Clarithromycin 250 mg film-coated tablets - Summary of Product Characteristics (SPC) (2023)

Each film-coated tablet contains 250 mg clarithromycin.

For the full list of sponsors, please see paragraph 6.1.

Film-coated tablet.

Capsule-shaped, dark yellow, film-coated tablets.

Clarithromycin film-coated tablets are indicated in adults and adolescents 12 years of age and older for the treatment of the following bacterial infections caused by clarithromycin-susceptible bacteria (see sections 4.4 and 5.1).

• Acute bacterial exacerbation of chronic bronchitis

• Mild to moderate community-acquired pneumonia

• Acute bacterial sinusitis

• Bacterial PHARMINGITIS

• Mild to moderate skin and soft tissue infections such as folliculitis, cellulitis, and erysipelas.

Clarithromycin film-coated tablets may also be used in appropriate combination with antibacterial regimens and a suitable ulcer-healing agent to eradicateHelicobacter pyloriin patients withHelicobacter pyloriassociated ulcers (see section 4.2).

Official guidelines on the appropriate use of antibacterial agents should be considered.

The dosage of Clarithromycin film-coated tablets depends on the clinical status of the patient and must be determined in each case by the doctor.

Children over 12 years and adults.:

• Usual dose: The usual dose is 250 mg twice a day.

• High-dose therapy (severe infections): The usual dose may be increased to 500 mg twice daily in severe infections.

• Clinical trials have been conducted using pediatric clarithromycin suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use Pediatric Clarithromycin Suspension (Granules for Oral Suspension).

Elimination of Helicobacter pylori in adults:

In patients with gastroduodenal ulcer due to Helicobacter pylori infection, clarithromycin 500 mg twice daily can be used during eradication therapy in combination with amoxicillin 1000 mg twice daily and omeprazole 20 mg twice daily* .

Dosage in patients with renal insufficiency:

The maximum recommended doses should be reduced according to renal insufficiency. In patients with renal insufficiency with creatinine clearance less than 30 ml/min, the clarithromycin dose should be halved, i.e. 250 mg once daily or 250 mg twice daily in more severe infections. In these patients, treatment should not be continued beyond 14 days.

Treatment duration:

The duration of treatment with clarithromycin film-coated tablets depends on the clinical status of the patient. The duration of the treatment must, in any case, be determined by the doctor.

• The usual duration of treatment is 6 to 14 days.

• EmStreptococcus pyogenes(such as beta-haemolytic streptococci), the duration of treatment should be at least 10 days.

• Combination therapy to eradicate Helicobacter pylori infection, p. eg Treatment should be continued with clarithromycin 500 mg (two 250 mg tablets or one 500 mg tablet) twice daily in combination with amoxicillin 1000 mg twice daily and omeprazole 20 mg twice daily for 7 days*.

Administration method:

Clarithromycin film-coated tablets can be taken without regard to food intake. Food does not affect the degree of bioavailability. Food only slightly delays the onset of clarithromycin absorption and the formation of the 14-hydroxy metabolite.

*As published in Gastroenterology. February 1999? 116(2): 248-53

Clarithromycin is contraindicated in patients with a known hypersensitivity to the active substance, to macrolide antibiotics, or to any of the excipients listed in section 6.1.

Concomitant administration of clarithromycin and any of the following drugs is contraindicated: astemizole, cisapride, domperidone, pimozide, terfenadine, as it may cause QT interval prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and spike.45.

Co-administration with ticagrelor or ranolazine is contraindicated.

Concomitant administration of clarithromycin and ergot alkaloids (eg.

Clarithromycin should not be administered to patients with a history of QT prolongation (congenital or documented acquired QT prolongation) or ventricular cardiac arrhythmia, including torsades de pointe (see sections 4.4 and 4.5).

Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin), due to an increased risk of myopathy, including rhabdomyolysis. (see paragraphs 4.4 and 4.5).

Concomitant administration of clarithromycin and lomitapide is contraindicated (see section 4.5).

Clarithromycin should not be given to patients with electrolyte abnormalities (hypokalemia or hypomagnesemia, due to the risk of QT prolongation).

Clarithromycin should not be used in patients with severe hepatic insufficiency combined with renal dysfunction.

As with other strong CYP3A4 inhibitors, clarithromycin should not be used in patients receiving colchicine.

Concomitant oral administration of clarithromycin and midazolam is contraindicated (see section 4.5).

Physicians should not prescribe clarithromycin to pregnant women without carefully weighing the benefits and risks, especially during the first three months of pregnancy (see section 4.6).

Caution is recommended in patients with severe renal impairment (see section 4.2).

Clarithromycin is mainly excreted by the liver. Therefore, caution should be exercised when administering the antibiotic to patients with hepatic impairment. Caution should also be exercised when administering clarithromycin to patients with moderate to severe renal impairment.

Hepatic failure, including elevated liver enzymes and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. This liver dysfunction can be severe and is usually reversible. Fatal liver failure has been reported in some cases and has generally been associated with serious underlying conditions and/or concomitant medications. Discontinue clarithromycin immediately if signs and symptoms of hepatitis develop, such as anorexia, jaundice, dark urine, abdominal itching, or tenderness.

Cases of fatal hepatic failure have been reported (see section 4.8). Some patients may have had pre-existing liver disease or may be taking other hepatotoxic drugs. Patients should be advised to discontinue treatment and contact their doctor if signs and symptoms of liver disease develop, such as anorexia, jaundice, dark urine, itching, or abdominal tenderness.

Pseudomembranous colitis has been reported with almost all antibacterial agents, including macrolides, and its severity can range from mild to life-threatening.Clostridium difficile-Diarrhea associated (CDAD) has been reported with the use of almost all antibacterial agents, including clarithromycin, and its severity can range from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, which can lead to excessive growth.It's hard.CDAD should be considered in all patients who develop diarrhea after antibiotic use. A careful medical history is essential, as CDAD has been reported to occur within two months of administration of antibacterial agents. Therefore, discontinuation of clarithromycin treatment should be considered regardless of the indication. Microbial tests should be performed and appropriate therapy initiated. Drugs that inhibit peristalsis should be avoided.

There have been postmarketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, particularly in the elderly, some of which have occurred in patients with renal impairment. Fatalities have been reported in some of these patients (see section 4.5). Concomitant administration of clarithromycin and colchicine is contraindicated (see section 4.3).

Caution is advised with concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam, and intravenous or oral midazolam (see section 4.5).

cardiovascular events

Prolonged cardiac repolarization and QT interval, carrying a risk of cardiac arrhythmia and torsades de pointes, have been observed with treatment with macrolides, including clarithromycin (see section 4.8). Therefore, because the following conditions may cause an increased risk of ventricular arrhythmias (including torsades de pointes), clarithromycin should be used with caution in the following patients:

• Patients with coronary artery disease, severe heart failure, conduction disturbances or clinically relevant bradycardia,

• Patients with electrolyte disturbances. Clarithromycin should not be administered to patients with hypokalaemia (see section 4.3).

• Patients receiving concomitant medications associated with prolongation of the QT interval (see section 4.5).

• Co-administration of clarithromycin with astemizole, cisapride, pimozide and terfenadine is contraindicated (see section 4.3).

• Clarithromycin should not be used in patients with documented congenital or acquired QT prolongation or a history of ventricular arrhythmia (see section 4.3).

Epidemiological studies that have investigated the risk of adverse cardiovascular outcomes with macrolides have shown mixed results. Some observational studies have identified a rare short-term risk of arrhythmia, myocardial infarction, and cardiovascular mortality associated with macrolides, including clarithromycin. Consideration of these results must be balanced against the benefits of treatment when prescribing clarithromycin.

Pneumonia: In view of its emerging resistancesteotococos neumoniaFor macrolides, susceptibility testing is important when clarithromycin is prescribed for community-acquired pneumonia. In nosocomial pneumonia, clarithromycin should be used in combination with appropriate additional antibiotics.

Mild to moderate infections of the skin and soft tissues.: These infections are most often caused bystaphylococcal diseasemiStreptococcus pyogenes, which may be resistant to macrolides. Therefore, it is important to perform susceptibility testing. In cases wherebeta-Lactam antibiotics cannot be used (for example, allergy), other antibiotics such as clindamycin may be the drug of choice. Currently, macrolides are thought to play a role only in certain skin and soft tissue infections, such as those caused byCorynebacterium minutismus, acne vulgaris and erysipelas and in situations where penicillin therapy cannot be used.

In case of severe acute hypersensitivity reactions such as anaphylaxis, serious skin adverse reactions (SCARs) (for example, acute generalized exanthematous pustule (AGEP), Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms (DRESS) , Clarithromycin treatment should be discontinued immediately and appropriate treatment initiated urgently.

Clarithromycin should be used with caution when co-administered with medicinal products that induce the cytochrome CYP3A4 enzyme (see section 4.5).

HMG-CoA reductase inhibitors (statins):Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section 4.3). Caution should be exercised when prescribing clarithromycin with other statins. Rhabdomyolysis has been reported in patients receiving clarithromycin and statins. Patients should be monitored for signs and symptoms of myopathy. In cases where the simultaneous use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered statin dose. A statin not dependent on CYP3A metabolism (eg fluvastatin) may be considered (see section 4.5).

Oral Hypoglycemic Agents/Insulin:Concomitant use of clarithromycin with oral hypoglycaemic agents (such as sulfonylureas) and/or insulin may result in significant hypoglycaemia. Careful monitoring of blood glucose is recommended (see section 4.5).

oral anticoagulants: There is a risk of major bleeding and significant increases in international normalized ratio (INR) and prothrombin time when clarithromycin is co-administered with warfarin (see section 4.5). Caution should be exercised when co-administering clarithromycin with direct-acting oral anticoagulants such as dabigatran, rivaroxaban and apixaban, especially in patients at high risk of bleeding (see section 4.5). INR and prothrombin times should be monitored frequently while patients are receiving clarithromycin and oral anticoagulants concomitantly.

Use of any antimicrobial therapy, such as clarithromycin, for treatment.Helicobacter pylori infectionthey can select for drug-resistant organisms.

Prolonged use can, as with other antibiotics, lead to colonization by increased numbers of non-susceptible bacteria and fungi. If infections occur, appropriate treatment should be initiated.

Attention should also be paid to the possibility of cross-resistance between clarithromycin and other macrolides, as well as lincomycin and clindamycin.

Clarithromycin contains sodium.

This medicinal product contains less than 1 mmol sodium (23 mg) per unit dose, ie it is essentially 'sodium-free'.

The use of the following drugs is strictly contraindicated due to the possibility of serious drug interaction effects:

Astemizolecisaprida, domperidona, pimozide and terfenadine

Elevated levels of cisapride have been reported in patients receiving clarithromycin and cisapride concomitantly. This can lead to prolongation of the QT interval and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes. Similar effects have been observed in patients receiving clarithromycin and pimozide at the same time (see section 4.3).

Macrolides have been reported to alter terfenadine metabolism, resulting in increased terfenadine levels, which have occasionally been associated with cardiac arrhythmias such as QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see section 4.3). In a study in 14 healthy volunteers, concomitant administration of clarithromycin and terfenadine produced a two- to three-fold increase in the serum level of the acid metabolite of terfenadine and prolongation of the QT interval without any clinically detectable effect. Similar effects have been observed with the simultaneous administration of astemizole and other macrolides.

Ergotamine/dihydroergotamine

Post-marketing reports indicate that co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute erysipelas toxicity characterized by vasospasm and ischemia of the extremities and other tissues, including the central nervous system. Concomitant administration of clarithromycin and these medicinal products is contraindicated (see section 4.3).

from the mouthmidazolam

When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), the AUC of midazolam was increased 7-fold after oral administration of midazolam. Simultaneous administration of oral midazolam and clarithromycin is contraindicated.

HMG-CoA reductase inhibitors (statins)

Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section 4.3), as these statins are extensively metabolized by CYP3A4 and concomitant treatment with clarithromycin increases their plasma concentrations, increasing the risk of myopathy, including rhabdomyolysis. Reports of rhabdomyolysis have been received in patients receiving clarithromycin concomitantly with these statins. If treatment with clarithromycin cannot be avoided, lovastatin or simvastatin should be discontinued during treatment.

Caution should be exercised when prescribing clarithromycin with statins. In cases where the simultaneous use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered statin dose. A statin that does not depend on CYP3A metabolism (eg, fluvastatin) may be considered. Patients should be monitored for signs and symptoms of myopathy.

Co-administration of clarithromycin with lomitapide is contraindicated due to the potential for significantly elevated transaminase levels to occur (see section 4.3).

Effects of other drugs on clarithromycin.

CYP3A-inducing drugs (eg, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort) can induce the metabolism of clarithromycin. This can result in subtherapeutic levels of clarithromycin, leading to reduced efficacy. In addition, it may be necessary to monitor plasma levels of the CYP3A inducer, which may be increased due to CYP3A inhibition by clarithromycin (see also relevant product information for the CYP3A4 inhibitor being administered). Co-administration of rifabutin and clarithromycin resulted in increased rifabutin and decreased serum clarithromycin levels, along with an increased risk of uveitis.

The following active substances are known or suspected to affect circulating concentrations of clarithromycin. The clarithromycin dose may need to be adjusted or alternative therapies may need to be considered.

Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine

Potent inducers of the cytochrome P450 metabolic system, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine, may accelerate clarithromycin metabolism and thus decrease clarithromycin plasma levels while increasing 14-OH- plasma levels. clarithromycin. microbiologically active. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the desired therapeutic effect may be reduced during simultaneous administration of clarithromycin and enzyme inducers.

Etravirina

Exposure to clarithromycin was decreased by etravirine. However, the concentrations of the active metabolite, 14-OH-clarithromycin, were elevated. As 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), the overall activity against this pathogen may be impaired. Therefore, alternatives to clarithromycin should be considered for the treatment of MAC.

fluconazole

Co-administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers resulted in increases in the mean steady-state trough concentration of clarithromycin (Cmax_min.) and area under the curve (AUC) of 33% and 18%, respectively. Steady-state concentrations of the active metabolite 14-OH-clarithromycin were not significantly affected by co-administration of fluconazole. No clarithromycin dose adjustment is necessary.

ritonavir

A pharmacokinetic study demonstrated that co-administration of ritonavir 200 mg every 8 hours and clarithromycin 500 mg every 12 hours produced significant inhibition of clarithromycin metabolism. Clarithromycin C_Maximumincreased by 31%, C_min.increased by 182% and AUC increased by 77% with co-administration of ritonavir. Substantially complete inhibition of 14-OH-clarithromycin formation was observed. Due to the wide therapeutic index of clarithromycin, a dose reduction should not be necessary in patients with normal renal function. However, for patients with renal insufficiency, the following dose adjustments should be considered: For CKD patients_CRFrom 30 to 60 ml/min the dose of clarithromycin should be reduced by 50%. For patients with CKD_CR<30 mL/min the clarithromycin dose should be reduced by 75%. Doses of clarithromycin greater than 1 g/day should not be co-administered with ritonavir.

Similar dose adjustments should be considered in patients with renal impairment when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors, including atazanavir and saquinavir (see Two-Way Drug Interactions section below).

Effect of clarithromycin on other drugs.

CYP3A-based interactions

Co-administration of clarithromycin, which is known to inhibit CYP3A, and a drug primarily metabolized by CYP3A may be associated with increases in drug concentrations that may ameliorate or prolong the therapeutic and adverse effects of the co-administered drug. The use of clarithromycin is contraindicated in patients receiving the CYP3A substrates astemizole, cisapride, domperidone, pimozide, and terfenadine due to the risk of QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and sections 4.3 and (sections 4.3 and ). The use of clarithromycin is also contraindicated with ergot alkaloids, oral midazolam, inhibitors of HMG CoA reductase metabolized primarily by CYP3A4 (eg lovastatin and simvastatin), colchicine, ticagrelor, and ranolazine (see section 4.3). Clarithromycin should be used with caution in patients treated with other drugs known to be substrates of the CYP3A enzyme, especially if the CYP3A substrate has a narrow margin of safety (eg, carbamazepine) and/or the substrate is widely metabolized by this enzyme.

Dose adjustments may be considered and, where possible, serum concentrations of drugs primarily metabolized by CYP3A should be closely monitored in patients receiving concomitant clarithromycin.

The following drugs or drug classes are known or suspected to be metabolized by the same CYP3A isoenzyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, ergot alkaloids, ibrutinib lovastatin, methylprednisolone, varelazolone, anti. , rivaroxaban, apixaban, see section 4.4), atypical antipsychotics (eg quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, tacrolimus, terfenadine, triazolam and vinblastine, but this list is not exhaustive. Drugs that interact by similar mechanisms through other isoenzymes in the cytochrome P450 system include phenytoin, theophylline, and valproate.

Direct acting oral anticoagulants (DOACs)

DOAC dabigatran is a substrate for the P-gp efflux transporter. Rivaroxaban and apixaban are metabolized by CYP3A4 and are also substrates for P-gp. Caution should be exercised when clarithromycin is co-administered with these agents, especially in patients at high risk of bleeding (see section 4.4).

antiarrhythmics

There have been postmarketing reports of torsades de pointes with the concomitant use of clarithromycin and quinidine or disopyramide. ECGs should be monitored for QT prolongation when clarithromycin is co-administered with these drugs. During treatment with clarithromycin, serum levels of quinidine and disopyramide should be monitored.

There have been postmarketing reports of hypoglycemia with concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.

Oral Hypoglycemic Agents/Insulin

With some hypoglycaemic drugs such as nateglinide and repaglinide, CYP3A enzyme inhibition by clarithromycin may be involved and cause hypoglycaemia when used concomitantly. Careful glucose monitoring is recommended.

omeprazole

Clarithromycin (500 mg every 8 hours) has been administered in combination with omeprazole (40 mg daily) in healthy adult subjects. Steady-state plasma concentrations of omeprazole were increased (Cmax_Maximum, AUC_0-24, y T_1/2increased by 30%, 89%, and 34%, respectively) with concomitant administration of clarithromycin. The mean 24-hour gastric pH was 5.2 when omeprazole was administered alone and 5.7 when omeprazole was co-administered with clarithromycin.

Sildenafil, Tadalafil and Vardenafil

Each of these phosphodiesterase inhibitors is metabolized, at least in part, by CYP3A, and CYP3A can be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil is likely to result in increased exposure to phosphodiesterase inhibitors. Dose reduction of sildenafil, tadalafil, and vardenafil should be considered when these drugs are co-administered with clarithromycin.

Theophylline, carbamazepine

Results from clinical studies indicate that there was a modest but statistically significant (p≤0.05) increase in circulating levels of theophylline or carbamazepine when either drug was co-administered with clarithromycin. A dose reduction may need to be considered.

Tolterodina

The main metabolic pathway of tolterodine is via the cytochrome P450 isoform 2D6 (CYP2D6). However, in a subset of the population that lacks CYP2D6, the recognized metabolic pathway is through CYP3A. In this subset of the population, CYP3A inhibition results in significantly higher tolterodine serum concentrations. A dose reduction of tolterodine may be necessary in the presence of CYP3A inhibitors such as clarithromycin in the poor CYP2D6 metaboliser population.

Triazolobenzodiazepinas (p. ej., alprazolam, midazolam, triazolam)

When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), the AUC of midazolam increased 2.7-fold after intravenous administration of midazolam and 7-fold after oral administration. Concomitant administration of oral midazolam and clarithromycin should be avoided. If intravenous midazolam is co-administered with clarithromycin, the patient should be closely monitored to allow for dose adjustment. Oromucosal administration of the active substance midazolam, which could prevent presystemic clearance of the active substance, is likely to produce an interaction similar to that observed after intravenous administration of midazolam instead of oral administration. The same precautions should be applied to other benzodiazepines metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines that do not depend on CYP3A for clearance (temazepam, nitrazepam, lorazepam), a clinically significant interaction with clarithromycin is unlikely.

There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (eg, drowsiness and confusion) with the concomitant use of clarithromycin and triazolam. It is recommended to monitor the patient to detect an increase in pharmacological effects in the CNS.

Other drug interactions

colchicine

Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may result in increased colchicine exposure. (see paragraphs 4.3 and 4.4).

digoxin

Digoxin is believed to be a substrate of the efflux transporter, P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are administered together, inhibition of Pgp by clarithromycin may result in increased digoxin exposure. Increases in serum digoxin concentrations have also been reported during post-marketing surveillance in patients receiving concomitant clarithromycin and digoxin. Some patients have developed clinical signs consistent with digoxin toxicity, including life-threatening arrhythmias. Serum digoxin concentrations should be carefully monitored while patients are receiving concomitant digoxin and clarithromycin.

zidovudine

Concomitant oral administration of clarithromycin tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state concentrations of zidovudine. As clarithromycin appears to interfere with the absorption of concomitant oral administration of zidovudine, this interaction can be largely avoided by staggering doses of clarithromycin and zidovudine so that there is a 4-hour interval between each drug. This interaction does not appear to occur in HIV-infected pediatric patients receiving clarithromycin suspension with zidovudine or dideoxyinosine. This interaction is unlikely when clarithromycin is administered by intravenous infusion.

phenytoin and valproate

There have been spontaneous or published reports of interactions of CYP3A inhibitors, including clarithromycin, with drugs not thought to be metabolized by CYP3A (eg, phenytoin and valproate). Determinations of serum levels of these drugs are recommended when co-administered with clarithromycin. Elevated serum levels have been reported

Bidirectional drug interactions

Atazanavir

Both clarithromycin and atazanavir are CYP3A substrates and inhibitors, and there is evidence of a two-way drug interaction. Co-administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily) resulted in a 2-fold increase in clarithromycin exposure and a 70% decrease in 14-OH-clarithromycin exposure, with a 28% increase in your dose. AUC. atazanavir. Due to the wide therapeutic index of clarithromycin, a dose reduction should not be necessary in patients with normal renal function. For patients with moderate renal function (creatinine clearance 30 to 60 mL/min), the clarithromycin dose should be reduced by 50%. For patients with creatinine clearance <30 mL/min, the clarithromycin dose should be reduced by 75% using an appropriate clarithromycin formulation. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.

Calcium channel blockers

Caution is advised when co-administering clarithromycin and calcium channel blockers metabolized by CYP3A4 (eg, verapamil, amlodipine, diltiazem) due to the risk of hypotension. Plasma concentrations of clarithromycin, as well as calcium channel blockers, may be increased due to the interaction. Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving clarithromycin and verapamil concomitantly.

itraconazole

Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, leading to a two-way drug interaction. Clarithromycin may increase itraconazole plasma levels, while itraconazole may increase clarithromycin plasma levels. Patients receiving itraconazole and clarithromycin concomitantly should be closely monitored for signs or symptoms of increased or prolonged drug action.

saquinavir

Both clarithromycin and saquinavir are CYP3A substrates and inhibitors, and there is evidence of a two-way drug interaction. Co-administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily) to 12 healthy volunteers resulted in steady-state AUC and Cmax._Maximumsaquinavir values ​​that were 177% and 187% higher than those seen with saquinavir alone. AUC and C of clarithromycin_MaximumValues ​​were approximately 40% higher than those seen with clarithromycin alone. No dose adjustment is required when the two drugs are co-administered for a limited period of time at the doses/formulations studied. Observations from drug interaction studies using the soft gelatin capsule formulation may not be representative of the effects observed with saquinavir hard gelatin capsule. Observations from drug interaction studies performed with saquinavir alone may not be representative of the effects seen with saquinavir/ritonavir therapy. When saquinavir is co-administered with ritonavir, the potential effects of ritonavir on clarithromycin should be considered.

The pregnancy

The safety of clarithromycin for use during pregnancy has not been established. Based on various results obtained in animal studies and human experience, the possibility of adverse effects on fetal development cannot be excluded. Some observational studies evaluating clarithromycin exposure during the first and second trimesters reported an increased risk of miscarriage compared with no antibiotics or other antibiotics during the same period. Available epidemiological studies on the risk of major birth defects with the use of macrolides, including clarithromycin, during pregnancy show conflicting results. Therefore, its use during pregnancy is not recommended without careful evaluation of the benefits and risks.

Breast-feeding

The safety of clarithromycin for use during lactation in infants has not been established. Clarithromycin is excreted in small amounts in breast milk. It has been estimated that an exclusively breastfed infant would receive approximately 1.7% of the mother's weight-adjusted dose of clarithromycin.

Fertility

There are no data available on the effect of clarithromycin on human fertility. In rats, fertility studies have shown no evidence of harmful effects.

one. Security Profile Summary

The most common and common adverse reactions associated with clarithromycin treatment in adult and pediatric populations are abdominal pain, diarrhea, nausea, vomiting, and taste distortion. These adverse reactions are generally mild in intensity and are consistent with the known safety profile of macrolide antibiotics (see section b in section 4.8).

There were no significant differences in the incidence of these gastrointestinal adverse events during clinical trials between the patient population with and without pre-existing mycobacterial infections.

Yes. Tabulated summary of adverse reactions.

The following table displays the adverse reactions reported in clinical trials and in post-marketing experience with clarithromycin immediate-release tablets.

Reactions considered at least possibly related to clarithromycin are listed by system organ class and frequency using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon ( ≥1/1000 to <1/100) and unknown (adverse effects from post-marketing experience cannot be estimated from the available data). Within each frequency category, adverse reactions are presented in order of decreasing seriousness where severity can be estimated.

infections and infestations

Uncommon: cellulitis^1,candidiasis, gastroenteritis², Pollution³, vaginal infection

Not known frequency: pseudomembranous colitis, erysipelas

Disorders of the blood and lymphatic system.

Uncommon: leukopenia, neutropenia⁴, eosinophilia⁴

Not known frequency: agranulocytosis, thrombocytopenia

Immune system disorders*

Uncommon: anaphylactic reaction¹, hypersensitivity

Not known frequency: anaphylactic reaction, angioedema.

Metabolism and nutrition disorders.

Uncommon: anorexia, decreased appetite.

psychiatric disorders

common: insomnia

Uncommon: anxiety, nervousness.³

Not known frequency: psychotic disorder, confusional state.⁵, depersonalization, depression, disorientation, hallucinations, abnormal dreams, mania

Nervous system disorders

Common: dysgeusia, headache, taste perversion.

Uncommon: loss of consciousness.¹, dyskinesia¹, dizziness, drowsiness⁵, terror

Not known frequency*: seizures, bad taste, parosmia, anosmia, paresthesia.

eye disorders

Not known frequency: visual impairment, blurred vision.

Ear and labyrinth disorders

Uncommon: vertigo, hearing loss, tinnitus.

Unknown*: deafness

heart disorders

Uncommon: cardiac arrest¹, atrial fibrillation¹, electrocardiogram QT prolonged

Desconocido: Torsade de Pointes^*, ventricular tachycardia^*, ventricular fibrillation

vascular disorders

Common: vasodilation¹

Unknown*: Bleeding^#

Respiratory, thoracic and mediastinal disorders.

Uncommon: asthma¹, epistaxis², pulmonary embolism¹

Gastrointestinal disorders

Common: diarrhoea*, vomiting, abdominal pain, nausea, indigestion,

Unusual: esophagitis¹, gastroesophageal reflux², gastritis, stomatitis, glossitis, abdominal distension⁴, bloating, constipation, dry mouth, flushing, flatulence,

Frequency not known*: pancreatitis, discolouration of the tongue, discolouration of the teeth.

Hepatic and biliary disorders.

Common: abnormal liver function test

Uncommon: cholestasis⁴, hepatitis⁴, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased⁴

Not known: hepatic failure*, hepatocellular jaundice

Disorders of the skin and subcutaneous tissues.

Common: rash, hyperhidrosis

Uncommon: bullous dermatitis^1,pruritus, hives, maculopapular rash³

Frequency not known: Stevens-Johnson syndrome*, toxic epidermal necrolysis*, drug eruption with eosinophilia and systemic symptoms (DRESS), acne, serious skin adverse reactions (SCARs) (eg, acute generalized exanthematous pusculitis (AGEP))

Musculoskeletal and connective tissue disorders and disorders.

Uncommon: muscle spasms³, musculoskeletal stiffness¹, myalgia²

Not known frequency*: rhabdomyolysis^2,6, myopathy

Disorders of the renal and urinary system.

Uncommon: increased blood creatinine.¹, increased blood urea¹

Not known frequency: renal failure, interstitial nephritis

General disorders and administration site conditions.

Very common: phlebitis at the injection site.¹

Common: pain at the injection site.¹, inflammation at the injection site¹

Uncommon: malaise⁴, Pirexia³, weakness, chest pain⁴, shaking chills⁴, fatigue⁴

Research

Uncommon: abnormal globulin to albumin ratio^1,increased blood alkaline phosphatase⁴blood lactate dehydrogenase increased⁴

Unknown: International Normalized Ratio increased^#, prolonged prothrombin time^#, abnormal urine color

¹Adverse reactions were reported for the powder for solution for injection formulation only.

²Adverse reactions have only been reported for the extended-release tablet formulation.

³Adverse reactions were reported only for the granules in the oral suspension formulation.

⁴ADRs reported for immediate-release tablet formulation only

^5,6see Description of selected adverse reactions

* As these reactions are reported voluntarily in a population of uncertain size, it is not always possible to reliably estimate their frequency or demonstrate a causal relationship with drug exposure. Patient exposure is estimated to exceed 1 billion patient-days of clarithromycin treatment..

do. Description of selected adverse reactions.

Injection site phlebitis, injection site pain, vascular puncture site pain, and injection site inflammation are specific to the intravenous formulation of clarithromycin.

In some of the reports of rhabdomyolysis, clarithromycin was co-administered with statins, fibrates, colchicine, or allopurinol (see sections 4.3 and 4.4).

There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (eg, drowsiness and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring of patients for increased CNS drug effects is recommended (see section 4.5).

There have been rare reports of clarithromycin ER tablets in the feces, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with reduced GI transit times. In several reports, tablet residues occurred in the context of diarrhoea. It is recommended that patients who develop tablet residues in the stool and do not improve their condition switch to a different formulation of clarithromycin (eg suspension) or another antibiotic.

Special population:

Adverse reactions in immunocompromised patients (see section e)

Hey. pediatric populations

Clinical trials with pediatric clarithromycin suspension have been conducted in children 6 months to 12 years of age. Therefore, children less than 12 years of age should use pediatric clarithromycin suspension. There are insufficient data to recommend a dosing regimen for the use of the intravenous formulation of clarithromycin in patients less than 18 years of age.

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

metro. Other special populations

Immunocompromised patients

In AIDS patients and other immunocompromised patients treated with higher doses of clarithromycin for longer periods for mycobacterial infections, it was often difficult to distinguish adverse effects possibly related to clarithromycin administration from underlying signs of AIDS virus disease. human immunodeficiency (HIV) or a transient illness.

In adult patients, the most frequently reported adverse reactions in patients receiving clarithromycin 1000 mg and 2000 mg total daily doses were: nausea, vomiting, taste disturbances, abdominal pain, diarrhoea, rash, flatulence, headache, constipation, hearing disorders, increased serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT). Other low frequency events included dyspnea, insomnia, and dry mouth. The incidences were comparable for patients treated with 1000 mg and 2000 mg, but overall were approximately 3 to 4 times more frequent for those patients receiving clarithromycin 4000 mg total daily doses.

In these immunocompromised patients, assessments of laboratory values ​​were performed by testing for those values ​​outside of the severely abnormal range (ie, borderline extremely high or low) for the specified test. Based on these criteria, approximately 2% to 3% of patients receiving clarithromycin 1000 mg or 2000 mg daily had grossly abnormally elevated SGOT and SPT levels and abnormally low white blood cell and platelet counts. A smaller proportion of patients in these two dose groups also had elevated blood urea nitrogen levels. Slightly higher incidences of abnormal values ​​were observed in patients receiving 4000 mg daily for all parameters except white blood cells.

Notification of suspected side effects.

It is important to report suspected adverse reactions after approval. It allows continuous monitoring of the benefit/risk ratio of the drug. Healthcare professionals are requested to report any suspected side effects via the yellow card scheme (www.mhra.gov.uk/amarillocard) or search for the MHRA yellow card on Google Play or the Apple App Store.

Reports indicate that ingestion of large amounts of clarithromycin is expected to cause gastrointestinal symptoms. A patient with a history of bipolar disorder received eight grams of clarithromycin and developed altered mental status, paranoid behavior, hypokalemia, and hypoxemia.

Adverse effects accompanying overdose should be treated with immediate removal of unabsorbed drug and supportive measures.

As with other macrolides, clarithromycin serum levels are not expected to be significantly affected by hemodialysis or peritoneal dialysis.

Pharmacotherapeutic group:

ATC Code J01FA09.

Clarithromycin is a semisynthetic derivative of erythromycin A.

Mechanism of action:

Clarithromycin exerts its antibacterial action by binding to the ribosomal subunit 50 of susceptible bacteria and suppressing protein synthesis. It is extremely potent against a wide variety of Gram-positive and Gram-negative aerobic and anaerobic organisms. The minimum inhibitory concentrations (MICs) of clarithromycin are generally two times lower than the MICs of erythromycin.

The 14-hydroxy metabolite of clarithromycin also has antimicrobial activity. The MICs of this metabolite are equal to or twice as high as those of the parent compound, except in the case of H. influenzae, where the 14-hydroxy metabolite is twice as active as the parent compound.

breakpoints

* National Committee for Clinical Laboratory Standards, 2001

** British Society for Antimicrobial Chemotherapy

sensitivity

The prevalence of resistance can vary geographically and over time for selected species, and local information on resistance is desirable, particularly in the treatment of severe infections. This information only provides adequate guidance as to whether or not organisms are susceptible to clarithromycin. Whenever possible, information on the European range of acquired resistance for each individual organism is provided in parentheses.

MRSA - resistant to methicillinstaphylococcal disease

¹⁾Hardiness Area Frequencies Calculated at NCCLS Breakpoints

other information

Its sensitivity and durability.steotococos neumoniamiStreptococcusspecies Clarithromycin concentration can be predicted by the erythromycin test.

The mechanisms of acquired resistance to macrolides are: efflux of drugs from an active pump mechanism, induced or constitutive production of a methylase enzyme that modifies the ribosomal target, hydrolysis of macrolides by esterases, chromosomal mutations that alter a ribosomal protein 50 S. Therefore, cross -reactivity between clarithromycin and other macrolides and clindamycin and lincomycin may occur. Methicillin- and oxacillin-resistant staphylococci (MRSA) and penicillin-resistant Streptococcus pneumoniae are resistant to all currently available beta-lactam and macrolide antibiotics, including clarithromycin.

The most available clinical experience from randomized controlled clinical trials shows that clarithromycin 500 mg twice daily in combination with another antibiotic, e.g. amoxicillin or metronidazole, e.g. Omeprazole (administered at approved levels) for 7 days achieves an eradication rate >80% of Helicobacter pylori in patients with gastroduodenal ulcer. As expected, significantly lower eradication rates were observed in patients with metronidazole-resistant H. pylori isolates at baseline. Therefore, local information on the prevalence of resistance and local treatment regimens should be taken into account when choosing an appropriate combination regimen for H. pylori eradication therapy. In addition, in patients with persistent infection, the possible development of secondary resistance (in patients with primarily susceptible strains) to an antimicrobial agent should be considered for a new treatment regimen.

Absorption:

Clarithromycin is rapidly and well absorbed from the gastrointestinal tract (mainly the jejunum) after oral administration. Due to its chemical structure (6-O-methylerythromycin), clarithromycin is quite resistant to breakdown by stomach acid. Serum levels of 1 to 2 µg/mL of clarithromycin have been observed in adults after oral administration of 250 mg twice daily. After administration of clarithromycin 500 mg twice daily, serum levels of 2.8 µg/ml were obtained.

After administration of clarithromycin 250 mg twice daily, the pharmacologically active 14-hydroxy metabolite reaches maximum plasma concentrations of 0.6 µg/ml.

Distribution:

Clarithromycin provides good penetration into different compartments. Therapeutic levels of drugs that exceed minimal inhibitory levels for common pathogens can be rapidly achieved. Clarithromycin provides tissue concentrations several times higher than circulating drug levels. Elevated levels were found in both tonsil tissue and lung tissue. Clarithromycin also penetrates the gastric mucosa.

Clarithromycin is 80% bound to plasma proteins at therapeutic levels.

Serum mean life:

The serum half-life of the active 14-(R)-hydroxy metabolite is between 5 and 6 hours.

Biotransformation and elimination:

Clarithromycin is rapidly and extensively metabolized in the liver. Metabolism mainly involves N-dealkylation, oxidation, and stereospecific hydroxylation at the C14 position.

After oral administration of radioactive clarithromycin, 70-80% of the radioactivity was found in the feces. Approximately 20-30% of clarithromycin is recovered as the unchanged parent molecule in the urine. This ratio increases as the dose increases. Renal failure increases plasma levels of clarithromycin if the dose is not reduced.

The pharmacokinetics of clarithromycin is not linear. This is an indication of saturation of hepatic metabolism at high doses. However, steady state is reached 2 days after administration.

In acute studies in mice and rats, the median lethal dose was greater than the highest possible dose for administration (5 g/kg).

In repeat-dose studies, toxicity was related to dose, duration of treatment, and species. Dogs were more sensitive than primates or rats. The main clinical signs at toxic doses included vomiting, weakness, reduced food intake and weight gain, drooling, dehydration and hyperactivity. In all species, the liver was the main target organ for toxic doses. Hepatotoxicity was detectable by early elevations in liver function tests. Discontinuation of the drug has generally resulted in a return or direction of normal results. Other less frequently affected tissues include the stomach, thymus and other lymphoid tissues, and the kidneys. At near-therapeutic doses, conjunctival injection and tearing occurred only in dogs. At a massive dose of 400 mg/kg/day, some dogs and monkeys developed opacification and/or corneal edema.

Fertility and reproduction studies in rats did not show adverse effects. Teratogenicity studies in rats (Wistar (p.o.) and Spraque-Dawley (p.o. and iv)), New Zealand white rabbits, and cynomolgus monkeys failed to demonstrate any teratogenicity of clarithromycin. However, another similar study in Sprague-Dawley populations showed a low incidence (6%) of cardiovascular abnormalities that appeared to be due to the spontaneous expression of genetic alterations. Two studies in rats revealed a variable incidence (3-30%) of cleft palate and fetal loss in monkeys, but only at doses clearly maternally toxic.

Basic: Croscarmellose sodium, microcrystalline cellulose, povidone, magnesium stearate, silicon colloidal anhydrous, talc.

Movie: Hypromellose, Propylene glycol, Titanium dioxide (E 171), Hydroxypropyl cellulose, Sorbitan monooleate, Quinoline yellow (E 104), Vanillin.

PVC/PVDC aluminum cell

Pack sizes:

Clarithromycin 250 mg film-coated tablets: 8, 10, 12, 14, 15, 16, 20, 21, 24, 49, 50, 100, 100x1.

Not all packages can be published.

No special requirement.

Any unused medication or waste must be disposed of in accordance with relevant local regulations.

Sandoz Limited

Park View, Riverside Way

park watcher

Camberley, Surrey

GU15 3YL

United Kingdom

First approval date: 23^thirdDecember 2004

Date of last renewal: 22^miDecember 2009