was 250 mg) or slightly higher. As with tablets, food slightly delayed absorption of clarithromycin suspension, but had no effect on the overall bioavailability of the drug. The maximum concentration (C_max), area under the concentration-time curve (AUC) and elimination half-life (T_1/2) of clarithromycin when taking the infant suspension (after meals) were 0.95 µg/mL, 6.5 µg×h/mL, and 3.7 h, respectively, and 1.10 µg/mL, 6.3 µg×h/mL, and 3.3 h, respectively, when the 250 mg tablet (fasting) was taken.

When clarithromycin suspension was administered at a dose of 250 mg every 12 h in adults, equilibrium concentrations (C_ss) in the blood were reached by the fifth dose. The pharmacokinetic parameters were as follows: C_max was 1.98 μg/mL, AUC was 11.5 μg×h/mL, time to reach maximum concentration (T_max) was 2.8 h and T_1/2 – 3.2 h for clarithromycin and, respectively, 0.67, 5.33, 2.9 and 4.9 for 14-OH clarithromycin.

In healthy subjects, serum concentrations peaked within 2 h after ingestion on an empty stomach. When the drug is taken in tablet form at a dose of 250 mg every 12 h, the peak equilibrium serum concentrations of clarithromycin were reached within 2-3 days and were approximately 1 mcg/ml. Corresponding peak concentrations for the 500 mg dose every 12 h ranged from 2 µg/ml to 3 µg/ml.

The T_1/2 of clarithromycin was 3-4 h when tablets were taken 250 mg every 12 h, but increased to 5-7 h after 500 mg every 12 h. The equilibrium C_max of the main metabolite, 14-OH-clarithromycin, is about 0.6 µg/mL, and the T_1/2 when the drug is taken at a dose of 250 mg every 12 h is 5-6 h. When clarithromycin is taken at a dose of 500 mg every 12 h, the equilibrium C_max of 14-OH-clarithromycin is slightly higher (up to 1 µg/mL), and the T_1/2 is about 7 h. With both doses, equilibrium concentrations of the metabolite are usually reached within 2-3 days.

When using clarithromycin at a dose of 250 mg every 12 h, approximately 20% of the dose is excreted unchanged by the kidneys. When using clarithromycin in a dose of 500 mg every 12 hours approximately 30% of the dose is excreted unchanged by the kidneys. Renal clearance of clarithromycin is not significantly dose-dependent and is approximately equal to normal glomerular filtration rate. The main metabolite detected in the urine is 14-OH clarithromycin, the proportion of which is 10-15% of the dose (250 or 500 mg every 12 hours).

Patients. Clarithromycin and its metabolite 14-OH-clarithromycin penetrate rapidly into tissues and body fluids. Tissue concentrations are usually several times higher than serum concentrations.

The table shows examples of tissue and serum concentrations:

In children who required oral antibiotic treatment, clarithromycin demonstrated high bioavailability, with a pharmacokinetic profile similar to that of adults taking the same dosage form. The drug is quickly and well absorbed in children. Food slightly delays absorption of clarithromycin, but has no significant effect on its bioavailability or pharmacokinetic properties. Equilibrium parameters of clarithromycin pharmacokinetics achieved after 5 days (ninth dose) were as follows: C_max was 4.60 μg/mL, AUC was 15.7 μg×h/mL, and T_max was 2.8 h; corresponding values for the 14-OH metabolite clarithromycin were 1.64 μg/mL, 6.69 μg×h/mL, and 2.7 h, respectively. The calculated T_1/2 of clarithromycin and its metabolite were 2.2 and 4.3 h, respectively.

In patients with otitis media, 2.5 h after the fifth dose (7.5 mg/kg 2 times/day), the mean concentrations of clarithromycin and its metabolite in middle ear fluid were 2.53 and 1.27 µg/g. Concentrations of the drug and its metabolite were twice as high as serum concentrations.

Pharmacokinetics in special clinical cases

Hepatic impairment. C_ss of clarithromycin in patients with impaired liver function do not differ from those in healthy subjects, while 14-OH-clarithromycin concentrations were lower. The decrease in 14-OH-clarithromycin formation in patients with hepatic impairment was at least partially offset by increased renal clearance of clarithromycin compared to that in healthy subjects.

Renal dysfunction. The pharmacokinetics of clarithromycin were also altered in patients with impaired renal function who received the drug in repeated doses of 500 mg. In such patients, plasma concentrations, T_1/2, C_max, C_min and AUC of clarithromycin and its metabolite were higher than in healthy subjects. Deviations of these parameters correlated with the degree of renal impairment: the differences were greater with more severe renal impairment.

Patients in the elderly. Elderly patients had higher blood concentrations of clarithromycin and its metabolite 14-OH-clarithromycin and slower excretion than the younger group (when clarithromycin was given in repeated doses of 500 mg). However, after adjusting the results for renal creatinine clearance (KK), there were no differences in the two groups. Thus, the main influence on the pharmacokinetic parameters of clarithromycin is renal function, not age.

Patients with mycobacterial infections. C_ss clarithromycin and 14-OH clarithromycin in patients with HIV infection who received clarithromycin at conventional doses (adult tablets, pediatric suspension) were similar to those in healthy subjects. However, when clarithromycin is given in higher doses, which may be necessary to treat mycobacterial infections, concentrations of the antibiotic may be significantly higher than usual.

In children with HIV infection who took clarithromycin at a dose of 15 to 30 mg/kg/day in two doses, equilibrium C_max values were typically 8 to 20 µg/mL. However, in children with HIV infection who received clarithromycin suspension at a dose of 30 mg/kg/day in two doses, C_max reached 23 µg/ml. When the drug was taken at higher doses, there was a prolongation of T_1/2 compared to that in healthy subjects receiving clarithromycin at normal doses. Increased plasma concentrations and prolongation of T_1/2 when using clarithromycin at higher doses are due to the non-linear pharmacokinetics of the drug.

Indications

Infectious inflammatory diseases caused by clarithromycin-sensitive microorganisms:

Active ingredient

Composition

Excipients:

carbomer (carbopol 974P) – 150 mg,

povidone K90 – 35 mg,

hypromellose phthalate – 304.2 mg,

castor oil – 32.1 mg,

silicon dioxide – 10 mg,

maltodextrin – 238.7 mg,

sucrose – 2276.2 mg,

titanium dioxide – 35.7 mg,

Xanthan gum – 3.8 mg,

Fruit flavoring – 35.7 mg,

potassium sorbate – 20 mg,

citric acid – 4.24 mg.

How to take, the dosage

For oral administration. Ready suspension should be taken orally regardless of meals (including with milk).

In order to obtain the suspension in the bottle gradually add water to the mark (60, 70 or 100 ml) and shake. The ready suspension can be stored for 14 days at room temperature (15° to 30°C). The suspension should be shaken well before each administration.

The recommended daily dose of clarithromycin suspension for non-mycobacterial infections in children is 7.5 mg/kg 2 times/day (maximum 500 mg 2 times/day). The usual duration of treatment is 5-10 days, depending on the causative agent and the severity of the condition.

In children with disseminated or localized mycobacterial infections (Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium kansasii) the recommended daily dose of clarithromycin is 7.5-15 mg/kg 2 times/day and should not exceed the maximum dose of 500 mg 2 times/day.

The treatment with clarithromycin should be continued as long as clinical effect persists. Clarithromycin should be used in combination with other antimicrobials active against these pathogens.

Patients with impaired renal function

In children with KK less than 30 ml/min/1.73 m2 the dose of clarithromycin should be reduced by half (e.g., 125 (250) mg/day or 125 mg (250 mg) 2 times/day for more severe infections). In such cases, the course of treatment should not exceed 14 days, although the usual duration of treatment is 5-10 days.

Interaction

The following drugs are contraindicated with clarithromycin due to the potential for serious adverse effects

Cyzapride, pimozide, terfenadine and astemizole

The following drugs are contraindicated with clarithromycin. When clarithromycin is coadministered with cisapride, pimozide, terfenadine, or astemizole, an increase in plasma concentrations of the latter has been reported, which may lead to prolonged QT interval and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and ventricular pirouette tachycardia.

Postmarketing studies have shown that the following effects associated with acute poisoning with ergotamine or dihydroergotamine can occur when clarithromycin is coadministered: vasospasm, ischemia of the extremities and other tissues, including the CNS. Concomitant use of clarithromycin and ergot alkaloids is contraindicated.

Oral midazolam

The co-administration of midazolam and clarithromycin in tablet form (500 mg twice daily) showed a 7-fold increase in AUC of midazolam after oral administration. Simultaneous oral administration of clarithromycin and midazolam is contraindicated.

HMG-CoA reductase inhibitors (statins)

. Co-administration of clarithromycin with lovastatin or simvastatin is contraindicated due to the fact that these statins are significantly metabolized by CYP3A4 isoenzyme and co-administration with clarithromycin increases their serum concentrations, which leads to increased risk of myopathy, including rhabdomyolysis. Rhabdomyolysis has been reported in patients taking clarithromycin in combination with these drugs. If clarithromycin should be used, lovastatin or simvastatin should be discontinued for the duration of therapy.

Clarithromycin should be used with caution when combined therapy with statins. If co-administration is necessary, it is recommended to take the lowest dose of statin. It is recommended to use statins that do not depend on CYP3A metabolism (e.g., fluvastatin). The development of signs and symptoms of myopathy should be controlled.

The effect of other drugs on clarithromycin

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

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

Efavirenz, nevirapine, rifampicin, rifabutin and rifapentin

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

Etravirine

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

Fluconazole

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

Ritonavir

A pharmacokinetic study has shown that co-administration of ritonavir at a dose of 200 mg every 8 hours and clarithromycin at a dose of 500 mg every 12 hours resulted in marked inhibition of clarithromycin metabolism. When ritonavir was coadministered, the Cmax of clarithromycin increased by 31%, the Cmin increased by 182% and the AUC increased by 77%. Complete inhibition of 14-OH clarithromycin formation was noted. Due to the wide therapeutic range of clarithromycin, no dose reduction is required in patients with normal renal function. In patients with renal impairment, it is reasonable to consider the following dose adjustments: at CKR 30-60 ml/min, the dose of clarithromycin should be reduced by 50%; at CKR less than 30 ml/min, the dose of clarithromycin should be reduced by 75%. Ritonavir should not be coadministered with clarithromycin in doses greater than 1 g/day.

Similar dose adjustments should be considered in patients with reduced renal function if ritonavir is used as a pharmacokinetic “booster” when using other HIV protease inhibitors, including atazanavir and saquinavir.

The effect of clarithromycin on other drugs

Antirhythmic drugs (quinidine and disopyramide)

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

In post-marketing use, cases of hypoglycemia have been reported with clarithromycin and disopyramide. Blood glucose concentrations should be monitored when using clarithromycin and disopyramide concomitantly.

Peroral hypoglycemic agents/insulin

The co-administration of clarithromycin and oral hypoglycemic agents (e.g. sulfonylurea derivatives) and/or insulin may cause significant hypoglycemia. Concomitant use of clarithromycin with some hypoglycemic drugs (e.g. nateglinide, pioglitazone, repaglinide and rosiglitazone) may lead to inhibition of CYP3A isoenzyme by clarithromycin, which may result in hypoglycemia. Close monitoring of glucose concentration is recommended.

CYP3A-dependent interactions

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

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

Indirect anticoagulants

Coadministration of warfarin and clarithromycin may cause bleeding, marked increase in MHO and prothrombin time. If combined with warfarin or other indirect anticoagulants, MHO and prothrombin time should be monitored.

Omeprazole

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

Sildenafil, tadalafil and vardenafil

Each of these phosphodiesterase inhibitors is metabolized at least in part with the CYP3A isoenzyme. However, the CYP3A isoenzyme may be inhibited in the presence of clarithromycin. Co-use of clarithromycin with sildenafil, tadalafil or vardenafil may lead to increased inhibitory effects on phosphodiesterase. When these drugs are used together with clarithromycin, consideration should be given to reducing the dose of sildenafil, tadalafil and vardenafil.

Theophylline, carbamazepine

The combined use of clarithromycin and theophylline or carbamazepine may increase systemic drug concentrations.

Tolterodine

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

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

When midazolam and clarithromycin are used together in tablet form (500 mg 2 times/day), there was a 2.7-fold increase in AUC of midazolam after intravenous administration of midazolam. If intravenous forms of midazolam are used together with clarithromycin, the patient’s condition should be closely monitored for possible dose adjustment. Oral mucosal administration, which bypasses the presystemic elimination of the drug, is likely to result in interactions similar to those seen with the intravenous administration of midazolam rather than with oral administration.

The same precautions should be applied to other benzodiazepines that are metabolized by the CYP3A isoenzyme, including triazolam and alprazolam. For benzodiazepines whose excretion is not dependent on CYP3A isoenzyme (temazepam, nitrazepam, lorazepam), a clinically significant interaction with clarithromycin is unlikely.

In co-administration of clarithromycin and triazolam, CNS effects such as drowsiness and confusion are possible. Therefore, it is recommended to monitor for CNS disturbance symptoms if used together.

Interaction with other drugs

Colchicine

Colchicine is a substrate of both the CYP3A isoenzyme and the protein transferase P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to be CYP3A and Pgp isoenzyme inhibitors. When clarithromycin and colchicine are coadministered, inhibition of Pgp and/or the CYP3A isoenzyme may result in an increased effect of colchicine. There have been post-marketing reports of cases of colchicine poisoning when coadministered with clarithromycin, more often in elderly patients. Some of the described cases occurred in patients with renal insufficiency. Some cases have been reported to be fatal. Concomitant use of clarithromycin and colchicine is contraindicated.

Digoxin

Digoxin is believed to be a substrate for Pgp. Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are taken together, the inhibition of Pgp by clarithromycin may increase the effect of digoxin. Post-marketing studies have shown that co-administration of digoxin and clarithromycin may also result in increased serum concentrations of digoxin. Clinical symptoms of digoxin poisoning, including potentially fatal arrhythmias, have been reported in some patients. Serum digoxin concentrations should be closely monitored when clarithromycin and digoxin are coadministered.

Zidovudine

The concomitant administration of clarithromycin tablets and zidovudine in HIV-infected adults may decrease the equilibrium concentration of zidovudine. Because clarithromycin affects oral absorption of zidovudine, interactions can be largely avoided by taking clarithromycin and zidovudine at 4-hour intervals. No such interaction has been observed in HIV-infected children taking clarithromycin infant suspension with zidovudine or dideoxynosine. Because clarithromycin can interfere with the absorption of zidovudine when they are taken simultaneously orally in adult patients, this interaction is unlikely to occur when clarithromycin is used by IV.

Phenytoin and valproic acid

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

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. Co-administration of clarithromycin (500 mg twice daily) and atazanavir (400 mg once daily) may result in a twofold increase in exposure to clarithromycin and a 70% decrease in exposure to 14-OH-clarithromycin, with a 28% increase in AUC of atazanavir. Due to the wide therapeutic range of clarithromycin, no dose reduction is required in patients with normal renal function. In patients with moderate renal impairment (KK 30-60 ml/min) the dose of clarithromycin should be reduced by 50%. In patients with KK less than 30 ml/min, the clarithromycin dose should be reduced by 75% using an appropriate clarithromycin dosage form. Clarithromycin in doses greater than 1000 mg/day should not be used with protease inhibitors.

Slow calcium channel blockers

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

Itraconazole

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

Saquinavir

Clarithromycin and saquinavir are substrates and inhibitors of CYP3A isoenzyme, which determines the bidirectional interaction of the drugs. Concomitant use of clarithromycin (500 mg 2 times/day) and saquinavir (soft gelatin capsules, 1200 mg 3 times/day) in 12 healthy volunteers caused a 177% and 187% increase in AUC and Cmax for saquinavir compared to taking saquinavir alone.

The AUC and Cmax values of clarithromycin were approximately 40% higher than those of clarithromycin monotherapy. No dose adjustments are required when the two drugs are coadministered for a limited time in the doses/compositions listed above. The results of drug interaction studies using saquinavir in soft gelatin capsules may not be consistent with the effects observed with saquinavir in hard gelatin capsules.

The results of drug interaction studies with saquinavir monotherapy may not be consistent with the effects observed with saquinavir/ritonavir therapy. The potential effects of ritonavir on clarithromycin should be considered when taking saquinavir with ritonavir.

Special Instructions

Prolonged use of antibiotics can lead to the formation of colonies with increased numbers of insensitive bacteria and fungi. In case of superinfection, appropriate therapy should be prescribed.

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

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

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

When treated with macrolides, including clarithromycin, prolongation of cardiac repolarization and the QT interval have been observed, causing a risk of cardiac arrhythmias and pirouette-type ventricular tachycardia. Because the following situations may increase the risk of ventricular arrhythmias (including pirouette-type ventricular tachycardia),

Epidemiologic studies examining the risk of adverse cardiovascular outcomes with macrolide use have had mixed results. Some observational studies have found a short-term risk of arrhythmias, myocardial infarction, and cardiovascular death associated with the use of macrolides, including clarithromycin. When prescribing clarithromycin, the anticipated benefits of the drug should be weighed against these risks.

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

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

Mild to moderate skin and soft tissue infections are most commonly caused by Staphylococcus aureus and Streptococcus pyogenes. Both pathogens may be resistant to macrolides. Therefore, it is important to test for sensitivity. Macrolides can be used for infections caused by Corynebacterium minutissimum, diseases of acne vulgaris and rye, and in situations where penicillin cannot be used.

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

If used together with warfarin or other indirect anticoagulants, the INR and prothrombin time should be monitored.

When prescribing the drug to patients with diabetes mellitus it should be taken into account that the drug contains sucrose: Clacid®, granules for oral suspension preparation 125 mg/5 ml, 1 ml of suspension contains 0.

Clacid®, oral suspension pellets 250 mg/5 ml, 0.046 units or 0.46 g of sucrose in 1 ml of suspension.

Impact on the ability to drive vehicles and mechanisms

There are no data on the effect of clarithromycin on the ability to drive vehicles and mechanisms. Caution should be exercised when driving vehicles and operating machinery, given the potential for dizziness, vertigo, confusion and disorientation that may occur while taking this drug.

Synopsis

Contraindications

Side effects

Allergic reactions: Frequent – rash; infrequent – anaphylactoid reaction1, hypersensitivity, bullous dermatitis1, itching, urticaria, maculopapular rash3; frequency unknown – anaphylactic reaction, angioneurotic edema, serious skin adverse reactions (e.g., acute generalized exanthematous pustulosis), Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptomatology (DRESS syndrome).

Nervous system disorders: frequent – headache, insomnia; infrequent – loss of consciousness1, dyskinesia1, dizziness, somnolence, tremor, anxiety, increased excitability3; frequency unknown- seizures, psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, dream disorders (nightmares), paresthesia, mania.

Skin disorders: often – intense sweating; frequency unknown – acne.

Urinary system disorders: frequency unknown – renal failure, interstitial nephritis.

Metabolism and nutrition: infrequent – anorexia, decreased appetite.

Muscular system disorders: Infrequent – muscle spasm3, musculoskeletal stiffness1, myalgia2; frequency unknown – rhabdomyolysis2*, myopathy.

Digestive system disorders: Frequent – diarrhea, vomiting, dyspepsia, nausea, abdominal pain; infrequent – esophagitis1, gastroesophageal reflux disease2, gastritis, proctalgia2, stomatitis, glossitis, bloating4, constipation, dry mouth, belching, flatulence, cholestasis4, hepatitis, including cholestasis.including cholestatic and hepatocellular4; frequency unknown – acute pancreatitis, discoloration of tongue and teeth, liver failure, cholestatic jaundice.

Respiratory system: infrequent – asthma1, nasal bleeding2, pulmonary embolism1.

Sense organs: frequent – dysgeusia; infrequent – vertigo, hearing impairment, tinnitus; frequency unknown – deafness, agueusia (loss of taste), parosmia, anosmia.

Cardiovascular system disorders: Frequent – vasodilation1; infrequent – cardiac arrest1, atrial fibrillation1Atrial fibrillation, prolongation of QT interval on ECG, extrasystole1, palpitations; frequency unknown – ventricular tachycardia, includingincluding pirouette type, ventricular fibrillation, bleeding.

Laboratory findings: frequent – abnormality in hepatic sample; infrequent – increase in creatinine concentration1, increase in urea concentration1, change in albumin-globulin ratio1, leukopenia, neutropenia4, eosinophilia4, thrombocythemia3, increased ALT, ACT, GGTP4, ALP4, LDH4; frequency unknown – agranulocytosis, thrombocytopenia, increased MHO value, prolongation of prothrombin time, change in urine color, increased blood bilirubin concentration.

General disorders: very common – phlebitis at the injection site1, common – pain at the injection site1, inflammation at the injection site1; infrequent – malaise4, hyperthermia3, asthenia, chest pain4, chills4, fatigue4.

Infectious and parasitic diseases: infrequent – cellulitis1, candidiasis, gastroenteritis2, secondary infections (including.including vaginal)3; frequency unknown – pseudomembranous colitis, rye.

The incidence, type, and severity of adverse reactions in children are presumed to be the same as in adults.

Patients with suppressed immunity

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

The most common adverse events in patients taking a daily dose of clarithromycin equal to 1000 mg were: nausea, vomiting, perversion of taste, abdominal pain, diarrhea, rash, flatulence, headache, constipation, hearing loss, and increased ACT and ALT blood concentrations. Adverse events with low frequency of occurrence, such as dyspnea, insomnia, and dry mouth, have also been reported.

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

* In some reports of rhabdomyolysis, clarithromycin has been taken together with other drugs known to be associated with rhabdomyolysis (statins, fibrates, colchicine or allopurinol).

1 Reports of these adverse reactions have been received during clinical studies as well as post-marketing use of Clacid®, lyophilizate for preparation of solution for infusion.

2 Reports of these adverse reactions have been received during clinical studies as well as post-marketing use of Clacid® SR, sustained-release film-coated tablets.

3 Reports of these adverse reactions have been received during clinical studies as well as post-marketing use of Clacid®, granules for oral suspension.

4 These adverse reactions have been reported during the use of Clacid®, film-coated tablets.Classification of adverse reactions by frequency of development (number of reported cases/number of patients): very common (≥1/10), common (≥1/100, < 1/10), infrequent (≥1/1000, < 1/100), frequency unknown (adverse effects from postmarketing experience; frequency cannot be estimated based on available data).

Allergic reactions: Frequent – rash; infrequent – anaphylactoid reaction1, hypersensitivity, bullous dermatitis1, itching, urticaria, maculopapular rash3; frequency unknown – anaphylactic reaction, angioneurotic edema, serious skin adverse reactions (e.g., acute generalized exanthematous pustulosis), Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptomatology (DRESS syndrome).

Nervous system disorders: frequent – headache, insomnia; infrequent – loss of consciousness1, dyskinesia1, dizziness, somnolence, tremor, anxiety, increased excitability3; frequency unknown- seizures, psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, dream disorders (nightmares), paresthesia, mania.

Skin disorders: often – intense sweating; frequency unknown – acne.

Urinary system disorders: frequency unknown – renal failure, interstitial nephritis.

Metabolism and nutrition: infrequent – anorexia, decreased appetite.

Muscular system disorders: Infrequent – muscle spasm3, musculoskeletal stiffness1, myalgia2; frequency unknown – rhabdomyolysis2*, myopathy.

Digestive system disorders: Frequent – diarrhea, vomiting, dyspepsia, nausea, abdominal pain; infrequent – esophagitis1, gastroesophageal reflux disease2, gastritis, proctalgia2, stomatitis, glossitis, bloating4, constipation, dry mouth, belching, flatulence, cholestasis4, hepatitis, including cholestasis.including cholestatic and hepatocellular4; frequency unknown – acute pancreatitis, discoloration of tongue and teeth, liver failure, cholestatic jaundice.

Respiratory system: infrequent – asthma1, nasal bleeding2, pulmonary embolism1.

Sense organs: frequent – dysgeusia; infrequent – vertigo, hearing impairment, tinnitus; frequency unknown – deafness, agueusia (loss of taste), parosmia, anosmia.

Cardiovascular system disorders: Frequent – vasodilation1; infrequent – cardiac arrest1, atrial fibrillation1Atrial fibrillation, prolongation of QT interval on ECG, extrasystole1, palpitations; frequency unknown – ventricular tachycardia, includingincluding pirouette type, ventricular fibrillation, bleeding.

Laboratory findings: frequent – abnormality in hepatic sample; infrequent – increase in creatinine concentration1, increase in urea concentration1, change in albumin-globulin ratio1, leukopenia, neutropenia4, eosinophilia4, thrombocythemia3, increased ALT, ACT, GGTP4, ALP4, LDH4; frequency unknown – agranulocytosis, thrombocytopenia, increased MHO value, prolongation of prothrombin time, change in urine color, increased blood bilirubin concentration.

General disorders: very common – phlebitis at the injection site1, common – pain at the injection site1, inflammation at the injection site1; infrequent – malaise4, hyperthermia3, asthenia, chest pain4, chills4, fatigue4.

Infectious and parasitic diseases: infrequent – cellulitis1, candidiasis, gastroenteritis2, secondary infections (including.including vaginal)3; frequency unknown – pseudomembranous colitis, rye.

The incidence, type, and severity of adverse reactions in children are presumed to be the same as in adults.

Patients with suppressed immunity

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

The most common adverse events in patients taking a daily dose of clarithromycin equal to 1000 mg were: nausea, vomiting, perversion of taste, abdominal pain, diarrhea, rash, flatulence, headache, constipation, hearing loss, and increased ACT and ALT blood concentrations. Adverse events with low frequency of occurrence, such as dyspnea, insomnia, and dry mouth, have also been reported.

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

* In some reports of rhabdomyolysis, clarithromycin has been taken together with other drugs known to be associated with rhabdomyolysis (statins, fibrates, colchicine or allopurinol).

1 Reports of these adverse reactions have been received during clinical studies as well as post-marketing use of Clacid®, lyophilizate for preparation of solution for infusion.

2 Reports of these adverse reactions have been received during clinical studies as well as post-marketing use of Clacid® SR, sustained-release film-coated tablets.

3 Reports of these adverse reactions have been received during clinical studies as well as post-marketing use of Clacid®, granules for oral suspension.

4 Reports of these adverse reactions have been received during use of Clacid®, film-coated tablets.

Overdose

Symptoms: high-dose clarithromycin administration may cause symptoms of gastrointestinal disorders. One patient with a history of bipolar disorder has described mental changes, paranoid behavior, hypokalemia and hypoxemia after taking 8 g of clarithromycin.

Treatment: in case of overdose the unabsorbed drug should be removed from the gastrointestinal tract (gastric lavage, administration of activated charcoal, etc.) and symptomatic therapy should be carried out. Hemodialysis and peritoneal dialysis have no significant effect on serum concentrations of clarithromycin, as is the case with other macrolide drugs.

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