Clarithromycin-OBL, 500 mg 7 pcs.

Pharmacokinetics:

Intake

The drug is rapidly absorbed in the gastrointestinal tract. Absolute bioavailability is about 50% . When multiple doses of the drug are taken practically no cumulation was detected and the metabolism pattern in the human body did not change. Eating immediately before taking the drug increased the bioavailability of the drug by 25% on average. Clarithromycin can be used before meals or with meals.

Distribution, metabolism and excretion

In vitro

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

In vivo

In vivo animal studies have shown that clarithromycin is present in all tissues except the central nervous system at concentrations several times greater than plasma concentrations. The highest concentrations (10-20 times higher than plasma concentrations) were found in the liver and lungs.

Health

When clarithromycin was administered in a dose of 250 mg twice daily, the maximum concentration (Cmax) of clarithromycin and 14-OH-clarithromycin in plasma was reached after 2-3 days and was 1 µg/ml and 0.6 µg/ml, respectively. The half-lives (T1/2) of clarithromycin and its main metabolite were 3-4 hours and 5-6 hours, respectively. When clarithromycin was administered at a dose of 500 mg twice daily, the Cmax of clarithromycin and 14-OH-clarithromycin in plasma was reached after the 5th dose and averaged 2.7 – 2.9 µg/ml and 0.88 – 0.83 µg/ml, respectively. The T1/2 of clarithromycin and its main metabolite was 4.5 to 4.8 hours and 6.9 to 8.7 hours, respectively.

The cmax of 14-OH clarithromycin did not increase in proportion to the clarithromycin dose, whereas the T1/2 of both clarithromycin and its hydroxylated metabolite tended to increase with increasing dose. This nonlinear pharmacokinetics of clarithromycin combined with decreased formation of 14-hydroxylated and N-demethylated products at high doses indicates a nonlinear metabolism of clarithromycin that becomes more pronounced at higher doses.

The urinary excretion is about 37.9% after oral clarithromycin doses of 250 mg and 46% after clarithromycin doses of 1200 mg; about 40.2% and 29.1%, respectively, are excreted through the intestine.

Patients

Clarithromycin and its metabolite 14-OH-clarithromycin rapidly penetrate tissues and body fluids. There is limited evidence that the concentration of clarithromycin in cerebrospinal fluid with oral administration is negligible (i.e., only 1-2% of the serum concentration with normal blood-brain barrier permeability). Tissue concentrations are usually several times higher than serum concentrations.

Hepatic disorders

In patients with moderate to severe hepatic impairment but with preserved renal function, clarithromycin dose adjustment is not necessary. Equilibrium plasma concentration and systemic clearance of clarithromycin do not differ between patients in this group and healthy patients. The equilibrium concentration of 14-OH clarithromycin is lower in people with hepatic impairment than in healthy patients.

In impaired renal function, the Cmax and minimum plasma concentrations (Cmin) of clarithromycin, the elimination half-life and the area under the pharmacokinetic concentration-time curve (AUC) of clarithromycin and its metabolite 14-OH- clarithromycin are increased. The elimination constant and renal excretion decreases. The degree of change in these parameters depends on the degree of renal impairment.

Elderly patients

Elderly patients had higher blood concentrations of clarithromycin and its metabolite 14-OH- clarithromycin and slower excretion than the younger group. However, after adjustment for renal creatinine clearance, 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

The equilibrium concentrations of clarithromycin and 14-OH clarithromycin in patients with HIV infection who received clarithromycin at conventional doses (500 mg twice daily) were similar to those in healthy subjects. However, when clarithromycin is used at higher doses that may be necessary to treat mycobacterial infections, antibiotic concentrations may be significantly higher than normal.

In HIV-infected patients who received clarithromycin at doses of 1000 mg/day or 2000 mg/day in two doses, equilibrium Stakh values were typically 2-4 µg/ml and 5-10 µg/ml, respectively. At higher doses, a prolongation of the elimination half-life was observed compared to that in healthy subjects receiving clarithromycin at normal doses. Increased plasma concentrations and prolonged half-life when using clarithromycin at higher doses are due to non-linear pharmacokinetics of the drug.

Combination treatment with omeprazole

Clarithromycin, 500 mg 3 times daily, in combination with omeprazole at a dose of 40 mg/day contributes to increase T1/2 and AUCo-24 of omeprazole. In all patients who received combination therapy compared to those who received omeprazole alone, there was an 89% increase in AUC0-24 and 34% increase in T1/2 of omeprazole. Clarithromycin had a 10%, 27% and 15% increase in Cmax, Cmin and AUCo-8, respectively, compared with data when clarithromycin alone was used without omeprazole.

In equilibrium, clarithromycin concentrations in gastric mucosa were 25 times higher 6 hours after administration in the group receiving the combination compared to those receiving clarithromycin alone. Clarithromycin concentrations in gastric tissue 6 hours after the 2-drug regimen were twice as high as in the clarithromycin alone group.

Indications

Infectious and inflammatory diseases caused by clarithromycin-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, rust)
– 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 spread of infection caused by Mycobacterium avium complex (MAC) to HIV-infected patients with CD4 (T-helper lymphocytes) content not more than 100 in 1mm;
– eradication of H.pylori and reduction of duodenal ulcer recurrence rate;
– odontogenic infections.

Active ingredient

Composition

1 film-coated tablet contains:

the active substance:

clarithromycin (in terms of 100% substance) 500 mg;

excipients: microcrystalline cellulose 260.77 mg, sodium lauryl sulfate 34.5 mg, croscarmellose sodium 15.54 mg, colloidal silicon dioxide (aerosil) 40 mg, povidone (polyvinylpyrrolidone low-molecular) 0.39 mg, magnesium stearate 8.8 mg;

Shell excipients: Hypromellose (hydroxypropyl methylcellulose) 23.52 mg, macrogol 6000 (polyethylene glycol 6000) 6.08 mg, titanium dioxide 5.8 mg, hyprolose (hydroxypropyl cellulose) 2.36 mg, quinoline yellow dye 1.1 mg, vanillin 1.14 mg.

How to take, the dosage

For oral administration. Regardless of food intake.

The usual recommended dose of clarithromycin in adults and children over 12 years is 250 mg twice daily.

In more severe infections, the dose is increased to 500 mg twice a day.

The usual duration of treatment is from 5 to 14 days.

The exceptions are community-acquired pneumonia and sinusitis, which require 6 to 14 days of treatment.

Doses for treatment of mycobacterial infections other than tuberculosis:

The recommended dose for mycobacterial infections is clarithromycin 500 mg twice daily.

The treatment of disseminated MAC infections in patients with AIDS should be continued as long as there is clinical and microbiological efficacy. Clarithromycin should be administered in combination with other antimicrobials active against these pathogens. The duration of treatment of other non-tuberculous mycobacterial infections is determined by the physician.

For prevention of infections caused by MAC:

The recommended dose of clarithromycin for adults is 500 mg twice daily.

For odontogenic infections, the dose of clarithromycin is 250 mg 2 times a day for 5 days.

For eradication of H. pylori.

In patients with peptic ulcer disease caused by P. pylori infection, clarithromycin may be given 500 mg 2 times daily in combination with other antimicrobial agents and proton pump inhibitors for 7-14 days according to the national and international guidelines for the treatment of H. pylori infection.

Patients with renal impairment and patients with creatinine clearance (CK) less than 30 mL/min are prescribed half the usual dose of clarithromycin i.e. 250 mg once daily or in more severe infections 250 mg twice daily. Treatment is continued for no more than 14 days in these patients.

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 (see Contraindications. See Contraindications).

After-marketing 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 central nervous system. Concomitant use of clarithromycin and ergot alkaloids is contraindicated (see section “Contraindications”).

HMG-CoA reductase inhibitors (statins)

The effect of other drugs on clarithromycin

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 weaken therapeutic effect, and at the same time increase the concentration of the 14-OH clarythromycin metabolite, which 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 and enzyme inducers are used together.

Etravirine

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 a 33% and 18% increase in the mean clarithromycin minimum equilibrium concentration (Cmin) and AUC, respectively. However, co-administration 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.

The pharmacokinetic study showed that co-administration of ritonavir at a dose of 200 mg every eight hours and clarithromycin at a dose of 500 mg every 12 hours resulted in a 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 clarithromycin dose should be reduced by 50%; at CKR less than 30 ml/min, the clarithromycin dose should be reduced by 75%. Ritonavir should not be coadministered with clarithromycin in doses greater than 1 g/day.

Effects of clarithromycin on other drugs

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 for prolongation of QT interval, and serum concentrations of these drugs should be monitored.

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

Peroral hypoglycemic agents/insulin

CYP3A isoenzyme-dependent interactions

Indirect anticoagulants

The co-administration of warfarin and clarithromycin may cause bleeding, marked increase in INR and prothrombin time. If combined with warfarin or other indirect anticoagulants, the INR and prothrombin time should be monitored.

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 used together, equilibrium plasma concentrations of omeprazole were increased (Cmax, AUC0-24 and T1/2 increased by 30%, 89% and 34% respectively). Mean gastric pH over 24 hours was 5.2 when omeprazole was taken alone and 5.7 when omeprazole was taken together with clarithromycin.

Each of these phosphodiesterase inhibitors is metabolized at least in part with the CYP3A isoenzyme. At the same time, 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 using these drugs 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

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

Interactions with other drugs

Aminoglycosides

When clarithromycin is coadministered with other ototoxic drugs, especially aminoglycosides, care should be taken to monitor vestibular and auditory function both during and after therapy.

Colchicine

Digoxin

Zidovudine

The concomitant oral administration of clarithromycin tablets and zidovudine in HIV-infected adults may decrease the equilibrium concentration of zidovudine.

Phenytoin and valproic acid

Bidirectional drug interactions

Atazanavir

Slow calcium channel blockers

Itraconazole

Saquinavir

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.

Given 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. Skin and soft tissue infections of mild to moderate severity are most often caused by Staphylococcus aureus and Streptococcus pyogenes. Both pathogens can be resistant to macrolides. Therefore, it is important to test for sensitivity.

Macrolides can be used in infections caused by Corynebacterium minutissimum diseases acne vulgaris and rye and in situations where penicillin cannot be used.

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

Clarithromycin should be used with caution in patients with coronary heart disease (CHD) severe heart failure hypomagnesemia severe bradycardia (less than 50 bpm) and concomitant use with antiarrhythmic drugs of class IA (quinidine procainamide) and class III (dofetilide amiodarone sotalol). Regular electrocardiogram monitoring for QT interval prolongation should be performed in these conditions and concomitant use of clarithromycin with these drugs.

Hepatic dysfunction (increased concentration of hepatic enzymes in 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 related to the presence of serious comorbidities and/or concomitant use of other drugs. If signs and symptoms of hepatitis occur, 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.

In case of co-administration with warfarin or other indirect anticoagulants, INR and prothrombin time should be monitored.

In treatment with virtually all antibacterials, including clarithromycin, there have been cases of pseudomembranous colitis, the severity of which can range from mild to life-threatening. Antibacterials can alter 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 antibiotics. After a course of antibiotic therapy, careful medical follow-up of the patient is necessary. There have been cases of pseudomembranous colitis two months after antibiotic treatment.

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), clarithromycin should be stopped immediately and appropriate therapy started.

There are no data on the effect of clarithromycin on the ability to operate vehicles and machinery.

Perhaps caution should be exercised when driving vehicles and operating machinery due to the potential for dizziness, vertigo, confusion, and disorientation that may occur with this drug.

Contraindications

– hypersensitivity to clarithromycin, other drug components and other macrolides;

– concomitant administration of clarithromycin with the following drugs: astemizole, cisapride, pimozide and terfenadine (see “Interaction with other drugs.

Concomitant administration of clarithromycin with ergot alkaloids, e.g. ergotamine, dihydroergotamine (see “Interaction with other medicinal products”).

– concomitant administration of clarithromycin with oral midazolam (see “Interaction with other medicinal products”).

– concomitant administration of clarithromycin with HMG-CoA reductase inhibitors (statins) that are largely metabolized by CYP3A4 isoenzyme (lovastatin, simvastatin), due to increased risk of myopathy, including rhabdomyolysis (see “Interaction with other drugs”).

– concomitant use of colchicine;

– concomitant use with ticagrelor or ranolazine;

– history of QT interval prolongation, ventricular arrhythmia, or pirouette-type ventricular tachycardia;

Hypkalemia (risk of QT interval prolongation);

Severe hepatic impairment concomitant with renal impairment; history of cholestatic jaundice/hempatitis with clarithromycin (see

Periodic use of clarithromycin).

– porphyria;

– period of breastfeeding;

– age less than 12 years.

– moderate to severe renal failure;

– moderate to severe hepatic failure;

– concurrent use of clarithromycin with other ototoxic drugs, especially aminoglycosides (see Interaction with other medicinal products);

– concomitant administration of clarithromycin with other ototoxic drugs, especially aminoglycosides. – concomitant administration with drugs that are metabolized by CYP3A isoenzymes, e.g., carbamazepine, cilostazol, cyclosporine, disopyramide, methylprednisolone, omeprazole, indirect anticoagulants (e.g., warfarin), quinidine, rifabutin, sildenafil, tacrolimus, vinblastine (see “Interaction with other drugs.

– coronary heart disease, severe heart failure, hypomagnesemia, marked bradycardia (less than 50 bpm);

– pregnancy.

Side effects

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

very common (≥1/10),

frequent (≥1/100, < 1/10),

infrequent (≥1/1000, < 1/100),

frequency unknown (side effects from postmarketing experience; frequency cannot be estimated based on available data).

Allergic reactions

Often: rash.

Infrequent: hypersensitivity, itching, urticaria, maculopapular rash2.

Frequent unknown: anaphylactic reaction, angioneurotic edema, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptomatology (DRESS syndrome).

Nervous system disorders

Often: headache, insomnia.

Infrequent: dizziness, somnolence, tremor, restlessness, increased

excitability2.

Prevalence unknown: seizures, psychotic disorders, confusion, depersonalization, depression, disorientation, hallucinations, dream disorders (“nightmare” dreams), paresthesia, mania.

Skin disorders

Often: intense sweating.

Prevalence unknown: acne, hemorrhages.

Urinary system disorders

Prevalence unknown: renal failure, interstitial nephritis.

Metabolism and nutrition disorders

Infrequent: anorexia, decreased appetite.

Musculoskeletal disorders

Infrequent: muscle spasm2, myalgia1.

Infrequent unknown: rhabdomyolysis1*, myopathy.

Digestive system disorders

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

Infrequent: gastroesophageal reflux disease1, gastritis, proctalgia1, stomatitis, glossitis, bloating3, constipation, dry mouth, belching, flatulence, cholestasis”, hepatitis including cholestatic or hepatocellular”.

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

Respiratory system disorders

Infrequent: nasal bleeding1.

Sensory system disorders

Often: dysgeusia, perversion of taste.

Infrequent: vertigo, hearing impairment, tinnitus.

Frequent unknown: deafness, agueusia (loss of taste), parosmia. anosmia. Cardiovascular system disorders

Infrequent: prolongation of the QT interval on electrocardiogram, atrial flutter. Frequency unknown: ventricular tachycardia, including pirouette type.

Laboratory indices

Often: abnormal liver function test.

Infrequent: leukopenia, neutropenia3, eosinophilia3, thrombocythemia2. Increased activity of: alanine aminotransferase (ALT), aspartate aminotransferase (ACT), gammaglutamyltransferase (GGTP)3, alkaline phosphatase’, lactate dehydrogenase (LDH)3, Frequency unknown: Agranulocytosis, thrombocytopenia, increased international normalized ratio (INR) value, prolonged prothrombin time, change in urine color, increased blood bilirubin concentration.

General disorders

Infrequent: malaise3, hyperthermia2, asthenia, chest pain3, chills3, fatigue3.

Infectious and parasitic diseases

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

Infrequent unknown: pseudomembranous colitis, rye.

Patients with suppressed immunity

1 These adverse reactions have only been reported with clarithromycin in the dosage form: sustained release film-coated tablets.

2 These adverse reactions have only been reported with clarithromycin in the dosage form: powder for oral suspension.

3 These adverse reactions have only been reported with clarithromycin in the dosage form of film-coated tablets.

Overdose

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

One patient with a history of bipolar disorder has described changes in mental status, 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.

Pregnancy use

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

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

Clarithromycin is excreted with the breast milk. Breast-feeding should be discontinued if it is necessary during breast-feeding.

Similarities