Clarithromycin-OBL, 500 mg 14 pcs.

Boils, Tonsillitis, Sinusitis, Angina, Colds, Pharyngitis, Skin infections, GI infections caused by Helicobacter pylori, Otitis media, Bronchitis, Gastric and duodenal ulcers

Infectious and inflammatory diseases caused by clarytromycin-sensitive microorganisms:

– Lower respiratory tract infections (such as bronchitis, pneumonia);

– Upper respiratory tract infections (such as pharyngitis, sinusitis);

– Skin and soft tissue infections (such as folliculitis, subcutaneous tissue inflammation, rye);

– Disseminated or localized mycobacterial infections caused by Mycobacterium avium and Mycobacterium intracellulare;

– Localized infections caused by Mycobacterium chelonae, Mycobacterium fortuitum and Mycobacterium kansasii;

– Preventing the spread of infection caused by Mycobacterium avium complex (MAC) to HIV-infected patients with a CD4 (Tcheloper lymphocyte) count of 100 or less in 1 mm3;

– Eradication of H. pylori and reduced recurrence rate of duodenal ulcer;

– Odontogenic infections.

Indications

Infectious and inflammatory diseases caused by microorganisms sensitive to clarithromycin:

· 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);

· Disseminated or localized mycobacterial infections caused by Mycobacterium avium and Mycobacterium intracellulare;

· Localized infections caused by Mycobacterium chelonae, Mycobacterium fortuitum and Mycobacterium kansasii;

· Prevention of the spread of infection caused by the Mycobacterium avium complex (MAC) to HIV-infected patients with a CD4 lymphocyte (T-helper lymphocyte) content of no more than 100 per 1 mm3;

· Eradication of H. pylori and reduction in the frequency of relapses of duodenal ulcers;

· Odontogenic infections.

Pharmacological effect

Pharmacotherapeutic group: Antibiotic-macrolide

Special instructions

Long-term use of antibiotics can lead to the formation of colonies with an increased number of insensitive bacteria and fungi. In case of superinfection, appropriate therapy must be prescribed.

Given the increasing resistance of Streptococcus pneumoniae to macrolides, it is important to perform susceptibility testing when prescribing clarithromycin to patients with community-acquired pneumonia. For hospital-acquired pneumonia, clarithromycin should be used in combination with appropriate antibiotics. Mild to moderate skin and soft tissue infections are most often caused by Staphylococcus aureus and Streptococcus pyogenes. Moreover, both pathogens can be resistant to macrolides. Therefore, it is important to conduct a sensitivity test.

Macrolides can be used for infections caused by Corynebacterium minutissimum, Acne vulgaris and erysipelas, as well as in situations where penicillin cannot be used.

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

Clarithromycin should be used with caution in patients with coronary heart disease (CHD), severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats/min), as well as when used simultaneously with class IA (quinidine, procainamide) and class III antiarrhythmic drugs (dofetilide, amiodarone, sotalol). In these conditions and when taking clarithromycin concomitantly with these drugs, the electrocardiogram should be regularly monitored for prolongation of the QT interval.

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

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

In case of co-administration with warfarin or other indirect anticoagulants, it is necessary to monitor the INR and prothrombin time.

When treated with almost all antibacterial agents, including clarithromycin, cases of pseudomembranous colitis have been described, the severity of which can range from mild to life-threatening. Antibacterial drugs can change the normal intestinal microflora, which can lead to the growth of C. difficile. Pseudomembranous colitis caused by Clostridium difficile should be suspected in all patients who experience diarrhea after using antibacterial agents. After a course of antibiotic therapy, careful medical monitoring of the patient is necessary. Cases of the development of pseudomembranous colitis 2 months after taking antibiotics have been described.

In the event of acute hypersensitivity reactions, such as anaphylactic reaction, 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 initiated.

Impact on the ability to drive vehicles and machinery

There are no data regarding the effect of clarithromycin on the ability to drive a car or use machinery.

Caution should be exercised when operating vehicles and machinery, given the potential for dizziness, vertigo, confusion and disorientation that may occur while using this drug.

Active ingredient

Clarithromycin

Composition

1 film-coated tablet contains:

Active ingredient:

Clarithromycin (based on 100% substance) 250 mg/500 mg;

Excipients:

Microcrystalline cellulose 130.385 mg/260.77 mg, sodium lauryl sulfate 17.25 mg/34.5 mg, croscarmellose sodium 7.77 mg/15.54 mg, colloidal silicon dioxide (Aerosil) 20 mg/40 mg, povidone (low molecular weight polyvinylpyrrolidone) 0.195 mg/0.39 mg, magnesium stearate 4.4 mg/8.8 mg;

Excipients for the shell:

Hypromellose (hydroxypropyl methylcellulose) 11.76 mg/23.52 mg, macrogol 6000 (polyethylene glycol 6000) 3.04 mg/6.08 mg, titanium dioxide 2.9 mg/5.8 mg, hyprolose (hydroxypropylcellulose) 1.18 mg/2.36 mg, quinoline yellow dye 0.55 mg/1.1 mg, vanillin 0.57 mg/1.14 mg.

Pregnancy

The safety of clarithromycin during pregnancy and breastfeeding has not been established.

The use of clarithromycin during pregnancy (especially in the first trimester) is possible only when there is no alternative therapy and the potential benefit to the mother outweighs the potential risk to the fetus.

Clarithromycin is excreted in breast milk. If it is necessary to take it during breastfeeding, breastfeeding should be discontinued.

Contraindications

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

· Concomitant use of clarithromycin with the following drugs: astemizole, cisapride, pimozide and terfenadine (see section “Interaction with other drugs”);

· Simultaneous use of clarithromycin with ergot alkaloids, for example, ergotamine, dihydroergotamine (see section “Interaction with other drugs”);

· Concomitant use of clarithromycin with midazolam for oral use (see section “Interaction with other drugs”);

· Concomitant use of clarithromycin with HMG-CoA reductase inhibitors (statins), which are largely metabolized by the CYP3A4 isoenzyme (lovastatin, simvastatin), due to an increased risk of myopathy, including rhabdomyolysis (see section “Interaction with other drugs”);

· Concomitant use of colchicine;

· Concomitant use with ticagrelor or ranolazine;

History of QT interval prolongation, ventricular arrhythmia or torsade de pointes;

Hypokalemia (risk of QT interval prolongation);

· Severe liver failure occurring simultaneously with renal failure;

· History of cholestatic jaundice/hepatitis that developed during the use of clarithromycin (history) of clarithromycin (see section “Special Instructions”);

· Porphyria;

· Breastfeeding period;

· Age up to 12 years.

With caution

· Moderate to severe renal failure;

· Moderate to severe liver failure;

· Concomitant use of clarithromycin with other ototoxic drugs, especially aminoglycosides (see section “Interaction with other drugs”);

· Concomitant use with drugs that are metabolized by the CYP3A isoenzyme, for example, carbamazepine, cilostazol, cyclosporine, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants (for example, warfarin), quinidine, rifabutin, sildenafil, tacrolimus, vinblastine (see section “Interaction with other drugs”);

· Concomitant use with drugs that induce the CYP3A4 isoenzyme, for example, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort (see section “Interaction with other drugs”);

· Concomitant use of clarithromycin with statins that do not depend on the metabolism of the CYP3A isoenzyme (for example, fluvastatin) (see section “Interaction with other drugs”);

· Concomitant use with benzodiazepines, such as alprazolam, triazolam, midazolam for intravenous use;

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

· Concomitant use with blockers of “slow” calcium channels that are metabolized by the CYP3A4 isoenzyme (for example, verapamil, amlodipine, diltiazem);

· Coronary heart disease, severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats/min);

· Pregnancy.

Side Effects

Classification of adverse reactions by frequency of development (number of reported cases/number of patients):

Very common (≥1/10),

Often (≥1/100, <1/10),

Uncommon (≥1/1000, <1/100),

Frequency unknown (adverse effects from post-marketing experience; frequency cannot be estimated based on available data).

Allergic reactions

Common: rash.

Uncommon: hypersensitivity, pruritus, urticaria, maculopapular rash2.

Not known: anaphylactic reaction, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome).

From the nervous system

Common: headache, insomnia.

Uncommon: dizziness, drowsiness, tremor, restlessness, increased excitability2.

Frequency unknown: seizures, psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, dream disturbances (nightmare dreams), paresthesia, mania.

From the skin

Common: intense sweating.

Frequency unknown: acne, hemorrhages.

From the urinary system

Frequency unknown: renal failure, interstitial nephritis.

Metabolism and nutrition

Uncommon: anorexia, decreased appetite.

From the musculoskeletal system

Uncommon: muscle spasm2, myalgia1.

Frequency unknown: rhabdomyolysis1*, myopathy.

From the digestive system

Common: diarrhea, vomiting, dyspepsia, nausea, abdominal pain.

Uncommon: gastroesophageal reflux disease1, gastritis, proctalgia1, stomatitis, glossitis, bloating3, constipation, dry mouth, belching, flatulence, cholestasis3, hepatitis incl. cholestatic or hepatocellular3.

Frequency unknown: acute pancreatitis, discoloration of the tongue and teeth, liver failure, cholestatic jaundice.

From the respiratory system

Uncommon: epistaxis1.

From the senses

Common: dysgeusia, taste perversion.

Uncommon: vertigo, hearing loss, tinnitus.

Frequency unknown: deafness, ageusia (loss of taste), parosmia, anosmia.

From the cardiovascular system

Uncommon: prolongation of the QT interval on the electrocardiogram, atrial flutter.

Frequency unknown: ventricular tachycardia, including pirouette type.

Laboratory indicators

Common: abnormal liver function test.

Uncommon: leukopenia, neutropenia3, eosinophilia3, thrombocythemia2, increased activity of: alanine aminotransferase (ALT), aspartate aminotransferase (AST), gammaglutamyltransferase (GGTP)3, alkaline phosphatase3, lactate dehydrogenase (LDH)3.

Frequency unknown: agranulocytosis, thrombocytopenia, increased international normalized ratio (INR), prolongation of prothrombin time, change in urine color, increased bilirubin concentration in the blood.

General disorders

Uncommon: malaise3, pyrexia2, asthenia, chest pain3, chills3, fatigue3.

Infectious and parasitic diseases

Uncommon: candidiasis, gastroenteritis1, secondary infections2 (including vaginal).

Frequency unknown: pseudomembranous colitis, erysipelas.

Immunosuppressed patients

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 distinguish adverse effects of the drug from symptoms of HIV infection or concomitant disease.

The most common adverse events in patients taking a daily dose of clarithromycin of 1000 mg were: nausea, vomiting, taste disturbance, abdominal pain, diarrhea, rash, flatulence, headache, constipation, hearing loss, increased AST and ALT activity in the blood. Low incidence adverse events such as shortness of breath, insomnia and dry mouth were also reported.

In patients with suppressed immunity, laboratory parameters were assessed, analyzing their significant deviations from the norm (sharp increase or decrease). Based on this criterion, a significant increase in AST and ALT activity in the blood, as well as a decrease in the number of leukocytes and platelets, was recorded in 2-3% of patients receiving clarithromycin at a dose of 1000 mg daily. Increases in residual urea nitrogen concentrations have also been reported in a small number of patients.

*In some reports of rhabdomyolysis, clarithromycin was co-administered with other drugs known to be associated with rhabdomyolysis (statins, fibrates, colchicine or allopurinol).

1 Reports of these adverse reactions were received only when using clarithromycin in the dosage form: extended-release film-coated tablets.

2 Reports of these adverse reactions have been received only when using clarithromycin in the dosage form: powder for oral suspension.

3 Reports of these adverse reactions were received only when using clarithromycin in the dosage form: film-coated tablets.

Interaction

The use of the following drugs with clarithromycin is contraindicated due to the potential for serious side effects

Cisapride, pimozide, terfenadine and astemizole

When clarithromycin was co-administered with cisapride, pimozide, terfenadine or astemizole, an increase in the concentration of the latter in the blood plasma was reported, which can lead to prolongation of the QT interval and the appearance of cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and torsade de pointes (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. The simultaneous use of clarithromycin and 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 do not depend on 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) can 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 concomitantly 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 that is also 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 low 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 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 coadministered 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 similarly through other isoenzymes within the cytochrome P450 system 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 in 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. Coadministration 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 alone. 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. The results of 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 saquinavir/ritonavir therapy. When taking saquinavir with ritonavir, the potential effect of ritonavir on clarithromycin should be considered.

Overdose

Symptoms: Taking a large dose of clarithromycin may cause gastrointestinal symptoms.

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 (gastric lavage, activated charcoal, etc.) and symptomatic therapy should be carried out. Hemodialysis and peritoneal dialysis do not have a significant effect on the concentration of clarithromycin in serum, which is also typical for other macrolide drugs.

Storage conditions

In a dry place, protected from light, at a temperature not exceeding 20 °C

Shelf life

2 years

Manufacturer

Alium JSC, Russia