Clarithromycin 500 mg powder for vials for solution for infusion - Summary of Product Characteristics (SPC) (2023)

Each vial contains 500 mg clarithromycin.

When reconstituted, the concentration of the solution is 2 mg/ml (see section 6.6).

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

Powder for solution for infusion.

White or almost white powder.

Clarithromycin 500 mg powder for solution for infusion is indicated in adults and children from 12 years of age.

Clarithromycin 500 mg powder for solution for infusion is indicated whenever parenteral therapy is required for the treatment of infections caused by susceptible organisms under the following conditions:

- Lower respiratory tract infections, eg bronchitis and acute and chronic pneumonia (see sections 4.4 and 5.1 on susceptibility testing).

- Upper respiratory tract infections, eg sinusitis and pharyngitis.

- Skin and soft tissue infections (eg folliculitis, cellulitis, erysipelas) (see sections 4.4 and 5.1 on susceptibility testing).

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

For intravenous use only.

Intravenous therapy may be given for 2 to 5 days in very ill patients and should be switched to oral clarithromycin therapy whenever possible, as determined by the physician.

Adults

The recommended dose is 1.0 gram daily divided into two 500 mg doses, appropriately diluted as described below (see section 6.6).

Children over 12 years

As for the adults.

Children under 12 years

Clarithromycin 500 mg powder for solution for infusion is not recommended in children under 12 years of age who need to use clarithromycin pediatric suspension.

Old man

As for the adults.

kidney dysfunction

In patients with renal insufficiency with creatinine clearance less than 30 mL/min, the dose of clarithromycin should be reduced to half the normal recommended dose.

mode of administration

Clarithromycin 500 mg powder for solution for infusion should be administered into one of the larger proximal veins as an intravenous infusion over 60 minutes using a solution concentration of approximately 2 mg/mL. Clarithromycin should not be given as a bolus or intramuscular injection.

For instructions on reconstitution and dilution, see section 6.6. The reconstituted product is a clear solution.

Hypersensitivity to macrolide antibiotics or to any of the excipients included in section 6.1.

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

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

Concomitant administration of clarithromycin and any of the following drugs: astemizole, cisapride, domperidone, pimozide, and terfenadine is contraindicated, as it may cause QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and sprains.4. ).

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 pointes (see sections 4.4 and 4.5).

Co-administration with ticagrelor or ranolazine is contraindicated.

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

As with other strong CYP3A4 inhibitors, clarithromycin should not be used in patients receiving colchicine (see sections 4.4 and 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.

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).

Clarithromycin is mainly metabolized in the liver. Therefore, caution should be exercised when administering this antibiotic to patients with hepatic impairment.

Caution should also be exercised when administering clarithromycin to patients with moderate to severe renal impairment (see section 4.2).

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 difficileDiarrhea 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

QT interval prolongation, reflecting effects on cardiac repolarization that carry a risk of developing cardiac arrhythmia andtorsades of points, have been observed in patients treated with macrolides, including clarithromycin (see section 4.8). Due to the increased risk of QT prolongation and ventricular arrhythmias (incl.torsades of points), the use of clarithromycin is contraindicated: in patients receiving astemizole, cisapride, domperidone, pimozide and terfenadine. in patients with hypokalemia. and in patients with a history of QT prolongation or ventricular arrhythmia (see section 4.3).

In addition, clarithromycin should be used with caution in the following cases:

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

• Patients simultaneously receiving drugs associated with prolongation of the QT interval other than those contraindicated.

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.

Carefully consider the balance of benefits and risks before prescribing clarithromycin to any patient receiving hydroxychloroquine or chloroquine, due to the potential for increased risk of cardiovascular events and cardiovascular mortality (see section 4.5).

Pneumonia

In view of their growing 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 usually caused bystaphylococcal diseasemiStreptococcus pyogenes, which may be resistant to macrolides. Therefore, it is important to perform susceptibility testing. In cases where beta-lactam antibiotics cannot be used (eg 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. The use of a statin that does not depend 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. Close glucose monitoring is recommended (see section 4.5).

oral anticoagulants

There is a risk of major bleeding and a significant increase in international normalized ratio (INR) and prothrombin time when clarithromycin is co-administered with warfarin (see section 4.5). INR and prothrombin times should be monitored frequently while patients are receiving clarithromycin and oral anticoagulants concomitantly. 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).

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.

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 with 14 healthy volunteers, concomitant administration of clarithromycin and terfenadine produced a 2- to 3-fold increase in the serum level of the acute metabolite of terfenadine and prolongation of the QT interval with no clinically detectable effect. . It's done. Similar effects have been observed with the simultaneous administration of astemizole and other macrolides.

ergot alkaloids

Post-marketing reports indicate that co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues, including the central nervous system. Concomitant administration of clarithromycin and ergot alkaloids 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 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. The use of a statin that does not depend on CYP3A metabolism (eg, fluvastatin) may be considered. Patients should be monitored for signs and symptoms of myopathy.

lomitapide

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 administered CYP3A4 inducer). Co-administration of rifabutin and clarithromycin resulted in increased rifabutin and decreased serum clarithromycin levels, along with an increased risk of uveitis.

The following drugs 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 patients with CLCR 30 to 60 mL/min, the clarithromycin dose should be reduced by 50%. For patients with CLCR <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 incision 4.3 and trunk incision (4.3 ). .

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 43).

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 drug classes known or suspected to be metabolized by the same CYP3A isoenzyme include (but this list is not complete) alprazolam, carbamazepine, cilostazol, cyclosporine, disopyramide, ibrotinib, methadone, methylprednisolone, midazolam (intravenous ), anticoagulants (eg, 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.

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 occurring 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_0-24y 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), midazolam AUC was increased 2.7-fold after intravenous administration of midazolam. If intravenous midazolam is co-administered with clarithromycin, the patient should be closely monitored to allow for dose adjustment. Administration of the drug midazolam to the oral mucosa, which could prevent perisystemic clearance of the drug, 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

Hydroxychloroquine/chloroquine

Observational data have shown that co-administration of azithromycin with hydroxychloroquine in patients with rheumatoid arthritis is associated with increased risk of cardiovascular events and cardiovascular mortality. Due to the potential risk similar to that of other macrolides when used in combination with hydroxychloroquine or chloroquine, the balance of benefits and risks should be carefully considered before prescribing clarithromycin to any patient receiving hydroxychloroquine or chloroquine.

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.

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 (CLCR 30 to 60 mL/min), the clarithromycin dose should be reduced by 50%. For patients with CLCR <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 (see section 4.5: Ritonavir).

oral contraceptives

Patients taking oral contraceptives should be warned that if diarrhoea, vomiting or bleeding occurs, there is a possibility that the contraceptive will fail.

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 (see section 5.3).

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

Fertility studies in rats showed no evidence of harmful effects (see section 5.3).

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 4.8 paragraph (b)).

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 lists adverse reactions reported in clinical trials and post-marketing experience with clarithromycin immediate-release tablets, granules for oral suspension, powder for solution for injection, extended-release tablets, and modified-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 not known (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.

¹Adverse reactions have only been reported for the Powder to Concentrate to Solution for Infusion formulation.

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

³ADRS was reported only for the formulation Granules for oral suspension

⁴SARDS have only been reported for the immediate-release tablet formulation.

^5,6See section (c)

* As these reactions are reported voluntarily in a population of uncertain size, it is not always possible to reliably estimate their frequency or prove 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.

Injection site phlebitis, injection 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).

special population

Adverse effects 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.

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

meter. 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 via the Yellow Card scheme at: www.mhra.gov.uk/amarillocard or search for MHRA Yellow Card on Google Play or the Apple App Store.

Reports indicate that ingesting large amounts of clarithromycin by mouth may cause gastrointestinal symptoms. A patient with a history of bipolar disorder received 8 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.

In case of overdose, intravenous clarithromycin (powder for solution for injection) should be discontinued and all other appropriate supportive measures instituted.

Pharmacotherapeutic group: Antibacterial for systemic use, macrolide, ATC code: J01FA09.

action mode

Clarithromycin is an antibiotic that belongs to the group of macrolide antibiotics. It exerts its antibacterial action by selectively binding to the ribosomal subunit of susceptible bacteria since the 1950s, preventing the translocation of activated amino acids. It inhibits the synthesis of intracellular proteins of sensitive bacteria.

The 14-hydroxy metabolite of clarithromycin, a product of parent drug metabolism, also has antimicrobial activity. The metabolite is less active than the parent compound for most organisms, including Mycobacterium spp. An exception is Haemophilus influenza, where the 14-hydroxy metabolite is twice as active as the parent compound.

Clarithromycin 500 mg powder for solution for injection is generally active against the following organismsin vitro:

Gram positive bacteria:

staphylococcal disease(susceptible to methicillin).Streptococcus pyogenes(Group A β-hemolytic streptococci);alpha-hemolytic strep(viridans group);Streptococcus (Diplococcus) pneumonia? Streptococcus agalactiae; listeria monocytogenes.

Gram-negative bacteria:

Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae; Legionella pneumophila, Bordetella pertussis, Helicobacter pylori; Campylobacter jejeuni.

micoplasma:

Mycoplasma pneumoniae; Ureaplasma urealitic.

Other organizations:

Chlamydia trachomate; Mycobacterium avium; Mycobacterial leprosy; chlamydia pneumonia.

anaerobic:

sensitive to macrolidesBacteroides fragilis; Clostridium perfringens; Peptococcus species; Peptostreptococcus species;Propionibacterium acnes.

Clarithromycin has bactericidal activity against many bacterial strains. These organizations include;H. influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, Helicobacter pyloriy Campylobacter spp.

The action of clarithromycin againstHelicobacter pyloriis greater at neutral pH than at acidic pH.

breakpoints

The following breakpoints have been established by the European Committee for Antimicrobial Susceptibility Testing (EUCAST).

The microbiologically active metabolite 14-hydroxyclarithromycin is formed by first-pass metabolism, as indicated by the decreased bioavailability of the metabolite after intravenous administration. After intravenous administration, clarithromycin blood levels achieved are well above the MIC 90 for common pathogens and 14-hydroxyclarithromycin levels exceed concentrations required for important pathogens, e.g.H influenzae.

The pharmacokinetics of clarithromycin and the 14-hydroxy metabolite are not linear. Steady state is reached on day 3 of intravenous dosing. After a single intravenous dose of 500 mg over 60 minutes, approximately 33% of clarithromycin and 11% of 14-hydroxyclarithromycin are excreted in the urine in 24 hours.

Fertility, reproduction and teratogenesis.

Fertility studies have not been performed with intravenous (IV) administration of clarithromycin. Oral fertility and reproduction studies in rats did not show adverse effects.

Intravenous embryotoxicity studies showed no evidence of embryotoxicity or teratogenicity at maternally toxic doses up to 160 mg/kg/day in rats (~1.5 times the maximum recommended human dose (MRHD) on a mg/m²base) and 30 mg/kg/day in rabbits (~0.6 times the MRHD on a mg/m²base). In rabbits,not uterusfetal loss occurred with an intravenous dose of 33 mg/m², which is 17 times less than the MRHD of 618 mg/m². Oral teratogenicity studies in rats, rabbits, and monkeys failed to demonstrate any teratogenicity of clarithromycin at the highest doses tested up to 1.5, 2.4, and 1.5 times the MRHD of 1 g/day orally on a mg basis. /m.²based on the respective species. However, a similar study in Sprague-Dawley rats showed a low incidence (6%) of cardiovascular abnormalities that appeared to be due to the spontaneous expression of genetic alterations. Two oral studies in mice revealed a variable incidence (3-30%) of cleft palate at 1000 mg/kg/day (~5 times the MRHD of 1 g/day PO on mg/m).²base). Fetal loss has been observed in monkeys, but only at doses clearly toxic to the mother.

lactobionic acid

water for injections

Closed bottle: 48 months.

Reconstituted Solution: Chemical and physical in-use stability has been demonstrated for 24 hours at 5 - 25°C when reconstituted in 10 mL Water for Injections and for 6 hours (at 25°C) or 24 hours at (5°C). C) after diluting with 250 ml of a suitable diluent (see section 6.6).

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and will normally not exceed 24 hours at 2-8°C, unless reconstitution/dilution has taken place in controlled aseptic facilities and validated. . conditions.

Ph. Type II Eur 20 ml clear glass vial with bromobutyl stopper and aluminum flip-off cap.

The box contains 1 or 5 vials.

preparation for use

Reconstitution (Step 1)

Reconstitute each vial with 10 ml of sterile water for injections (final volume: 10.75 ml).

Shake until the contents of the vial are dissolved. Use only Sterile Water for Injections, as other diluents may cause precipitation during reconstitution. Do not use thinners that contain preservatives or mineral salts. Each ml contains 50 mg of clarithromycin.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Dilution (Step 2)

The reconstituted solution must be added to at least 250 ml of one of the following diluents before administration:

0.9% sodium chloride solution.

5% dextrose solution.

5% dextrose in 0.3% or 0.45% sodium chloride solution.

5% dextrose in Ringer's solution

5% dextrose in Lactated Ringer's solution.

Each 1 ml of solution for infusion thus prepared contains 2 mg of clarithromycin.

For storage conditions after drug dilution, see section 6.3.

IMPORTANT: BOTH DILUTION STEPS (1 AND 2) MUST BE COMPLETED PRIOR TO USE.

Clarithromycin 500 mg powder for solution for infusion should be administered into one of the larger proximal veins as an intravenous infusion over 60 minutes using a solution concentration of approximately 2 mg/mL. Clarithromycin should not be given as a bolus or intramuscular injection.

For one use only. The vial and any unused solution must be disposed of properly in accordance with local requirements.

Bigen S.r.l.,

Calle Fossignano 2

04011 – Aprilia (LT)

Italia