Clarithromycin 500 mg powder for concentrate for solution for injection. - Summary of Product Characteristics (RCP) (2023)

Each vial contains 500 mg clarithromycin as clarithromycin lactobionate.

When reconstituted and diluted, the final diluted solution contains approximately 2 mg/mL clarithromycin.

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

Powder for concentrated solution for injection.

A white to off-white pastel powder.

Clarithromycin is indicated when parenteral therapy is required for the treatment of infections caused by susceptible organisms in the following situations (see sections 4.4 and 5.1).

- 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, pharyngitis and tonsillitis.

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

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

Clarithromycin is indicated for adults and children from 12 years of age.

Dose

Intravenous therapy can be given for 2 to 5 days and should be changed to oral clarithromycin therapy whenever possible, as determined by the physician. The total duration of treatment should not exceed 14 days. The usual duration of treatment is 6 to 14 days.

Adults:The recommended dose of clarithromycin is 1 gram daily divided into two 500 mg doses, appropriately diluted (see section 6.6).

pediatric population

Children over 12 years:As for the adults.

Children under 12 years:Intravenous clarithromycin is not recommended for use in children under 12 years of age. Use pediatric clarithromycin suspension.

Old man

As for the adults.

Renal insufficiency

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.

preparation for use

See section 6.6

Administration method:

For intravenous use only.

Hypersensitivity to the active substance or to any of the excipients mentioned 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).

Co-administration of clarithromycin and any of the following medicinal products: astemizole, cisapride, pimozide and terfenadine is contraindicated as it may cause QT prolongation and cardiac arrhythmias including ventricular fibrillation and torsades de pointes (see section 4.5). Elevated levels of cisapride, pimozide and terfenadine have been reported in patients receiving any of these medicinal products and clarithromycin concomitantly. 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.

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 administered to patients with hypokalaemia (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).

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

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

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

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.

Prolonged or repeated use of clarithromycin may cause overgrowth of nonsusceptible bacteria or fungi. If superinfection occurs, clarithromycin should be discontinued and appropriate treatment initiated.

Pseudomembranous colitis has been reported with almost all antibacterial agents, including macrolides, and its severity can range from mild to life-threatening. Clostridium difficile-associated diarrhea (CDAD) has been reported with the use of nearly all antibacterial agents, including clarithromycin, and can range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, which can lead to an overgrowth of C. difficile. 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.

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

cardiovascular events

Prolonged cardiac repolarization and QT interval, conferring a risk of developing cardiac arrhythmia and torsades de pointes, have been observed with treatment with macrolides, including clarithromycin (see section 4.8). Therefore, since 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 such as hypomagnesemia.

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: Due to the emerging resistance of Streptococcus pneumoniae to macrolides, it is important to perform susceptibility testing 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 by Staphylococcus aureus and Streptococcus pyogenes, both of 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. Macrolides are currently thought to play a role only in certain skin and soft tissue infections, such as those caused by Corynebacterium minutissimum, 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 treatment should be started urgently if indicated

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 significant increases 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.

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:

Cisaprida, pimozida, astemizol 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. A statin that does not depend on CYP3A metabolism (eg, fluvastatin) may be considered. Patients should be monitored for signs and symptoms of myopathy.

Effects of other drugs on clarithromycin.

Clarithromycin is metabolized by the CYP3A4 enzyme. Therefore, strong inhibitors of this enzyme may inhibit clarithromycin metabolism, resulting in increased clarithromycin plasma concentrations.

CYP3A4 inducers (eg, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort-containing products) may result in the metabolism of clarithromycin. This can lead to sub-therapeutic levels of clarithromycin that reduce the efficacy of the product. 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 and 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.

ritonavir

Ritonavir (ritonavir 200 mg three times daily) has been shown to be an inhibitor of the metabolism of clarithromycin (500 mg twice daily), while the increase in Cmax, Cmin and AUC when co-administered with ritonavir is 31 , 182 and 77%. respectively. The formation of the active metabolite 14-OH-clarithromycin hydroxyclarithromycin is almost completely inhibited. In patients with normal renal function, it is not necessary to reduce the dose of clarithromycin; however, the daily dose of clarithromycin should not exceed 1 g. A dose reduction should be considered in patients with renal insufficiency. In patients with creatinine clearance of 30-60 ml/min (0.5 – 1 ml/s) the dose of clarithromycin should be reduced by 50% and in patients with creatinine clearance <30 ml/min (<0.5 ml/s) the dose should be reduced by 75%.

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).

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 a mean increase in clarithromycin trough concentration (Cmin) and area under the curve (AUC) at steady state. 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.

Effects 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. Clarithromycin should be used with caution in patients treated with other drugs known to be substrates of the CYP3A enzyme, especially if the CYP3A substrate has a narrow margin of safety (eg, carbamazepine) and/or the substrate is widely metabolized by this enzyme.

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

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

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.

Antacids

Increases in plasma concentrations of clarithromycin may also occur when co-administered with antacids or ranitidine.

It is not necessary to adjust the dose.

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 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 also be applied when using other benzodiazepines metabolized by CYP3A, particularly triazolam and alprazolam. An interaction of clarithromycin with benzodiazepines that are not metabolized via CYP3A4 (temazepam, nitrazepam, lorazepam) 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.

Cyclosporine, tacrolimus and sirolimus

Co-administration of the oral form of clarithromycin with ciclosporin or tacrolimus results in a more than two-fold increase in plasma Cmin concentrations of ciclosporin and tacrolimus. Similar results can also be expected with sirolimus.

Plasma levels of ciclosporin, tacrolimus, or sirolimus should be closely monitored when initiating clarithromycin therapy in patients receiving any of the above-mentioned immunosuppressants, and their doses should be reduced if necessary.

Discontinuation of clarithromycin in these patients also requires careful monitoring of ciclosporin, tacrolimus, or sirolimus plasma levels to guide dose adjustment.

Other drug interactions

Clarithromycin is a potent inhibitor of the P-glycoprotein (Pgp) transporter protein. This can lead to increased plasma concentrations of the active substances transported by this transporter and can also increase the distribution of said active substances in organs that have Pgp as a distribution barrier, e.g. CNS.

digoxin

Digoxin is believed to be a substrate of the efflux transporter, P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. The concentration of the Pgp substrate digoxin may be increased when co-administered with clarithromycin. 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. Monitoring of serum digoxin concentrations should be considered when initiating or terminating concomitant treatment with clarithromycin, as dose adjustment may be necessary.

colchicine

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

As with other strong CYP3A4 inhibitors, clarithromycin should not be used in patients receiving colchicine (see sections 4.3).

zidovudine

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

phenytoin and valproate

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

Bidirectional drug interactions

Atazanavir

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

Calcium channel blockers

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

itraconazole

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

saquinavir

Both clarithromycin and saquinavir are CYP3A substrates and inhibitors, and there is evidence of a two-way drug interaction. Co-administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily) to 12 healthy volunteers resulted in steady-state AUC and Cmax._Maximumsaquinavir values ​​that were 177% and 187% higher than those seen with saquinavir alone. AUC and C of clarithromycin_MaximumValues ​​were approximately 40% higher than those seen with clarithromycin alone. No dose adjustment is required when the two drugs are co-administered for a limited period of time at the doses/formulations studied. Observations from drug interaction studies using the soft gelatin capsule formulation may not be representative of the effects observed with saquinavir hard gelatin capsule. Observations from drug interaction studies performed with saquinavir alone may not be representative of the effects seen with saquinavir/ritonavir therapy. When saquinavir is co-administered with ritonavir, the potential effects of ritonavir on clarithromycin should be considered (see section 4.5: Ritonavir).

oral contraceptive pill

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 during pregnancy has not been established. Considering the conflicting results obtained in studies in mice, rats, rabbits and monkeys, the possibility of adverse effects on fetal development cannot be excluded. Therefore, its use during pregnancy is not recommended without careful evaluation of the benefits and risks.

Data on the use of clarithromycin in the first trimester of more than 200 pregnancies show no clear evidence of teratogenicity or adverse effects on the health of the newborn. Data from a limited number of pregnant women exposed during the first trimester indicate a possible increased risk of miscarriage. To date there are no other relevant epidemiological data.

Data from animal studies have shown reproductive toxicity (see section 5.3). The risk to humans is unknown. Clarithromycin should not be given to pregnant women unless clearly necessary.

Breast-feeding

Clarithromycin and its active metabolite are excreted in breast milk. 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.

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.

Adverse reactions were reported in more than one case, listed below by system organ and their frequency using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon ( ≥1/10). 1,000 to <1/100), rare (≥1/10,000 to <11,000), very rare (<1/10,000) 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.

* 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 reactions in immunocompromised patients (see section e).

Hey. pediatric populations

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.Serum glutamic oxaloacetate transaminase(SGOT) andSerum glutamate pyruvate transaminasealtitudes (SGPT). Other low frequency events included dyspnea, insomnia, and dry mouth. The incidences were comparable for patients treated with 1000 mg and 2000 mg, but overall were approximately 3 to 4 times more frequent for those patients receiving clarithromycin 4000 mg total daily doses.

In these immunocompromised patients, assessments of laboratory values ​​were performed by testing for those values ​​outside of the severely abnormal range (ie, borderline extremely high or low) for the specified test. Based on these criteria, approximately 2% to 3% of patients receiving clarithromycin 1000 mg or 2000 mg daily 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 the MHRA Yellow Card on Google Play or the Apple App Store.

There is no experience of overdose after intravenous administration of clarithromycin. However, reports indicate that ingestion of large amounts of oral clarithromycin can be expected to 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.

Clarithromycin serum levels are not expected to be significantly affected by hemodialysis or peritoneal dialysis.

In case of overdose, intravenous clarithromycin should be discontinued and all other appropriate supportive measures instituted.

pharmacotherapeutic group: Antibacterial for systemic use, macrolides.

ATC Code:J01FA09

Mechanism of action

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 concentrate for solution for infusion is generally active against the following organisms in vitro:

gram-positive bacteria staphylococcal disease(susceptible to methicillin).Streptococcus pyogenes(Group A β-hemolytic streptococci); alpha-hemolytic streptococcus (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 jejuni.

Micoplasma:Micoplasma pneumoniae; Ureaplasma urealyticum.

Other organizations: Chlamydia trachomate; Mycobacterium avium; Mycobacterial leprosy; Chlamydia pneumonia.

Anaerobic:sensitive to macrolidesBacteriodes 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, Morazella (Brahamella) 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, the clarithromycin blood levels achieved are well above the MIC.₉₀s 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.

Clarithromycin 500 mg powder for concentrate for solution for infusion is free of tartrazine and other azo dyes, lactose and gluten.

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

In repeat-dose studies, toxicity was related to dose, duration of treatment, and species. Dogs were more sensitive than primates or rats. The main clinical signs at toxic doses included vomiting, weakness, reduced food intake and weight gain, drooling, dehydration and hyperactivity. In all species, the liver was the main target organ for toxic doses. Hepatotoxicity was detectable by early elevations in liver function tests. Discontinuation of the drug has generally resulted in a return or direction of normal results. Other less frequently affected tissues include the stomach, thymus and other lymphoid tissues, and the kidneys.

At near-therapeutic doses, conjunctival injection and tearing occurred only in dogs. At a massive dose of 400 mg/kg/day, some dogs and monkeys developed opacification and/or corneal edema.

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

4 years closed.

Reconstituted/diluted solutions: Chemical and physical in-use stability has been shown to be 6 hours at 25°C.

From a microbiological point of view, the reconstituted and diluted 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 under controlled aseptic conditions and validated. . .

Packaged for sale: Do not store at temperatures above 30°C. Keep the vial in the outer carton in order to protect from light.

For the storage conditions of the diluted medicine, see paragraph 6.3.

Type II clear glass vial closed with a bromobutyl stopper specially designed for lyophilized products and sealed with a tamper-evident aluminum cap.

Pack sizes: 30 ml bottle. Available in single pack.

Clarithromycin 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.

Dilution must be carried out under aseptic conditions. The solution should be visually inspected for particles and discoloration prior to administration. The solution should only be used if it is clear and free of particles.

Suitable diluents include:

• Solution for infusion of dextrose 50 mg/ml (5%) in lactated Ringer's solution

• Dextrose 50 mg/ml (5%) solution for infusion

• Lactated Ringer's solution

• Dextrose 50 mg/ml (5%) in sodium chloride 3 mg/ml (0.3%) solution for infusion.

• Dextrose 50 mg/ml (5%) in sodium chloride 4.5 mg/ml (0.45%) solution for infusion.

• Sodium chloride 9 mg/ml (0.9%) solution for infusion.

For one use only. Discard any unused solution.

martindale Pharmaceutical Limited,

bampton Road,

Harold Colina,

Romford,

Essex.

RM3 8E

United Kingdom