Description
Release form
film-coated tablets
Indications
Infectious and inflammatory diseases caused by organisms sensitive to clarithromycin:
– upper respiratory tract infections (such as pharyngitis, sinusitis)
– lower respiratory tract infections (such as bronchitis, pneumonia)
– soft skin infections such as folliculitis, inflammation of the subcutaneous tissue, erysipelas)
– disseminated and localized mycobacterial infections caused by Mycobacterium avium and Mycobacterium intracellulare. Localized infections caused by Mycobacterium chelonae, Mycobacterium fortuitum and Mycobacterium kansasii
– prevention of the spread of infection caused by the complex Mycobacterium avium (MAC), HIV-infected patients with CD4 lymphocytes (T-helper lymphocytes) no more than 100 / mm pylori and reduce the recurrence rate of duodenal ulcers.
Use during pregnancy and lactation
The safety of clarithromycin in pregnant and lactating women has not been established. The use of the drug during pregnancy (especially in the first trimester) is possible only if there are clear indications and only if the intended benefit to the mother outweighs the potential risk to the fetus and / or there is no safer therapy with alternative drugs. If pregnancy occurs during the period of use of the drug, the patient should be warned about the possible risks to the fetus.
It is known that clarithromycin passes into breast milk, therefore, if necessary, use during lactation should decide on the abolition of breastfeeding.
Special instructions
Prolonged use of antibiotics can lead to the formation of colonies with an increased number of insensitive bacteria and fungi. With superinfection, appropriate therapy should be prescribed.
When using clarithromycin, cases of impaired liver function have been reported (increased concentration of liver enzymes in the blood, hepatocellular and / or cholestatic hepatitis with or without jaundice). Hepatic dysfunction can be severe, but is usually reversible. There are cases of fatal liver failure, mainly associated with the presence of serious concomitant diseases and / or the simultaneous use of other drugs. When signs and symptoms of hepatitis appear, such as anorexia, jaundice, dark urine, itching, tenderness of the abdomen during palpation, it is necessary to immediately stop clarithromycin therapy.
In the presence of chronic liver disease, regular monitoring of serum enzymes is necessary.
In the treatment of almost all antibacterial agents, including clarithromycin, cases of pseudomembranous colitis have been described, the severity of which can vary from mild to life-threatening. Antibacterial drugs can change the normal intestinal microflora, which can lead to the growth of Clostridium difficile. Pseudomembranous colitis caused by Clostridium difficile, must be suspected in all patients experiencing the appearance of diarrhea after the use of antibacterial agents. After a course of antibiotic therapy, careful medical monitoring of the patient is necessary. Cases of development of pseudomembranous colitis 2 months after taking antibiotics were described.
Clarithromycin should be used with caution in patients with coronary heart disease, severe heart failure, hypomagnesemia, severe bradycardia (less than 50 beats / min), as well as when used with antiarrhythmic drugs of class IA (quinidine, procainamide) and class III (dofetilide , amiodarone, sotalol). With these conditions and while taking the drug with these drugs, ECG monitoring should be regularly performed to increase the QT interval.
Perhaps the development of cross-resistance to clarithromycin and other antibiotics of the macrolide group, as well as lincomycin and clindamycin.
Given the increasing resistance of Streptococcus pneumoniae to macrolides, it is important to conduct sensitivity testing when prescribing clarithromycin to patients with community-acquired pneumonia. In hospital pneumonia, clarithromycin should be used in combination with appropriate antibiotics.
Infections of the skin and soft tissues of mild to moderate severity are most often caused by Staphylococcus aureus and Streptococcus pyogenes. In this case, 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 (erythrasma), acne vulgaris and erysipelas, as well as in those situations when penicillin cannot be used.
In case of acute hypersensitivity reactions, such as anaphylactic reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome), you should immediately stop taking clarithromycin and start the appropriate therapy.
If used together with warfarin or other indirect anticoagulants, it is necessary to control the MHO and prothrombin time.
Effects on ability to drive vehicles and mechanisms
Caution should be exercised when driving vehicles and engaging in other potentially hazardous activities, as some side effects of clarithromycin, such as dizziness, drowsiness, can adversely affect the ability to drive a vehicle and perform potentially hazardous activities that require an increased concentration of attention and speed of psychomotor reactions.
Composition
Composition per tablet:
Active ingredient: clarithromycin – 500.00 mg.
Excipients: croscarmellose sodium – 42.50 mg, microcrystalline cellulose – 222.50 mg, colloidal silicon dioxide – 25.50 mg, pregelatinized starch – 34.00 mg, stearic acid – 8.50 mg, sodium stearyl fumarate – 17.00 mg.
Shell
VIVACOAT ® PA-2P-097 [hypromellose (hydroxypropyl methylcellulose 6 cPs) – 18.330 mg, titanium dioxide – 15.068 mg, polydextrose (E1200) – 7.050 mg, talc – 3.290 mg, macrogol – 3350 – 35050 (polyethylene) mg, quinoline yellow (E104) dye – 0.423 mg, yellow iron oxide dye (E172) – 0.019 mg] – 47,000 mg.
Dosage and administration
Tablets should be taken orally, regardless of food intake.
Adults and children over 12 years of age are prescribed 500 mg 2 times a day for severe infections. The usual duration of treatment is 5-6 to
14 days. The exception is community-acquired pneumonia and sinusitis, which require treatment from 6 to 14 days.
With mycobacterial infections, the drug is prescribed 500 mg 2 times a day. The duration of treatment for other non-tuberculous mycobacterial infections is determined by the doctor.
To prevent the spread of infections caused by MAC, the drug is prescribed 500 mg 2 times a day. Treatment of disseminated MAS infections in AIDS patients should be continued as long as there is clinical and microbiological efficacy. Clarithromycin should be prescribed in combination with other antimicrobial preparations that are active against other pathogens.
In patients with peptic ulcer caused by H. pylori infection, clarithromiuin can be prescribed 500 mg 2 times a day in combination with other antimicrobials and proton pump inhibitors for 7-14 days, in accordance with national and international guidelines for the treatment of H. pylori infection.
Side effects
Side effects are presented depending on the effect on organs and organ systems.
The following adverse events observed with clarithromycin, distributed according to the frequency of occurrence in accordance with the following gradation: very often (? 1/10), often (? 1/100 to <1/10), infrequently (? 1/1000 to <1/100), rarely (? 1 / 10000 to <1/1000), very rarely (<1/10000), unspecified frequency (cannot be calculated according to available data). Infectious and parasitic diseases: infrequently – candidiasis of the oral mucosa. As with the use of other antibacterial drugs, secondary infections are also possible (development of resistance of microorganisms). From the blood and lymphatic systems: rarely – leukopenia, eosinophilia, neutropenia, thrombocytopenia, unspecified frequency – agranulocytosis, hemorrhage. From the side of the immune system: often – rash infrequently – allergic reactions (urticaria, skin itching), anaphylactic / anaphylactoid reactions, unspecified frequency – Stevens-Johnson syndrome, toxic epidermal necrolysis – Lyell syndrome (potentially life-threatening), drug rash with eosinophilia and systemic symptoms (DRESS syndrome), angioedema. Mental disorders: often – insomnia infrequently – drowsiness, unspecified frequency – confusion, depersonalization, depression, disorientation, hallucinations, psychotic disorders, “nightmare” dreams, mania. From the nervous system: often – headache, taste change (dysgeusia) infrequently – dizziness, paresthesia, tremor, asthenia, anxiety rarely – anosmia, unspecified frequency – convulsions. On the part of the sensory organs: often – ageusia (loss of taste) is rare – vertigo, tinnitus is rare – hearing loss, the unspecified frequency that occurs after discontinuation of the drug is parosmia. From the cardiovascular system: infrequently – prolongation of the QT interval on the ECG (as in other macrolides) rarely – ventricular tachycardia, including the type of “pirouette” (“torsade de pointes”), flutter and atrial fibrillation and ventricles. From the gastrointestinal tract: often – diarrhea, nausea, abdominal pain, dyspepsia infrequently – vomiting, glossitis, stomatitis, bloating, pseudomembranous colitis, anorexia, poor appetite, constipation, belching, flatulence, dry oral mucosa, gastritis unspecified frequency – acute pancreatitis, discoloration of the teeth and tongue. From the liver and biliary tract: infrequently – hepatocellular and cholestatic hepatitis, cholestasis, cholestatic jaundice is very rare – in isolated cases, facts of death from liver failure, which were usually observed in the presence of serious concomitant diseases and / or the simultaneous use of other drugs, were recorded. From the skin and subcutaneous tissues: often – hyperhidrosis rarely – erysipelas, unspecified frequency – acne. From the side of the musculoskeletal system and connective tissue: infrequently – myalgia, arthralgia, unspecified frequency – myopathy. From the kidneys and urinary tract: rarely – interstitial nephritis, unspecified frequency – renal failure. Laboratory indicators: often – increased activity of “liver” enzymes infrequently – increased concentrations of creatinine, hypoglycemia (including the simultaneous use of hypoglycemic drugs), increased activity of alkaline phosphatase, increased bilirubin, unspecified frequency – an increase in the value of the international normalized ratio (INR), lengthening of the prothrombin time, and a change in the color of urine. General disorders: infrequently – malaise, chest pain, chills, fatigue. Immunocompromised Patients In patients with AIDS and other immunodeficiencies who have been taking higher-dose clarithromycin for longer periods of time to treat mycobacterial infections, it is often difficult to distinguish between the adverse effects of the drug and the symptoms of HIV infection or concomitant illness. The most common adverse events in patients taking a daily dose of clarithromycin equal to 1000 mg were: nausea, vomiting, taste perversion, abdominal pain, diarrhea, rash, flatulence, headache, constipation, hearing loss, increased concentrations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the blood. Cases of adverse events with a low incidence have also been reported, such as shortness of breath, insomnia and dry mouth. In immunocompromised patients, laboratory parameters were evaluated by analyzing their significant deviations from the norm (a sharp increase or decrease). Based on this criterion, in 2-3% of patients receiving clarithromycin at a dose of 1000 mg daily, a significant increase in the concentration of ALT and AST in the blood was registered, as well as a decrease in the number of leukocytes and platelets. In a small number of patients, an increase in the concentration of residual urea nitrogen was also recorded. Drug interaction Co-administration with such drugs as astemizole, cisapride, pimozide, terfenadine, ergotamine, dihydroergotamine, is contraindicated, midazolam (oral dosage forms), simvastatin, lovastatin due to the possibility of developing serious side effects (see “Contraindications”). Cisapride and pimozide When used together, it is possible to: increase the concentration of cisapride, increase the QT interval, the appearance of cardiac arrhythmias, including ventricular tachycardia, including pirouette type, ventricular fibrillation. Terfenadine and astemizole When used together, the following are possible: an increase in the concentration of terfenadine / astemizole in the blood, the occurrence of cardiac arrhythmias, an increase in the QT interval, ventricular tachycardia, ventricular fibrillation and pirouette tachycardia. Ergotamine / dihydroergotamine When used together, the following effects are possible associated with acute poisoning with ergotamine group drugs: vascular spasm, ischemia of limbs and other tissues, including the central nervous system. Effect of other drugs on clarithromycin Drugs that induce CYP3A isoenzyme (for example: rifampicin, phenytoin, carbamazepine, phenobarbital, hypericum perforatum) can induce clarithromycin metabolism. This can lead to a subtherapeutic concentration of clarithromycin, which leads to a decrease in its effectiveness. In addition, it is necessary to monitor the concentration of the inducer of the isoenzyme CYP3A in the blood plasma, which may increase due to inhibition of the inducer of the isoenzyme CYP3A by clarithromycin. With the combined use of rifabutin and clarithromycin, an increase in plasma concentration and a decrease in the serum concentration of clarithromycin were observed with an increased risk of uveitis. The following drugs have a proven or suspected effect on the concentration of clarithromycin in plasma, if used together with clarithromycin, dose adjustment or a switch to an alternative treatment may be required. Efavirenz, nevirapine, rifampicin, rifabutin and rifapentin Strong cytochrome P450 inducers, such as efavirenz, nevirapine, rifampicin, rifabutin and rifapentin, can accelerate the clarithromycin metabolism and, therefore, decrease its concentration and decrease its concentration at the same time increase the concentration of 14-OH-clarithromycin? metabolite, which is also microbiologically active. Since the microbiological activity of clarithromycin and 14-OH-clarithromycin is different for different bacteria, therapeutic effect may decrease with the combined use of clarithromycin and inducers of cytochrome P450 isoenzymes. etravirine The concentration of clarithromycin decreases with etravirine, but the concentration of the active metabolite of 14-OH-clarithromycin increases. Since 14-OH-clarithromycin has low activity against Mycobacterium avium complex (MAC) infections, the overall activity against their pathogens may change, therefore, alternative treatment should be considered for MAC treatment. Fluconazole Concomitant use of fluconazole at a dose of 200 mg daily and clarithromycin at a dose of 500 mg 2 times a day in 21 adult volunteers led to an increase in the minimum mean equilibrium concentration of clarithromycin (Css) and AUC by 33% and 18%, respectively. Moreover, co-administration did not significantly affect the average equilibrium concentration of the active metabolite of 14-OH-clarithromycin. Dose adjustment of clarithromycin in case of concomitant use of fluconazole is not required. Ritonavir With the combined use of ritonavir 600 mg per day and clarithromycin 1 g per day, a decrease in the metabolism of clarithromycin (an increase in Cmax by 31%, Cmin by 182% and AUC by 77%), a complete suppression of the formation of 14-hydroxyclarithromycin. Due to its wide therapeutic range, dosage reduction in patients with normal renal function is not required. In patients with renal failure, it is advisable to consider the following dose adjustment options: with creatinine clearance of 30-60 ml / min, the dose of clarithromycin should be reduced by 50%, with creatinine clearance less than 30 ml / min, the dose of clarithromycin should be reduced by 75%. Ritonavir should not be taken with clarithromycin in doses exceeding 1 g per day. Oral hypoglycemic agents / Insulin Concomitant use of clarithromycin and oral hypoglycemic agents and / or insulin can lead to severe hypoglycemia. With the simultaneous use of clarithromycin with some oral hypoglycemic drugs, such as nateglinide, pioglitazone, repaglinide, rosiglitazone, hypoglycemia may occur due to inhibition of the CYP3A isoenzyme by clarithromycin. Careful monitoring of blood glucose concentration is recommended. Effect of clarithromycin on other drugs Antiarrhythmic drugs (quinidine and disopyramide) When used together with quinidine or disopyramide, ventricular tachycardia of the pirouette type may occur. With the simultaneous administration of clarithromycin with these drugs, an electrocardiogram should be regularly monitored for an increase in the QT interval, and serum concentrations of these drugs should also be monitored. With post-marketing use, cases of the development of hypoglycemia have been reported with the combined use of clarithromycin and disopyramide. It is necessary to control the concentration of blood glucose while using clarithromycin and disopyramide. Interactions due to CYP3A4 Co-administration of clarithromycin, which is known to inhibit the enzyme CYP3A, and drugs that are primarily metabolized by the CYP3A isoenzyme, may be associated with a mutual increase in their concentrations, which may enhance 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 range (for example: carbamazepine) and / or are extensively metabolized by this enzyme. If necessary, dose adjustment of the drug taken with clarithromycin should be carried out. Also, whenever possible, serum concentrations of drugs that are primarily metabolized by the CYP3A isoenzyme should be monitored. The metabolism of the following drugs / classes is carried out by the same CYP3A isoenzyme as the metabolism of clarithromycin, for example, alprazolam, carbamazepine, cilostazol, cyclosporine, disopyramide, methylprednisolone, midazolam, omeprazole, indirect anticoagulants (e.g. warfarin), 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 (see section “Contraindications”). Phenytoin, theophylline, and valproic acid include drugs that interact in a similar way through other isoenzymes within the cytochrome P450 system. HMG-CoA reductase inhibitors (statins) Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section “Contraindications”) due to that these statins are significantly metabolized by the CYP3A4 isoenzyme, and combined use with clarithromycin increases their serum concentrations, which leads to an increased risk of myopathy, including rhabdomyolysis. Rare cases of rhabdomyolysis in patients taking these drugs together have been reported. If you need to use clarithromycin, you should stop taking lovastatin or simvastatin for the duration of therapy. Clarithromycin should be used with caution in combination therapy with statins. If necessary, co-administration, it is recommended to take the lowest dose of statin. It is necessary to use statins that are independent of the metabolism of the CYP3A isoenzyme (for example: fluvastatin). The development of signs and symptoms of myopathy should be monitored. Oral anticoagulants There is a risk of serious bleeding and a significant increase in prothrombin time while the use of clarithromycin and warfarin. If patients receive clarithromycin and oral anticoagulants at the same time, prothrombin time and INR should be carefully monitored. Omeprazole With the combined use of clarithromycin and omeprazole, it is possible to increase the equilibrium plasma concentrations of omeprazole (Cmax, AUC0-24, T1 / 2 by 30%, 89%, and 34%, respectively). Sildenafil, tadalafil, and vardenafil Each of these phosphodiesterase inhibitors is metabolized, at least in part, by CYP3A. At the same time, the CYP3A isoenzyme can be inhibited in the presence of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil, may lead to an increase in the inhibitory effect on phosphodiesterase. When prescribing these drugs, you should jointly consider the possibility of reducing the dose of sildenafil, tadalafil and vardenafil. Theophylline, carbamazepine May increase the concentration of theophylline or carbamazepine in the systemic circulation. Tolterodine The primary metabolism of tolterodine is via the 2D6 isoform of cytochrome P450 (CYP2D6). However, in the part of the population lacking the CYP2D6 isoenzyme, metabolism occurs through CYP3A. In this population, suppression of the CYP3A isoenzyme leads to significantly higher serum tolterodine concentrations. In a population with a low metabolic rate through the CYP2D6 isoenzyme, a dose reduction of tolterodine in the presence of CYP3A isoenzyme inhibitors such as clarithromycin may be required. Benzodiazepines (for example: alprazolam, midazolam, triazolam) With the combined use of clarithromycin (500 mg 2 times a day), the AUC of midazolam may increase: 7 times after oral administration and 2.7 times after intravenous administration. The combined oral administration of midazolam and clarithromycin should be avoided. If an intravenous form of midazolam is used together 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 the CYP3A isoenzyme, including triazolam and alprazolam. For benzodiazepines, the elimination of which is independent of CYP3A (temazepam, nitrazepam, lorazepam), a clinically significant interaction with clarithromycin is unlikely. When using clarithromycin and triazolam together, it can affect the central nervous system (CNS), for example, drowsiness and confusion. In this regard, in the case of joint use, it is recommended to monitor the symptoms of central nervous system disorders. Interaction with other drugs Aminoglycosides While taking clarithromycin with other ototoxic drugs, especially aminoglycosides, care must be taken to control the functions of the vestibular and hearing apparatus, both during therapy and after it. Colchicine Colchicine is a substrate of both CYP3A and the carrier protein responsible for the excretion of the drug, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. With the combined use of clarithromycin and colchicine, inhibition of Pgp and / or CYP3A can lead to increased action of colchicine. The simultaneous use of clarithromycin and colchicine is contraindicated (see section “Contraindications”). Digoxin Digoxin is believed to be a substrate of Pgp. Clarithromycin is known to inhibit Pgp. With the combined use of digoxin and clarithromycin, inhibition of Pgp by clarithromycin can lead to increased action of digoxin. The combined use of digoxin and clarithromycin can also lead to an increase in serum concentration of digoxin. Some patients showed significant clinical symptoms of digoxin poisoning, including potentially fatal arrhythmias. With the combined use of clarithromycin and digoxin, it is necessary to carefully monitor the concentration of digoxin in the blood serum. Zidovudine Concomitant oral administration of clarithromycin and zidovudine in adult HIV-infected patients may lead to a decrease in the equilibrium concentration of zidovudine. Since clarithromycin affects the absorption of zidovudine when taken orally, interactions can be largely avoided by taking clarithromycin and zidovudine at 4-hour intervals. This type of interaction does not occur in HIV-infected children receiving clarithromycin in the form of a suspension together with zidovudine or dideoxyinosine. Since clarithromycin can interfere with the absorption of zidovudine when they are taken orally in adult patients, such an interaction is hardly possible when using clarithromycin intravenously. Phenytoin and valproic acid There is evidence of 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, it is recommended to determine their serum concentrations, since there are reports of their increase. Bidirectional drug interactions Atazanavir Clarithromycin and atazanavir are both substrates and inhibitors of CYP3A. There is evidence of a bi-directional interaction of these drugs. The combined use of clarithromycin (500 mg 2 times a day) and atazanavir (400 mg 1 time per day) can lead to a twofold increase in the effects of clarithromycin and a decrease of 14-OH-clarithromycin by 70%, with an increase in AUC of atazanavir by 28%. Due to the wide therapeutic range of clarithromycin, dose reduction in patients with normal renal function is not required. In patients with moderate renal failure (creatinine clearance 30-60 ml / min), the dose of clarithromycin should be reduced by 50%. In patients with creatinine clearance less than 30 ml / min, the dose of clarithromycin should be reduced by 75%. 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 and blockers of “slow” calcium channels that are metabolized by the isoenzyme CYP3A4 (for example: verapamil, amlodipine, diltiazem), care should be taken, since 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 while taking clarithromycin and verapamil. When taken together with clarithromycin, a decrease in blood pressure, bradyarrhythmia and lactic acidosis is possible. Itraconazole Clarithromycin and itraconazole are substrates and inhibitors of the CYP3A isoenzyme, which determines the bi-directional interaction of drugs. Clarithromycin can increase the plasma concentration of itraconazole, while itraconazole can increase the plasma concentration of clarithromycin. Patients taking itraconazole and clarithromycin at the same time it should be carefully 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 bi-directional drug interactions. With the simultaneous use of clarithromycin (500 mg 2 times a day) and saquinavir (in soft gelatin capsules, 1200 mg 3 times a day), AUC and css of saquinavir may increase by 177% and 187%, and clarithromycin – by 40%. When combined use of these two drugs for a limited time and in the doses / formulations indicated above, dose adjustment is not required. The results of a study of drug interactions with saquinavir monotherapy may not correspond to the effects observed with saquinavir / ritonavir therapy. When taking saquinavir together with ritonavir, the potential effect of ritonavir on clarithromycin should be considered. Overdose Symptoms: taking a large dose of clarithromycin can cause nausea, vomiting, abdominal pain, diarrhea, headache, confusion. Treatment: gastric lavage, symptomatic therapy. Hemodialysis and peritoneal dialysis have no significant effect on the concentration of clarithromycin in serum, which is also characteristic of other drugs of the macrolide group. Storage Conditions At a temperature not exceeding 25 ° C. Keep out of the reach and sight of children. Expiration 2 years. active substance Clarithromycin Terms of dispatch from pharmacies by prescription Dosage form tablets. Prescribing Pregnant as prescribed but adults prescribed by a doctor, children doctor intended for children aged 12 years Destination
