Clarithromycin 250 mg/5 ml suspension - Summary of Product Characteristics (SmPC) (2023)

After reconstitution, 1 ml of oral suspension contains 50 mg clarithromycin,

5 ml of oral suspension contains 250 mg clarithromycin.

Excipient with known action:

Each 5 ml of ready-to-use suspension contains 2.4 g of sucrose.

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

Granules for oral suspension.

White to beige granules.

Clarithromycin Suspension 250 mg/5 ml is indicated in adults, adolescents and children, 6 months to 12 years of age, for the treatment of the following acute and chronic infections when caused by organisms sensitive to clarithromycin.

• Upper respiratory tract infections such as tonsillitis/pharyngitis as an alternative when beta-lactam antibiotics are not suitable.

• Acute otitis media at children.

• Lower respiratory tract infections, such as community-acquired pneumonia.

• Sinusitis and acute exacerbation of chronic bronchitis in adults and adolescents over 12 years of age.

• Mild to moderate skin and soft tissue infections.

In appropriate combination with antibacterial regimens and a suitable ulcer-healing drug for the eradication ofHelicobacter pyloriin adult patients withHelicobacter pyloriassociated ulcers. See section 4.2.

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

The dosage of Clarithromycin 250 mg/5 ml suspension depends on the clinical status of the patient and must be determined in each case by the doctor.

Adults and adolescents:

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

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

Elimination of Helicobacter pylori in adults:

In patients with gastroduodenal ulcer due toHelicobacter pyloriClarithromycin, as part of first-line triple therapy, is given in a dose of 500 mg twice daily. The national recommendations forHelicobacter pyloriEradication should be considered.

Dosage in patients with renal insufficiency:

The maximum recommended doses should be reduced according to renal insufficiency.

With creatinine clearance less than 30 mL/min, the dose should be halved to 250 mg daily or, in more severe infections, 250 mg twice daily. The duration of treatment should not exceed 14 days in these patients.

Children from 6 months to 12 years:

The recommended dose is 7.5 mg/kg twice daily.

Children weighing less than 8 kg should be treated according to their body weight.

Clinical trials with pediatric clarithromycin suspension have been conducted 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). Experience in the treatment of children less than 6 months of age is limited.

The effect of community-acquired pneumonia in children under 3 years of age is not documented for this indication.

In patients with renal insufficiency with a creatinine clearance less than 30 ml/min, the dose of clarithromycin should be halved, i.e. 7.5 mg/kg once daily, and the duration of treatment should not exceed 14 days.

Treatment duration:

The duration of treatment with Clarithromycin Suspension 250 mg/5 ml 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 for children up to 12 years of age is 5 to 10 days.

• The usual duration of treatment for adults and adolescents is 6 to 14 days.

• Treatment should be continued for at least 2 days after the symptoms have disappeared.

• In infections caused by Streptococcus pyogenes (such as beta-hemolytic streptococcus) the duration of treatment should be at least 10 days.

• Combination therapy to eradicate Helicobacter pylori infection, p. eg Clarithromycin 500 mg twice daily should be continued in combination with amoxicillin 1000 mg twice daily and omeprazole 20 mg twice daily for 7 days.

Administration method:

Before administration, the granules must be reconstituted with water, see section 6.6.

For administration after reconstitution an oral dosing syringe made of PE/PP or a dosing spoon made of PP is used.

The oral suspension granules may cause a bitter taste when left in the mouth. This can be avoided by eating or drinking something immediately after taking the suspension.

Clarithromycin can be administered regardless of food intake. Food does not affect the degree of bioavailability. Food only slightly delays the onset of clarithromycin absorption.

Hypersensitivity to the active substance or to any of the excipients mentioned 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 prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and Torsade.4. .

Co-administration with ticagrelor or ranolazine is contraindicated.

Concomitant administration of clarithromycin and ergot alkaloids (eg ergotamine or dihydroergotamine) is contraindicated as it may cause ergot osteotoxicity (see section 4.5).

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 metabolised by CYP3A4 (lovastatin or simvastatin), due to an increased risk of myopathy, including rhabdomyolysis (see sections 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 metabolized in the liver. Therefore, caution should be exercised when administering clarithromycin 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.

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 regarding concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam, and intravenous or buccal (buccal) midazolam (see section 4.5).

Caution is advised regarding the concomitant administration of clarithromycin with other ototoxic drugs, particularly aminoglycosides. Auditory and vestibular function should be monitored during and after treatment.

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.

Patients who are hypersensitive to lincomycin or clindamycin may also be hypersensitive to clarithromycin. Therefore, caution is required when prescribing clarithromycin to these patients.

When renal function is poor, the dose of clarithromycin should be reduced accordingly depending on the degree of impairment (see section 4.2). In elderly patients, the possibility of renal failure should be considered. Caution is advised in case of severe renal insufficiency.

Clarithromycin is a CYP3A4 inhibitor and concomitant use with other drugs extensively metabolized by this enzyme should be limited to clearly indicated situations (see section 4.5).

An exacerbation or worsening of myasthenia gravis may occur.

Clarithromycin Suspension 250 mg/5 ml contains sucrose and sodium.

This medicinal product contains 2.4 g of sucrose per 5 ml of ready-to-use suspension. This should be considered in patients with diabetes mellitus. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency should not take this medicine.

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:

Astemizol, cisaprida, domperidona, pimozida y terfenadina

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).

Midazolam oral

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. Concomitant administration of oral midazolam and clarithromycin is contraindicated (see section 4.3).

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 interval prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and 4.4 points and torsees. 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).

Caution is advised if clarithromycin is co-administered with other drugs known to be substrates of the CYP3A enzyme, especially if the CYP3A substrate has a narrow safety margin (eg, carbamazepine) and/or the substrate is extensively metabolized by it. 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. Drugs or classes of drugs known or suspected to be metabolized by the same CYP3A isoenzyme include (but this list is not exhaustive) alprazolam, carbamazepine, cilostazol, cyclosporine, disopyramide, ibrotinib, methylprednisolone, midazolam (intravenous or omeprazole ), p. warfarin, rivaroxaban, apixaban), atypical antipsychotics (eg, quetiapine), quinidine, rifabutin, sildenafil, sirolimus, tacrolimus, triazolam, and vinblastine. Drugs that interact by similar mechanisms through other isoenzymes in the cytochrome P450 system include phenytoin, theophylline, and valproate.

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.

Cyclosporine, tacrolimus and sirolimus

Concomitant use of oral clarithromycin and cyclosporine or tacrolimus resulted in a more than 2-fold increase in Cmax._min.-ciclosporin and tacrolimus levels. Similar effects are expected for sirolimus. When initiating clarithromycin treatment in patients already receiving any of these immunosuppressive agents, plasma levels of ciclosporin, tacrolimus, or sirolimus should be carefully monitored and their doses reduced as necessary. When clarithromycin is discontinued in these patients, careful monitoring of ciclosporin, tacrolimus, or sirolimus plasma levels is again required to guide dose adjustment.

Oral anticoagulants (eg, warfarin, rivaroxaban, apixaban)

The use of clarithromycin in patients receiving warfarin may potentiate the effects of warfarin.

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).

Prothrombin time should be monitored frequently in these patients (see sections 4.4 and 4.8).

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 of these drugs 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

aminoglycosides

Caution is advised regarding the concomitant administration of clarithromycin with other ototoxic drugs, particularly aminoglycosides. see 4.4

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 sections 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.

Other ototoxic drugs, especially aminoglycosides.

In case of simultaneous administration of clarithromycin with other ototoxic drugs, especially aminoglycosides, monitoring of vestibular and auditory function should be performed during and after treatment (see section 4.4).

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.

verapamil

Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving clarithromycin and verapamil concomitantly.

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

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. Therefore, diarrhea and fungal infections of the mucous membranes may occur in the infant, for which breastfeeding should be discontinued. The potential for sensitization should be considered. The benefit of treatment to the mother must be weighed against the potential risk to the baby.

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.

There are no data on the effect of clarithromycin on the ability to drive and use machines. Before patients drive or operate machinery, the possibility of dizziness, vertigo, confusion, and disorientation, which can occur with medication, should be considered.

Vision and blurred vision may affect the patient's ability to drive or use machines (see section 4.8).

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 section lists the adverse reactions reported in clinical trials and post-marketing experience with all formulations of clarithromycin (granules for oral suspension, film-coated tablets, and prolonged-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: cellulitis¹, candidiasis, gastroenteritis², Pollution³, vaginal infection

Not known frequency*: pseudomembranous colitis, erysipelas

Disorders of the blood and lymphatic system.

Uncommon: leukopenia, neutropenia⁴trombocitemia³, 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

Frequency not known*: psychotic disorder, confusional state⁵, depersonalization, depression, disorientation, hallucinations, abnormal dreams, mania

Nervous system disorders

Common: dysgeusia, headache.

Uncommon: unconsciousness1, dyskinesia1, dizziness, somnolence5, tremor

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 problems, tinnitus.

Unknown*: Deafness

heart disorders

Uncommon: cardiac arrest¹, atrial fibrillation¹, electrocardiogram QT prolonged, extrasystoles¹, palpitations

Frequency not known*: Torsades 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, indigestion, nausea, abdominal pain.

Uncommon: esophagitis¹, gastroesophageal reflux², gastritis, stomatitis, glossitis, abdominal distension⁴, constipation, dry mouth, flushing, flatulence, proctalgia

Not Known Frequency*: Pancreatitis, reversible discoloration of teeth and tongue.

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 dermatitis¹, pruritus, urticaria, maculopapular rash

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

Musculoskeletal and connective tissue 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 ratio¹, blood alkaline phosphatase increased⁴blood lactate dehydrogenase increased⁴.

Unknown*: The 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 prolonged-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 be greater than 1 billion patient-days of clarithromycin treatment.

do. Description of selected adverse reactions.

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).

Special population: adverse reactions in immunocompromised patients (see section e)

Hey. pediatric population

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.

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 distortion, abdominal pain, diarrhoea, rash, flatulence, headache, constipation, hearing disorders, increased glutamic oxaloacetate transaminase (SGOT) and serum glutamic 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 common 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 have 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 through the Yellow Card Scheme (www.mhra.gov.uk/yellow).

Symptoms of poisoning:

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.

Poisoning treatment:

There is no specific antidote for overdose. As with other macrolides, clarithromycin serum levels are not expected to be significantly affected by hemodialysis or peritoneal dialysis.

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

pharmacotherapeutic group: Macrolides, ATC Code J01FA09.

Mechanism of action:

Clarithromycin exerts its antibacterial action by binding to the ribosomal subunit of susceptible 1950s 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 the MICs of the parent compound, exceptHaemophilus influenzaewhere the 14-hydroxy metabolite is twice as active as the parent compound.

PK/PD ratio

For clarithromycin, AUC/MIC is the major PK/PD parameter that best correlates with clarithromycin efficacy.

Resistance mechanism:

The mechanisms of acquired resistance to macrolides are: release of active substance from an active pump mechanism, induced or constitutive production of the enzyme methylase that modifies the ribosomal target, hydrolysis of macrolides by esterases, chromosomal mutations that alter a ribosomal protein 50.

Therefore, cross-resistance between clarithromycin and other macrolides and clindamycin and lincomycin may occur. Methicillin-Oxacillin-Resistant Staphylococci (MRSA) and Penicillin-Resistant Staphylococcisteotococos neumoniathey are resistant to all currently available beta-lactam and macrolide antibiotics, such as clarithromycin.

breakpoints

EUCAST (European Committee for Antimicrobial Susceptibility Testing)

sensitivity

The prevalence of acquired resistance can vary geographically and over time for selected species, and local information on resistance is desirable, particularly in the treatment of severe infections. If necessary, specialist advice should be sought when the local prevalence of resistance is such that the usefulness of the agent in at least some types of infection is questionable.

Pathogens for which resistance may be a problem: the prevalence of resistance is 10% or more in at least one EU country

^°No updated data was available at the time the tables were published. Primary literature, standard scientific literature, and treatment recommendations assume sensitivity.

^psThe intrinsic susceptibility of most isolates shows intermediate resistance.

⁺At least in the region, it has resistance rates above 50%.

¹Resistance rates are, in some studies, ≥10%.

²The resistance rate is ≥10% of previously treated patients.

other information

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 and e.g. omeprazole (administered at approved levels) for 7 days reaches > 80%Helicobacter pyloriEradication rate in patients with gastroduodenal ulcer. As expected, significantly lower eradication rates were observed in patients with initial resistance to metronidazole.Helicobacter pyloriisolated. Therefore, local information on the prevalence of resistance and local treatment regimens should be taken into account when choosing an appropriate combination regimen forHelicobacter pylorieradication therapy. In addition, in patients with persistent infection, the possible development of secondary resistance (in patients with primarily susceptible strains) to an antimicrobial drug should be considered for a new retreatment regimen.

Absorption:

Clarithromycin is rapidly and well absorbed from the gastrointestinal tract, primarily from the jejunum, but undergoes extensive first-pass metabolism after oral administration. The absolute bioavailability of a 250 mg clarithromycin tablet is approximately 50%. The bioavailability of the suspension is equal to or slightly higher than the bioavailability of the tablets. The pharmacokinetic profile of the suspension in children corresponds to the pharmacokinetic profile of the suspension in adults. Food slightly delays absorption but does not affect the degree of bioavailability. Therefore, clarithromycin can be administered without regard to food. Due to its chemical structure (6-O-methylerythromycin), clarithromycin is quite resistant to breakdown by stomach acid. Peak plasma 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, the maximum plasma level was 2.8 µg/ml. The following steady-state parameters were observed in children after the ninth dose at a 7.5 mg/kg twice daily regimen: Average for clarithromycin: C_Maximum4,60 µg/ml, AUC 15,7 µg.hr/ml y T_Maximum2.8 hours. The corresponding mean values ​​for the 14-OH metabolite were respectively: 1.64 µg/ml, 6.69 µg.hr/ml and 2.7 hours.

After administration of clarithromycin 250 mg twice daily, the microbiologically active 14-hydroxy metabolite reaches maximum plasma concentrations of 0.6 µg/ml. Steady state is reached 2 days after administration.

Distribution:

Clarithromycin penetrates well into different compartments, with an estimated volume of distribution of 200 to 400 L. Clarithromycin provides concentrations in some tissues that are several times higher than its circulating level.active substance. Elevated levels were found in tonsils and lung tissue. Clarithromycin also penetrates the gastric mucosa.

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

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.

The pharmacokinetics of clarithromycin is not linear due to saturation of hepatic metabolism at high doses. The elimination half-life increased from 2 to 4 hours after clarithromycin 250 mg twice daily to 5 hours after clarithromycin 500 mg twice daily. At a dose of 250 mg every 12 hours, the half-life of the active 14-hydroxy metabolite is between 5 and 6 hours.

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

Total plasma clearance was estimated to be approximately 700 mL/min, with renal clearance of approximately 170 mL/min.

special populations

Renal Insufficiency: Renal insufficiency results in increased plasma levels of clarithromycin and increased plasma levels of the active metabolite.

In 4-week animal studies, clarithromycin toxicity was found to be related to dose and duration. In all species, the first signs of toxicity were seen in the liver, where lesions were seen at 14 days in dogs and monkeys. The systemic exposure levels associated with this toxicity are not fully known, but the toxic doses (300 mg/kg/day) were clearly higher than the recommended therapeutic doses in humans. Other affected tissues included the stomach, thymus and other lymphoid tissues, as well as 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 opacities and/or corneal edema. Juvenile animals showed similar toxicity profiles to adult animals, although increased nephrotoxicity has been reported in neonatal rats.

in vitromiliveStudies have shown that clarithromycin has no genotoxic potential.

Reproductive toxicity studies have shown that administration of clarithromycin at twice the clinical dose in the rabbit (iv) and x10 the clinical dose in the monkey (po) resulted in an increased incidence of spontaneous abortion. These doses have been associated with maternal toxicity. In general, embryotoxicity and teratogenicity were not observed in rat studies. However, cardiovascular malformations were observed in two studies in rats treated with doses of 150 mg/kg/day. In mice dosed x70, cleft palates occurred at the clinical dose with variable incidence (3-30%). Clarithromycin has been found in the milk of lactating animals.

I placed 188

Povidone K30

hypromellose

Macrogol 6000

Titanium dioxide (E 171)

Methacrylic acid - ethyl acrylate copolymer (1:1)

Citrato de trietila

Glycerin Monostearate

Polysorbate 80

saccharose

maltodextrin

potassium sorbate

colloidal anhydrous silica

Ten times

Fruit flavors (natural and artificial flavors such as maltodextrin, modified starch, sodium, and maltol)

3 years.

After recovery 14 days.

Do not store at temperatures above 25°C.

After reconstitution: Do not store above 25°C.

60 ml, 120 ml and 240 ml HDPE bottles with PP screw cap (press + twist) for children with guarantee ring, PE/PP dosing syringe (5 ml) for oral administration (5 ml) with 2.5 ml, 3.75 ml and 5.0 ml and/or a PP measuring spoon with 1.25 ml, 2.5 ml and 5.0 ml fill marks.

Pack sizes:

1 bottle contains 34.1 g of granules for oral suspension per 50 ml of ready-to-use suspension (amount of water required: 28.5 ml) or

41.0 g granules for oral suspension for 60 ml of ready-to-use suspension (required amount of water: 34.2 ml) or

47.8 g of granules for oral suspension per 70 ml of ready-to-use suspension (amount of water required: 39.9 ml) or

54.6 g of granules for oral suspension for 80 ml of ready-to-use suspension (amount of water required: 45.6 ml) or

68.3 g of granules for oral suspension per 100 ml of ready-to-use suspension (amount of water required: 57.0 ml).

Double pack of 2 x 60 ml ready-to-use suspension: 2 x 41.0 g granules for oral suspension each for 2 x 60 ml ready-to-use suspension each (amount of water required: 2 x 34.2 ml each)

1, 2, 5, 10, 20, 30, 40, 50, 100 bottles.

Not all packages can be published.

The bottle should be filled with two-thirds of the total amount of water required, then shaken well and filled with water up to the mark and shaken again. The vial must be shaken vigorously before each application.

After reconstitution with water, the drug results in a white to beige suspension.

If the dose is administered using the oral dosing syringe, the syringe adapter must be inserted into the neck of the bottle.

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

Sandoz Ltd.

Park View, Riverside Way

park watcher

Camberley-Surrey

GU15 3YL

United Kingdom

First approval date: 2^miMarch 2005

Date of last renewal: 21^Calle.January 2009