Clacid SR, 500 mg 5 pcs

Pharmacodynamics

Clarithromycin is a semi-synthetic antibiotic of macrolide group and has antibacterial effect by interacting with 50S ribosomal subunit and inhibiting protein synthesis of bacteria sensitive to it.

The sustained release tablets have a homogeneous base that allows prolonged release of the active ingredient as it passes through the gastrointestinal tract.

Clarithromycin is highly effective in vitro against both standard laboratory strains of bacteria and those isolated from patients in clinical practice. It is highly active against a wide range of aerobic and anaerobic, Gram-positive and Gram-negative microorganisms. The MAC of clarithromycin for most pathogens is lower than that of erythromycin.

In in vitro studies, clarithromycin has been shown to be highly active against Legionella pneumophila, Mycoplasma pneumoniae, but Enterobacteriaceae, Pseudomonas spp. and other non-lactose-fermenting Gram-negative microorganisms are not susceptible to clarithromycin.

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

Aerobic gram-positive microorganisms – Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes; aerobic gram-negative microorganisms – Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Legionella pneumophila; other microorganisms – Mycoplasma pneumoniae, Chlamydia pneumoniae; mycobacteria – Mycobacterium avium complex (MAC) – a complex including Mycobacterium avium, Mycobacterium intracellulare.

Beta-lactamases do not affect the activity of clarithromycin.

Clarithromycin in vitro is active against most strains of the microorganisms listed below:

– aerobic gram-positive microorganisms – Streptococcus agalactiae; Streptococcus spp. group C, F, G; Streptococcus spp. Viridans group; Listeria monocytogenes;

– aerobic Gram-negative microorganisms – Bordetella pertussis; Pasteurella multocida; Neisseria gonorrhoeae;

– anaerobic gram-positive microorganisms – Clostridium perfringens; Peptococcus niger; Propionibacterium acnes;

– anaerobic gram-negative microorganisms – Bacteroides melaninogenicus;

Spirochaetes – Borrelia burgdorferi; Treponema pallidum;

– Mycobacteria – Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum;

– Campylobacter – Campylobacter jejuni.

The main metabolite of clarithromycin in humans is microbiologically active metabolite 14(R)-hydroxy-clarithromycin (14-OH-clarithromycin), which is twice as active against Haemophilus influenzae (H. influenzae) as the parent compound. The parent compound (clarithromycin) and its metabolite in combination can have both additive and synergistic effects on H. influenzae in vitro and in vivo, depending on the bacterial strain.

Pharmacokinetics

Clarithromycin is metabolized in the liver cytochrome P450 3A (CYP3A) system. Absolute bioavailability is about 50%. No cumulation was found when taking the drug multiple times; the character of metabolism in human body was not changed.

In vitro

In vitro studies showed that on average about 70% of clarithromycin binds to human serum proteins at drug concentrations of 0.45-4.5 µg/ml. When the concentration was increased to 45.0 µg/ml, clarithromycin binding decreased to 41%, which may indicate saturation of the binding centers. This phenomenon was observed only at drug concentrations significantly higher than the therapeutic ones.

Healthy volunteers

In patients who received 500 mg of Clacid® SR once daily, Cmax of clarithromycin and 14-OH-clarithromycin – in plasma was 1.3 and 0.48 µg/ml, respectively. T1/2 of the original drug and metabolite were 5.3 and 7.7 h, respectively. At a single dose of Clacid®CP 1000 mg (2 times 500 mg) the Cmax of clarithromycin and its hydroxylated metabolite was 2.4 and 0.67 µg/ml, respectively. The T1/2 of clarithromycin when administered at a dose of 1000 mg was 5.8 h, whereas the same figure for 14-OH-clarithromycin was 8.9 h. Tmax for both 500 mg and 1000 mg was approximately 6 h. The Cmax of 14-OH-clarithromycin did not increase in proportion to the clarithromycin dose, while 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 kidneys excrete approximately 40% of the intake of clarithromycin. The intestine excretes approximately 30%.

Patients taking clarithromycin as indicated

Clarithromycin and its 14-OH metabolite readily penetrate tissues and body fluids. Limited data from trials with a small number of patients suggest that the concentration of clarithromycin in cerebrospinal fluid when administered orally is negligible. Tissue concentrations are usually several times higher than serum concentrations.

Hepatic disorders

In a comparative study it has been shown that no dosage adjustment is required in patients with preserved renal function in patients with moderate to severe hepatic impairment.

Kidney disease

In people with renal impairment, plasma concentrations, T1/2, Cmax and Cmin of clarithromycin and its 14-OH metabolite were higher than in those with normal renal function. In patients with impaired renal function, the AUC was greater and the elimination constant and renal excretion was less. The degree of these differences correlated with the severity of renal disease: the more severe the renal impairment, the greater the differences.

The elderly

The elderly have higher plasma levels of clarithromycin and its 14-OH metabolite and slower excretion compared to the young. However, the main influence on the pharmacokinetic parameters of clarithromycin is renal function, not age.

Indications

Active ingredient

Composition

How to take, the dosage

Orally, do not break, chew, swallow whole, with meals. Generally, adults are given 1 tablet of clarithromycin 500 mg once daily. For more severe infections, the dose is increased to 2 tablets (1000 mg) once daily.

The usual duration of treatment is 5-14 days; the exception is for patients with community-acquired pneumonia and sinusitis; the duration of treatment is 6-14 days.

Interaction

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

Cyzapride and pimozide

Combined use may increase cisapride concentrations, increase QT interval, and cause cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, ventricular pirouette tachycardia.

Terphenadine and astemizole

The co-administration may increase terphenadine/astemizole blood concentrations, increase QT interval, and cause cardiac arrhythmias, ventricular tachycardia, ventricular fibrillation, and pirouette tachycardia.

Ergotamine / dihydroergotamine

The following effects associated with acute poisoning by drugs of the ergotamine group are possible when used together: vasospasm, ischemia of the extremities and other tissues, including the CNS.

The effect of other drugs on clarithromycin

The following drugs have proven or suspected effects on clarithromycin concentrations; doses may need to be adjusted or alternative treatment may be necessary if they are combined 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 thereby decrease plasma levels of clarithromycin, weaken the therapeutic effect, and increase levels of 14-OH clarithromycin, a metabolite that is also microbially active.

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 minimum mean Css and AUC of clarithromycin, respectively.

The co-administration did not significantly affect the mean Css of the active metabolite 14-OH clarithromycin. No dose adjustment of clarithromycin is required for concomitant administration of fluconazole.

Ritonavir

A pharmacokinetic study has shown 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 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.

With a wide therapeutic range, no dosage reduction is required in patients with normal renal function. In patients with renal impairment it is reasonable to consider the following dose adjustments: at Cl creatinine 30-60 ml/min, the dose of clarithromycin should be reduced by 50% (not more than one Clacid® SR tablet per day). Patients with severe renal impairment (Cl creatinine <30 ml/min) should not take Clacid® SR due to the inability to adequately adjust (reduce) the dose (see “Contraindications”). Clarithromycin tablets of normal release can be used in such patient groups. Ritonavir should not be coadministered with clarithromycin in doses greater than 1 g/day.

The effect of clarithromycin on other drugs

Antiarrhythmic drugs (quinidine and disopyramide)

Pirouette tachycardia may occur when clarithromycin and quinidine or disopyramide are taken together. If clarithromycin is coadministered with these drugs, regular ECG monitoring for QT interval prolongation should be performed, and serum concentrations of these drugs should be monitored.

CYP3A-induced interactions

The co-administration of clarithromycin, which is known to inhibit CYP3A isoenzymes, and drugs primarily metabolized by CYP3A isoenzymes may be associated with a mutual increase in their concentrations, which may enhance or prolong both therapeutic and adverse effects. Clarithromycin should be administered with caution to patients receiving drugs that are substrates of CYP3A enzyme, especially if the CYP3A substrate has a narrow therapeutic range (e.g., carbamazepine), and/or is extensively metabolized by this enzyme. If necessary, the dose of the drug taken together with Clacid® SR should be adjusted, and co-administration of some drugs should be excluded (see “Contraindications”). Serum levels of drugs that are primarily metabolized by CYP3A should also be monitored when possible. The following drugs/classes are metabolized by the same CYP3A isoenzyme as clarithromycin: Alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, Oral anticoagulants (e.g., warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam, and vinblastine. Drugs that interact similarly through other isoenzymes within the cytochrome P450 system include phenytoin, theophylline and valproic acid.

HMG-CoA reductase inhibitors

Like other macrolides, clarithromycin increases concentrations of HMG-CoA reductase inhibitors (such as lovastatin and simvastatin). Rare cases of rhabdomyolysis have been reported in patients taking these drugs together.

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

Peroral anticoagulants

The effect of oral anticoagulants may be enhanced. If patients receive clarithromycin and oral anticoagulants concomitantly, PV should be monitored closely.

Sildenafil, tadalafil and vardenafil

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

Theophylline, carbamazepine

Theophylline or carbamazepine may increase concentration in systemic blood flow.

Tolterodine

The primary metabolism of tolterodine is via cytochrome P450 isoform 2D6 (CYP2D6). However, in a portion of the population lacking the CYP2D6 isoenzyme, 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, a dose reduction of tolterodine in the presence of CYP3A inhibitors such as clarithromycin may be required.

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

The co-administration of midazolam and clarithromycin (500 mg 2 times daily) showed a 2.7-fold increase in the AUC of midazolam following intravenous administration of midazolam and a 7-fold increase following oral administration. Co-administration of midazolam and clarithromycin should be avoided. If clarithromycin is concomitantly administered with intravenous midazolam, the patient should be closely monitored for possible dose adjustments. The same precautions should be applied to other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines whose excretion is not dependent on CYP3A (temazepam, nitrazepam, lorazepam), a clinically significant interaction with clarithromycin is unlikely.

When clarithromycin and triazolam are used together, CNS effects such as drowsiness and confusion may occur.

Interaction with other drugs

Colchicine

Colchicine is a substrate of both CYP3A and the carrier protein responsible for drug excretion, P-glycoprotein (P-gp). Clarithromycin and other macrolides are known to inhibit CYP3A and P-gp. When clarithromycin and colchicine are taken together, inhibition of P-gp and/or CYP3A may increase the effect of colchicine. There have been post-marketing reports of cases of colchicine poisoning when coadministered with clarithromycin, more frequently in elderly patients. Some of the described cases occurred in patients with renal insufficiency. Some cases have been reported to be fatal.

Digoxin

Digoxin is thought to be a substrate for P-gp. Clarithromycin is known to inhibit P-gp. When clarithromycin and digoxin are coadministered, the inhibition of P-gp by clarithromycin may enhance the effects of digoxin. Co-administration of digoxin and clarithromycin may also lead to increased serum concentrations of digoxin in patients, development of clinical symptoms of digoxin poisoning, including potentially fatal arrhythmias. Serum digoxin concentrations should be closely monitored when clarithromycin and digoxin are coadministered.

Zidovudine

The concomitant oral administration of conventional-release clarithromycin tablets and zidovudine in adult HIV-infected patients may result in lower Css of zidovudine. Because clarithromycin affects the absorption of zidovudine when taken orally, the interaction can be largely avoided by adjusting the doses of clarithromycin and zidovudine. This type of interaction does not occur in HIV-infected children receiving clarithromycin in suspension form with zidovudine. No studies of interaction of Clacid® SR with zidovudine have been conducted.

Bidirectional drug interaction

Atazanavir

Clarithromycin and atazanavir are both CYP3A substrates and inhibitors. There is evidence of a bidirectional interaction between these drugs. Concomitant administration of clarithromycin (500 mg twice daily) and atazanavir (400 mg once daily) may increase AUC of atazanavir by 28%, increase AUC of clarithromycin two-fold and decrease AUC of 14-OH clarithromycin by 70%. 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 (creatinine Cl 30-60 ml/min) the clarithromycin dose should be reduced by 50%. Clarithromycin in doses greater than 1000 mg/day should not be administered together with protease inhibitors.

Itraconazole

Clarithromycin and itraconazole are substrates and inhibitors of CYP3A. Clarithromycin can increase plasma levels of itraconazole, while itraconazole can increase clarithromycin levels. 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 both CYP3A substrates and inhibitors. Concomitant administration of clarithromycin (500 mg twice daily) and saquinavir (in soft gelatin capsules, 1200 mg three times daily) may cause an increase in AUC and Cmax of saquinavir by 177 and 187%, respectively, compared with taking saquinavir. The AUC and Cmax values of clarithromycin were approximately 40% higher than those of clarithromycin. No dose adjustments are required when the two drugs are co-administered 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 when saquinavir is administered in isolation 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.

Verapamil

Hypotension, bradyarrhythmia and lactate acidosis may occur when co-administered with clarithromycin.

Special Instructions

Most staphylococcal strains resistant to methicillin and oxacillin are resistant to clarithromycin.

Long-term use of clarithromycin, as well as other antibiotics, can provoke colonization with an increase in the number of nonresistant bacteria and fungi. Adequate therapy should be prescribed if a secondary infection occurs.

In treatment with almost all antibacterials, cases of pseudomembranous colitis have been described, the severity of which can range from mild to life-threatening. One of the symptoms of pseudomembranous colitis is diarrhea caused by Clostridium difficile. Therefore, if diarrhea occurs after prescribing antibiotics, the possibility of this disease should be considered.

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.

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

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

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

Synopsis

Contraindications

With caution: hepatic and renal dysfunction; myasthenia gravis (possible worsening of symptoms); simultaneous use with drugs that are metabolized by the liver (see “Interactions”).

Side effects

Side effects are presented according to the effect on organs and organ systems. For cases with indication of frequency consider: often >1%, <10%; rarely <1%, including individual cases.

Systems: rarely – ventricular tachycardia, including “pirouette” type, ventricular flutter and fibrillation, increased QT interval on ECG.

Digestive system disorders: frequently – dyspepsia, nausea, abdominal pain, vomiting, diarrhea, gastralgia, acute pancreatitis, glossitis, stomatitis, candidiasis of oral mucosa, discoloration of tongue and teeth, pseudomembranous enterocolitis. Liver function disorders, including often – increased liver enzyme activity, hepatocellular and cholestatic hepatitis, cholestatic jaundice. In very rare cases it was reported about liver failure with lethal outcome, mainly against the background of severe comorbidities and/or concomitant drug therapy.

Nervous system disorders: headaches (often); dizziness, anxiety, insomnia, dream disorders (“nightmares” dreams), tinnitus, depersonalization, hallucinations, seizures, psychotic disorders, confusion, disorientation, depression.

Skeletal and muscular system disorders: myalgia.

Urinary system: interstitial nephritis.

Sense organs: often – distortion or loss of taste sensation; deafness, cases of changes in sense of smell.

Allergic reactions: anaphylactic reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria, skin hyperemia, skin itching, rash.

Changes of laboratory parameters: leukopenia, thrombocytopenia, increased blood creatinine, hypoglycemia – rare (including in concurrent use of hypoglycemic agents).

Overdose

Symptoms: Taking a large dose of clarithromycin 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, symptomatic therapy including gastric lavage aimed at maintenance of vital body functions should be performed. Hemodialysis and peritoneal dialysis have no significant effect on serum levels of clarithromycin, which is also true for other drugs in the macrolide group.

Pregnancy use

The safety of clarithromycin in pregnant and breastfeeding women has not been studied.

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

If pregnancy occurs while using the drug, the patient should be warned about the possible risks to the fetus.

Clarithromycin is known to be excreted with breast milk. Withdrawal of breastfeeding should be considered during lactation.

Similarities