Summary of Product Characteristics (SmPC) - Clarithromycin 500 mg powder for concentrate for solution for infusion
1 NAME OF THE MEDICINAL PRODUCT
Clarithromycin 500 mg powder for concentrate for solution for infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 500 mg clarithromycin as clarithromycin lactobionate.
When reconstituted and diluted as directed, the final diluted solution contains 2 mg/ml of clarithromycin as clarithromycin lactobionate.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Powder for concentrate for solution for infusion.
White to off white cake or powder.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
| Clarithromycin is indicated in adults and children 12 years and older. |
Clarithromycin is indicated when parenteral therapy is required for treatment of infections caused by susceptible organisms in the following conditions (see sections 4.4 and 5.1);
- Acute exacerbation of chronic bronchitis
- Community acquired pneumonia
- Acute bacterial sinusitis (adequately diagnosed)
- Streptococcal pharyngitis and tonsillitis
- Skin and soft tissue infections
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology and method of administration
Posology
Intravenous therapy may be given for 2 to 5 days in the very ill patient and should be changed to oral clarithromycin therapy whenever possible as determined by the physician. The total duration of treatment with clarithromycin should not extend 14 days.
Adults
The recommended dosage of Clarithromycin 500 mg powder for concentrate for solution for infusion is 1.0 gram daily, divided into two 500 mg doses, appropriately diluted as described below.
Paediatric population
Children older than 12 years: As for adults.
Children under 12 years: Use of Clarithromycin 500 mg powder for concentrate for solution for infusion is not recommended for children younger than 12 years. Clinical trials have been conducted using clarithromycin paediatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use clarithromycin paediatric suspension (granules for oral suspension). There are insufficient data to recommend a dosage regimen for use of the clarithromycin IV formulation in patients less than 18 years of age.
Special populations
Elderly
As for adults.
Renal impairment
In patients with renal impairment who have creatinine clearance less than 30 ml/min, the dosage of clarithromycin should be reduced to one half of the normal recommended dose.
Method of administration
| For intravenous administration only. |
| For instructions on reconstitution/dilution of the medicinal product before |
| administration, see section 6.6. |
4.3 Contraindications
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- Clarithromycin 500 mg powder for concentrate for solution for infusion is contra-indicated in patients with known hypersensitivity to macrolide antibiotics.
Concomitant administration of clarithromycin and ergot alkaloids (e.g.
ergotamine or dihydroergotamine) is contraindicated, as this may result in ergot toxicity (see section 4.5).
- Concomitant administration of clarithromycin and oral midazolam is contraindicated (see section 4.5).
- Concomitant administration of clarithromycin and any of the following medicinal products is contraindicated: astemizole, cisapride, domperidone, ivabradine, pimozide and terfenadine as this may result in QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see section 4.4 and 4.5).
Clarithromycin must not be given to patients with 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).
- Concomitant administration with ticagrelor, ivabradine or ranolazine is contraindicated.
- Clarithromycin must not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4, (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see section 4.5).
Concomitant administration of clarithromycin and lomitapide is contraindicated
(see section 4.5).
- As with other strong CYP3A4 inhibitors, Clarithromycin must not be used in patients taking colchicine (see sections 4.4 and 4.5).
Clarithromycin must not be given to patients with electrolyte disturbances
(hypokalaemia or hypomagnesaemia, due to the risk of prolongation of the QT interval).
- Clarithromycin must not be used in patients who suffer from severe hepatic failure in combination with renal impairment (see section 4.4).
4.4 Special warnings and precautions for use
| Pregnancy: |
| The physician should not prescribe clarithromycin to pregnant women without |
| carefully weighing the benefits against risk, particularly during the first and second |
| trimester of pregnancy (see section 4.6). |
| Renal and hepatic impairment: |
| Clarithromycin is principally metabolised by the liver. Therefore, caution should be |
| exercised in administering this antibiotic to patients with impaired hepatic function. |
| Caution should also be exercised when administering clarithromycin to patients with |
| moderate to severe renal impairment (see section 4.2). Clinical trials in patients with |
| hepatic impairment have shown that in patients with moderate to severe hepatic |
| impairment and normal renal function, no dose adjustment is needed. |
| Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or |
| cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. |
| This hepatic dysfunction may be severe and is usually reversible. Cases of fatal |
| hepatic failure (see section 4.8) have been reported. Some patients may have had pre- |
| existing hepatic disease or may have been taking other hepatotoxic medicinal |
| products. Patients should be advised to stop treatment and contact their doctor if signs |
| and symptoms of hepatic disease develop, such as anorexia, jaundice, dark urine, |
| pruritus, or tender abdomen. |
| Antibiotic-associated diarrhoea and colitis: | |
| Pseudomembranous colitis has been reported with nearly all antibacterial agents, | |
| including macrolides, and may range in severity from mild to life-threatening. | |
| Clostridioides difficile- associated diarrhoea (CDAD) has been reported with use of | |
| nearly all antibacterial agents including clarithromycin, and may range in severity | |
| from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the | |
| normal flora of the colon, which may lead to overgrowth of C. difficile. CDAD must | |
| be considered in all patients who present with diarrhoea following antibiotic use. | |
| Careful medical history is necessary since CDAD has been reported to occur over two | |
| months after the administration of antibacterial agents. Therefore, discontinuation of | |
| clarithromycin therapy should be considered regardless of the indication. Microbial | |
| testing should be performed and adequate treatment initiated. Medicinal products | |
| inhibiting peristalsis should be avoided. | |
| Interaction with medicinal products: | |
| There have been post-marketing reports of colchicine toxicity with concomitant use | |
| of clarithromycin and colchicine, especially in the elderly, some of which occurred in | |
| patients with renal insufficiency. Deaths have been reported in some such 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 oromucosal | |
| midazolam (see section 4.5). | |
| Cardiovascular events: Prolongation of the QT interval, reflecting effects on cardiac | |
| repolarisation imparting a risk of developing cardiac arrhythmia and torsade de | |
| pointes, have been seen in patients treated with macrolides including clarithromycin | |
| (see section 4.8). Due to increased risk of QT prolongation and ventricular | |
| arrhythmias (including torsade de pointes), the use of clarithromycin is | |
| contraindicated: in patients taking any of astemizole, cisapride, domperidone, | |
| ivabradine, pimozide and terfenadine; in patients with electrolyte disorders such as | |
| hypokalaemia or hypomagnesaemia; and in patients with a history of QT prolongation | |
| or ventricular cardiac arrhythmia (see section 4.3). | |
| Carefully consider the balance of benefits and risks before prescribing clarithromycin | |
| for any patients taking hydroxychloroquine or chloroquine, because of the potential | |
| for an increased risk of cardiovascular events and cardiovascular mortality (see | |
| section 4.5). | |
| Furthermore, clarithromycin should be used with caution in the following patients: | |
| |
| conduction disturbances or clinically relevant bradycardia. | |
| |
| prolongation other than those which are contraindicated. | |
| Epidemiological studies investigating the risk of adverse cardiovascular outcomes | |
| with macrolides have shown variable 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 findings should be balanced with treatment benefits when | |
| prescribing clarithromycin. | |
Pneumonia: In view of the emerging resistance of Streptococcus pneumoniae to macrolides, it is important that sensitivity testing be performed when prescribing clarithromycin for community-acquired pneumonia. In hospital-acquired pneumonia, clarithromycin should be used in combination with additional appropriate antibiotics.
Caution is advised when co-administering clarithromycin with other ototoxic medicinal products, especially with aminoglycosides. Monitoring of vestibular and auditory function should be performed during and after treatment.
Skin and soft tissue infections of mild to moderate severity: These infections are most often caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Therefore, it is important that sensitivity testing be performed. In cases where beta–lactam antibiotics cannot be used (e.g. allergy), other antibiotics, such as clindamycin, may be the medicinal product of first choice. Currently, macrolides are only considered to play a role in some skin and soft tissue infections, such as those caused by Corynebacterium minutissimum, acne vulgaris, and erysipelas and in situations where penicillin treatment cannot be used.
In the event of severe acute hypersensitivity reactions, such as anaphylaxis, severe cutaneous adverse reactions (SCAR) (e.g. Acute generalised exanthematous pustulosis (AGEP)， Stevens-Johnson Syndrome, toxic epidermal necrolysis, and drug rash with eosìnophilia and systemic symptoms (DRESS), clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.
Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see section 4.5). Clarithromycin is a CYP3A4 inhibitor and concomitant use with other medicinal products that are extensively metabolized by this enzyme should be limited to situations where clearly indicated (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 taking clarithromycin and statins. Patients should be monitored for signs and symptoms of myopathy.
In situations where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered. (see section 4.5).
Oral hypoglycaemic agents/Insulin: The concomitant use of clarithromycin and oral hypoglycaemic agents (such as sulfonylurias) and/or insulin can result in significant hypoglycaemia. Careful monitoring of glucose is recommended (see section 4.5).
Oral anticoagulants: There is a risk of serious haemorrhage and significant elevations 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 frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently.
Caution should be exercised when clarithromycin is co-administered with direct acting oral anticoagulants such as dabigatran, rivaroxaban, apixaban and edoxaban, particularly to patients at high risk of bleeding (see section 4.5).
The use of antimicrobial therapy of any kind, such as clarithromycin, to treat H. pylori infection can lead to drug-resistant microorganisms.
Long-term use may, as with other antibiotics, result in colonisation with increased numbers of non-susceptible bacteria and fungi. If superinfections occur, appropriate therapy should be initiated.
Attention should also be paid to the possibility of cross resistance between clarithromycin and other macrolide antibiotics, as well as lincomycin and clindamycin.
This medicinal product contains less than 1 mmol sodium (23 mg) per 500 mg, that is to say essentially 'sodium-free'.
4.5 Interaction with other medicinal products and other forms of interaction
| The use of the following medicinal products is strictly contraindicated due to the |
| potential for severe drug interaction effects: |
| Astemizole, cisapride, domperidone, ivabradine, pimozide and terfenadine |
| Elevated cisapride levels have been reported in patients receiving clarithromycin and |
| cisapride concomitantly. This may result in QT prolongation and cardiac arrhythmias |
| including ventricular tachycardia, ventricular fibrillation and torsades de pointes. |
| Similar effects have been observed in patients taking clarithromycin and pimozide |
| concomitantly (see section 4.3). |
| Concomitant administration of clarithromycin and ivabradine is known to increase the |
| exposure of ivabradine and may result in a higher risk of torsades de pointes. |
| Macrolides have been reported to alter the metabolism of terfenadine resulting in |
| increased levels of terfenadine which has occasionally been associated with cardiac |
| arrhythmias, such as QT prolongation, ventricular tachycardia, ventricular fibrillation |
| and torsades de pointes. Concomitant use is contraindicated (see section 4.3). In one |
| study in 14 healthy volunteers, the concomitant administration of clarithromycin and |
| terfenadine resulted in 2- to 3-fold increase in the serum level of the acid metabolite |
| of terfenadine and in prolongation of the QT interval which did not lead to any |
| clinically detectable effect. Similar effects have been observed with concomitant |
| 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 ischaemia of the extremities and other tissues |
| including the central nervous system. Concomitant administration of clarithromycin |
| and ergot alkaloids is contraindicated (see section 4.3). |
| Oral Midazolam |
| When midazolam was co-administered with clarithromycin tablets (500 mg twice |
| daily), midazolam AUC 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 concentration, which increases the risk of myopathy, including rhabdomyolysis. Reports of rhabdomyolysis have been received for patients taking clarithromycin concomitantly with these statins. If treatment with clarithromycin cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment.
Caution should be exercised when prescribing clarithromycin with statins. In situations where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered. Patients should be monitored for signs and symptoms of myopathy.
Concomitant administration of clarithromycin with colchicine, ticagrelor and ranolazine is contraindicated (see section 4.3).
The concomitant use of the following medicinal products is not recommended.
The following medicinal products are known or suspected to alter the plasma concentration of clarithromycin. Dose adjustment of clarithromycin or consideration of alternative treatments may be required.
Concomitant use of clarithromycin and antifungals, azoles (ketoconazole) increases the risk of cardiac toxicity (prolonged QT interval, torsades de pointes, cardiac arrest), therefore combination therapy is not recommended.
Concomitant use of clarithromycin and nifedipine increases the risk of cardiac toxicity (prolonged QT interval, torsades de pointes, cardiac arrest), therefore combination therapy is not recommended.
Hypotension and bradycardia have been observed in a patient treated with clarithromycin and verapamil concomitantly.
Lactic acidosis has been reported with concomitant use of verapamil and a ketolide antibiotic, telithromycin (1 case), due to the possibility of CYP3A inhibition. Since clarithromycin is also a macrolide and a CYP3A inhibitor, a similar interaction with verapamil may occur.
Effects of Other Medicinal Products on Clarithromycin
Medicinal products that are inducers of CYP3A (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St John's wort) may induce the metabolism of clarithromycin. This may result in sub-therapeutic levels of clarithromycin leading to reduced efficacy. Furthermore, it might be necessary to monitor the plasma levels of the CYP3A inducer, which could be increased owing to the inhibition of CYP3A by clarithromycin (see also the relevant product information for the CYP3A4 inducer administered). Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis.
The following medicinal products are known or suspected to affect circulating concentrations of clarithromycin; clarithromycin dosage adjustment or consideration of alternative treatments may be required.
Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine
Strong inducers of the cytochrome P450 metabolism system such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine may accelerate the metabolism of clarithromycin and thus lower the plasma levels of clarithromycin, while increasing those of 14-OH-clarithromycin, a metabolite that is also microbiologically active. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers.
Etravirine
Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be reduced; therefore, alternatives to clarithromycin should be considered for the treatment of MAC.
Fluconazole
Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers led to increases in the mean steady-state minimum clarithromycin concentration (Cmin) 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 concomitant administration of fluconazole. No clarithromycin dose adjustment is necessary.
Ritonavir
A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200 mg every eight hours and clarithromycin 500 mg every 12 hours resulted in a marked inhibition of the metabolism of clarithromycin. The clarithromycin Cmax increased by 31%, Cmin increased 182% and AUC increased by 77% with concomitant administration of ritonavir. An essentially complete inhibition of the formation of 14-OH-clarithromycin was noted. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. However, for patients with renal impairment, the following dosage adjustments should be considered: For patients with CLCR 30 to 60 ml/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR <30 ml/min the dose of clarithromycin should be decreased 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 reduced renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors including atazanavir and saquinavir (see section below, Bi-directional drug interactions).
Protease inhibitors (ritonavir, nelfinavir) increase the bioavailability of clarithromycin, therefore combination therapy may require dose adjustment. 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 section below, Bi-directional drug interactions).
Effect of Clarithromycin on Other Medicinal Products
CYP3A-based interactions
Co-administration of clarithromycin, which is known to inhibit CYP3A, and a medicinal product primarily metabolised by CYP3A may be associated with elevations in active substance concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant medicinal product. 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 torsades de pointes (see sections 4.3 and 4.4).
The use of clarithromycin is also contraindicated with ergot alkaloids, oral midazolam, HMG CoA reductase inhibitors metabolised mainly by CYP3A4 (e.g. lovastatin and simvastatin), colchicine, ticagrelor, ivabradine and ranolazine (see section 4.3).
Concomitant administration of clarithromycin with lomitapide is contraindicated due the potential for markedly increased transaminases (see section 4.3). Caution is required if clarithromycin is co-administered with other medicinal products known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e.g. carbamazepine) and/or the substrate is extensively metabolised by this enzyme.
Dosage adjustments may be considered, and when possible, serum concentrations of medicinal products primarily metabolised by CYP3A should be monitored closely in patients concurrently receiving clarithromycin. Medicinal products or drug classes that are known or suspected to be metabolised by the same CYP3A isozyme include (but this list is not comprehensive) alprazolam, carbamazepine, cilostazole, ciclosporin, disopyramide, ibrutinib, methylprednisolone, midazolam (intravenous), omeprazole, oral anticoagulants (e.g. warfarin, rivaroxaban, apixaban), atypical antipsychotics (e.g. quetiapine), quinidine, rifabutin, sildenafil, sirolimus, tacrolimus, triazolam and vinblastine.
Medicinal products interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate.
Corticosteroids
Caution should be exercised in concomitant use of clarithromycin with systemic and inhaled corticosteroids that are primarily metabolised by CYP3A due to the potential for increased systemic exposure to corticosteroids. If concomitant use occurs, patients should be closely monitored for systemic corticosteroid undesirable effects.
Antiarrhythmics
There have been post-marketed reports of torsades de pointes occurring with the concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QT prolongation during co-administration of clarithromycin with these medicinal products. Serum levels of quinidine and disopyramide should be monitored during clarithromycin therapy.
There have been post marketing reports of hypoglycaemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
Oral anticoagulants
Clarithromycin decreases the clearance of warfarin, therefore monitoring and dose adjustment of warfarin may be necessary. Spontaneous post-marketing reports suggest that co-administration of clarithromycin and oral anticoagulants may increase the effect of the anticoagulants. Prothrombin times should be closely monitored while patients are receiving clarithromycin and oral anticoagulants concomitantly (see section 4.4).
Direct acting oral anticoagulants (DOACs)
The DOACs dabigatran and edoxaban are substrates for the efflux transporter P-gp. Rivaroxaban and apixaban are metabolised via CYP3A4 and are also substrates for P-gp. Caution should be exercised when clarithromycin is co-administered with these agents particularly to patients at high risk of bleeding (see section 4.4).
Oral hypoglycaemic agents/Insulin
With certain hypoglycaemic medicinal products such as nateglinide, and repaglinide, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypoglycaemia when used concomitantly. Careful monitoring of glucose is recommended.
Omeprazole
Clarithromycin (500 mg every 8 hours) was given in combination with omeprazole (40 mg daily) to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (Cmax, AUC0-24, and t1/2 increased by 30%, 89%, and 34%, respectively), by the concomitant administration of clarithromycin. The mean 24-hour gastric pH value 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 metabolised, at least in part, by CYP3A, and CYP3A may be inhibited by concomitantly administered clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil would likely result in increased phosphodiesterase inhibitor exposure. Reduction of sildenafil, tadalafil and vardenafil dosages should be considered when these medicinal products are co-administered with clarithromycin.
Theophylline, carbamazepine
Results of clinical studies indicate that there was a modest but statistically significant (p≤0.05) increase of circulating theophylline or carbamazepine levels when either of these medicinal products were administered concomitantly with clarithromycin. Dose reduction may need to be considered.
Tolterodine
The primary route of metabolism for tolterodine is via the 2D6 isoform of cytochrome P450 (CYP2D6). However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. A reduction in tolterodine dosage may be necessary in the presence of CYP3A inhibitors, such as clarithromycin in the CYP2D6 poor metaboliser population.
Triazolobenzodiazepines (e.g., 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 must be closely monitored to allow dose adjustment. Drug delivery of midazolam via oromucosal route, which could bypass pre-systemic elimination of the medicinal product, will likely result in a similar interaction to that observed after intravenous midazolam rather than oral administration. The same precautions should also apply to other benzodiazepines that are metabolised by CYP3A, including triazolam and alprazolam. For benzodiazepines which are not dependent on CYP3A for their elimination (temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Clarithromycin thus increases the bioavailability of benzodiazepines and benzodiazepine derivatives (midazolam, alprazolam, diazepam, triazolam). Combination therapy may require dose adjustment.
There have been post-marketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.
Other drug interactions
Colchicine
Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine (see section 4.3 and 4.4).
Digoxin
Digoxin is thought to be a substrate for 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 lead to increased exposure to digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have also been reported in post marketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored while patients are receiving digoxin and clarithromycin simultaneously.
Zidovudine
Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Because clarithromycin appears to interfere with the absorption of simultaneously administered oral zidovudine, this interaction can be largely avoided by staggering the doses of clarithromycin and zidovudine to allow for a 4-hour interval between each medication. This interaction does not appear to occur in paediatric HIV-infected patients taking clarithromycin suspension with zidovudine or dideoxyinosine. This interaction is unlikely when clarithromycin is administered via intravenous infusion.
Phenytoin and Valproate
There have been spontaneous or published reports of interactions of CYP3A inhibitors, including clarithromycin with medicinal products not thought to be metabolised by CYP3A (e.g. phenytoin and valproate). Serum level determinations are recommended for these medicinal products when administered concomitantly with clarithromycin. Increased serum levels have been reported.
Hydroxychloroquine and Chloroquine
Clarithromycin should be used with caution in patients receiving these medicines known to prolong the QT interval due to the potential to induce cardiac arrhythmia and serious adverse cardiovascular events.
Fluoxetine
Co-administration of clarithromycin and fluoxetine increases the risk of psychiatric side effects.
Bi-directional drug interactions
Atazanavir
Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Co-administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily) resulted in a 2-fold increase in exposure to clarithromycin and a 70% decrease in exposure to 14-OH-clarithromycin, with a 28% increase in the AUC of atazanavir. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. For patients with moderate renal function (creatinine clearance 30 to 60 ml/min), the dose of clarithromycin should be decreased by 50%. For patients with creatinine clearance <30 ml/min, the dose of clarithromycin should be decreased 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 regarding the concomitant administration of clarithromycin and calcium channel blockers metabolized by CYP3A4 (e.g. verapamil, amlodipine, diltiazem) due to the risk of hypotension. Plasma concentrations of clarithromycin as well as calcium channel blockers may increase due to the interaction. Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients taking clarithromycin and verapamil concomitantly.
Concomitant use of clarithromycin and verapamil increases the risk of cardiac toxicity (prolonged QT interval, torsades de pointes, cardiac arrest).
Itraconazole
Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, leading to a bidirectional drug interaction. Clarithromycin may increase the plasma levels of itraconazole, while itraconazole may increase the plasma levels of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effect.
Saquinavir
Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Concomitant 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 values of saquinavir which were 177% and 187% higher than those seen with saquinavir alone. Clarithromycin AUC and Cmax values were approximately 40% higher than those seen with clarithromycin alone. No dose adjustment is required when the two medicinal products are co-administered for a limited time at the doses/formulations studied. Observations from drug interaction studies using the soft gelatin capsule formulation may not be representative of the effects seen using the 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, consideration should be given to the potential effects of ritonavir on clarithromycin (see section 4.5: Ritonavir).
Patients taking oral contraceptives should be warned that if diarrhoea，vomiting or breakthrough bleeding occur there is a possibility of contraceptive failure.
4.6 Fertility, Pregnancy and lactation
Pregnancy
Data on the use of clarithromycin during the first trimester of more than 200 pregnancies show no clear evidence of teratogenic effects, or of adverse effects on the health of the neonate. Data from a limited number of pregnant women exposed in the first trimester indicate a possible increased risk of abortions. To date no other relevant epidemiological data are available.
Data from animal studies have shown reproductive toxicity (see section 5.3). The risk for humans is unknown. Clarithromycin should only be used during pregnancy after a careful benefit/risk assessment.
Breast-feeding
Clarithromycin and its active metabolite are excreted in breast milk. Therefore, diarrhoea and fungus infection of the mucous membranes could occur in the breast-fed infant, so that nursing might have to be discontinued. The possibility of sensitisation should be considered. The benefit of treatment of the mother should be weighed against the potential risk for the infant.
Fertility
There is no data available on the effect of clarithromycin on fertility in humans. In rats, the limited data available do not indicate any effects on fertility.
4.7 Effects on ability to drive and use machines
There are no data on the effect of clarithromycin on the ability to drive or use machines. The potential for dizziness, vertigo, confusion and disorientation, which may occur with the medication, should be taken into account before patients drive or use machines.
4.8 Undesirable effects
| a. Summary of the safety profile |
| The most frequent and common adverse reactions related to clarithromycin therapy |
| for both adult and paediatric populations are abdominal pain, diarrhoea, nausea, |
| vomiting and altered taste. These adverse reactions are usually mild in intensity and |
| are consistent with the known safety profile of macrolide antibiotics (see section b of |
| section 4.8). |
| There was no significant difference in the incidence of these gastrointestinal adverse |
| reactions during clinical trials between the patient population with or without pre- |
| existing mycobacterial infections. |
b. Tabulated summary of adverse reactions
The following table displays adverse reactions reported in clinical trials and from post-marketing experience with clarithromycin immediate-release tablets, granules for oral suspension, powder for solution for injection, extended-release tablets and modified-release tablets.
The reactions considered at least possibly related to clarithromycin are displayed by system organ class and frequency using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (adverse reactions from post-marketing experience; cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness when the seriousness could be assessed.
| System Organ Class | Very common ≥ 1/10 | Common ≥ 1/100 to < 1/10 | Uncommon ≥ 1/1,000 to < 1/100 | Rare ≥ 1/10,000 to < 1/1,000 | Very rare < 1/10,000 | Not Known* (cannot be estimated from the available data) |
| Infections and infestations | Oral candidiasis | Cellulitis1, candidiasis, gastroenteritis2 , infection3, vaginal infection | Pseudomemb ranous colitis, erysipelas, | |||
| Blood and lymphatic system | Leukopenia, neutropenia4, thrombocythae mia3, eosinophilia4 | Agranulocyto sis, thrombocyto penia | ||||
Immune system disorders | Anaphylactoid reaction1, hypersensitivit y | Anaphylactic reaction. angioedema | ||||
| Metabolism and nutrition disorders | Anorexia, decreased appetite | |||||
| Psychiatric disorders | Insomnia | Anxiety, nervousness3 | Psychotic disorder, confusional state, depersonalisa tion, depression, disorientation , hallucination, abnormal dreams, mania | |||
| Nervous | Dysgeusia, | Loss of | Brain fog | Convulsion, |
system disorders | headache, altered sense of smell | consciousness1 , dyskinesia1, dizziness, somnolence6, tremor | ageusia, parosmia, anosmia, paraesthesia, cramp | |||
| Ear and labyrinth disorders | Vertigo, hearing impaired, tinnitus | Reversible hearing loss | Deafness | |||
| Cardiac disorders | Cardiac arrest1, atrial fibrillation1, electrocardiogr am QT prolonged7, extrasystoles1, palpitations | Torsades de pointes7, ventricular tachycardia7, ventricular fibrillation | ||||
| Vascular disorders | Vasodilation1 | Haemorrhage 8 | ||||
| Respiratory, thoracic and mediastinal disorder | Asthma1, epistaxis2, pulmonary embolism1 | |||||
| Gastrointestin al disorders | Diarrhoea9, vomiting, dyspepsia, nausea, abdominal pain | Oesophagitis1, gastrooesopha geal reflux disease2, gastritis, proctalgia2, stomatitis, glossitis, abdominal distension4, constipation, dry mouth, eructation, flatulence, | Pancreatitis acute, tongue discolouratio n, tooth discolouratio n | |||
| Hepatobiliary disorders | Liver function test abnormal | Hepatic dysfunction (usually transient and reversible), Jaundice, Cholestasis4, hepatitis4, alanine aminotransfera se increased, aspartate aminotransfera se increased, gamma- glutamyltransf | Hepatic failure, jaundice hepatocellula r |
erase increased4 | ||||||
Skin and subcutaneous tissue disorders | Rash, hyperhidrosis | Dermatitis bullous1, pruritus, urticaria, rash maculo- papular3, exanthema | Severe cutaneous adverse reactions (SCAR) (e.g Acute generalised exanthemato us pustulosis (AGEP), Stevens- Johnson syndrome5, toxic epidermal necrolysis5, drug rash with eosinophilia and systemic symptoms (DRESS), acne | |||
Musculoskelet al and connective tissue disorders | Muscle spasms3, musculoskeleta l stiffness1, myalgia2 , arthralgia | Rhabdomyol ysis2,11, myopathy | ||||
Renal and urinary disorders | Blood creatinine increased1, blood urea increased1 | Renal insufficiency | Renal failure, nephritis interstitial | |||
General disorders and administration site conditions | Injection site phlebitis1 | Injection site pain1, injection site inflammation 1 | Malaise4, pyrexia3, asthenia, chest pain4, chills4, fatigue4 | |||
| Investigations | Elevated plasma urea | Elevated plasma creatinine, Elevated liver transaminases, Albumin globulin ratio abnormal1, blood alkaline phosphatase increased4, blood lactate | International normalised ratio increased8, prothrombin time prolonged8, urine colour abnormal |
| dehydrogenase increased4 | |||||||
| 1 ADRs reported only for the powder for concentrate for solution for infusion | |||||||
| 2ADRs reported only for the extended-release tablets | |||||||
| 3 ADRs reported only for the granules for oral suspension | |||||||
| 4 ADRs reported only for the immediate-release tablets | |||||||
| 5, 7, 9, 10 See section a) | |||||||
| 6, 8, 11 See section c) | |||||||
| * Because these reactions are reported voluntarily from a population of uncertain | |||||||
| size, it is not always possible to reliably estimate their frequency or establish a causal | |||||||
| relationship to drug exposure. Patient exposure is estimated to be greater than 1 | |||||||
| billion patient treatment days for clarithromycin. | |||||||
| c. Description of selected adverse reactions | |||||||
| Injection site phlebitis, injection site pain, and injection site inflammation are specific | |||||||
| to the clarithromycin intravenous formulation. | |||||||
| In some of the reports of rhabdomyolysis, clarithromycin was administered | |||||||
| concomitantly with statins, fibrates, colchicine or allopurinol (see section 4.3 and | |||||||
| 4.4). | |||||||
| There have been post-marketing reports of drug interactions and central nervous | |||||||
| system (CNS) effects (e.g. somnolence and confusion) with the concomitant use of | |||||||
| clarithromycin and triazolam. Monitoring the patient for increased CNS | |||||||
| pharmacological effects is suggested (see section 4.5). | |||||||
| There have been rare reports of clarithromycin extended-release tablets in the stool, | |||||||
| many of which have occurred in patients with anatomic (including ileostomy or | |||||||
| colostomy) or functional gastrointestinal disorders with shortened GI transit times. In | |||||||
| several reports, tablet residues have occurred in the context of diarrhoea. It is | |||||||
| recommended that patients who experience tablet residue in the stool and no | |||||||
| improvement in their condition should be switched to a different clarithromycin | |||||||
| formulation (e.g. suspension) or another antibiotic. | |||||||
| Special population: Adverse Reactions in Immunocompromised Patients (see section | |||||||
| e). | |||||||
| d. Paediatric populations | |||||||
| Clinical trials have been conducted using clarithromycin paediatric suspension in | |||||||
| children 6 months to 12 years of age. Therefore, children under 12 years of age | |||||||
| should use clarithromycin paediatric suspension. | |||||||
| Frequency, type and severity of adverse reactions in children are expected to be the | |||||||
| same as in adults. | |||||||
| e. Other special populations | |||||||
| Immunocompromised patients | |||||||
| In AIDS and other immunocompromised patients treated with the higher doses of | |||||||
| clarithromycin over long periods of time for mycobacterial infections, it was often | |||||||
| difficult to distinguish adverse events possibly associated with clarithromycin | |||||||
| administration from underlying signs of Human Immunodeficiency Virus (HIV) | |||||||
| disease or intercurrent illness. | |||||||
| In adult patients, the most frequently reported adverse reactions by patients treated | |||||||
| with total daily doses of 1000 mg and 2000 mg of clarithromycin were: nausea, | |||||||
| vomiting, taste perversion, abdominal pain, diarrhoea, rash, flatulence, headache, | |||||||
| constipation, hearing disturbance, Serum Glutamic Oxaloacetic Transaminase | |||||||
| (SGOT) and Serum Glutamic Pyruvate Transaminase (SGPT) elevations. Additional | |||||||
| low-frequency events included dyspnoea, insomnia and dry mouth. The incidences | |||||||
were comparable for patients treated with 1000 mg and 2000 mg, but were generally about 3 to 4 times as frequent for those patients who received total daily doses of 4000 mg of clarithromycin.
In these immunocompromised patients, evaluations of laboratory values were made by analysing those values outside the seriously abnormal level (i.e. the extreme high or low limit) for the specified test. On the basis of these criteria, about 2% to 3% of those patients who received 1000 mg or 2000 mg of clarithromycin daily had seriously abnormal elevated levels of SGOT and SGPT, and abnormally low white blood cell and platelet counts. A lower percentage of patients in these two dosage groups also had elevated Blood Urea Nitrogen levels. Slightly higher incidences of abnormal values were noted for patients who received 4000 mg daily for all parameters except White Blood Cell.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
| Symptoms |
| Reports indicate that the ingestion of large amounts of clarithromycin orally can be |
| expected to produce gastro-intestinal symptoms. One patient who had a history of |
| bipolar disorder ingested 8 grams of clarithromycin and showed altered mental status, |
| paranoid behaviour, hypokalaemia and hypoxaemia. |
| Treatment |
| Adverse reactions accompanying overdosage should be treated by the prompt |
| elimination of unabsorbed medicinal product and supportive measures. As with other |
| macrolides, clarithromycin serum levels are not expected to be appreciably affected |
| by haemodialysis or peritoneal dialysis. |
| In the case of overdosage, treatment should be discontinued and all other appropriate |
| supportive measures should be instituted. |
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
| Pharmacotherapeutic group: |
| Antibacterial for systemic use, macrolide, ATC code: J01FA09 |
| Mechanism of action |
| Clarithromycin is an antibiotic belonging to the macrolide antibiotic group. It exerts |
| its antibacterial action by selectively binding to the 50S ribosomal sub-unit of |
| susceptible bacteria preventing translocation of activated amino acids. It inhibits the |
| intracellular protein synthesis of susceptible bacteria. |
| The 14-hydroxy metabolite of clarithromycin, a product of parent drug metabolism |
| also has anti-microbial activity. The metabolite is less active than the parent |
compound for most organisms, including Mycobacterium spp. An exception is Haemophilus influenzae where the 14-hydroxy metabolite is two-fold more active than the parent compound.
Resistance
The mechanisms of acquired resistance in macrolides are: efflux of active substance by an active pump mechanism, inducible or constitutive production of a methylase enzyme that modifies the ribosomal target, hydrolysis of macrolides by esterases, chromosomal mutations that alter a 50S ribosomal protein. Cross-resistance between clarithromycin and other macrolides and clindamycin and lincomycin may therefore occur. Methicillin-resistant and oxacillin-resistant staphylococci (MRSA) and penicillin-resistant Streptococcus pneumoniae are resistant to all currently available Beta-lactam antibiotics and macrolides such as clarithromycin.
Susceptibility testing breakpoints
MIC (minimum inhibitory concentration) interpretive criteria for susceptibility testing have been established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for clarithromycin and are listed here: https://www.ema.europa.eu/documents/other/minimum-inhibitory-concentration-mic-breakpoints_en.xlsx.
Susceptibility
The prevalence of acquired resistance may vary geographically and over time for selected species and local information on resistance is desirable, particularly when treating severe infections. Expert advice should be sought as needed when the local prevalence of resistance is such that the usefulness of a medicinal product, at least for some types of infections, is questionable. Clarithromycin has a pronounced effect on a wide range of aerobic, anaerobic, Gram-positive, Gram-negative and acid-resistant bacteria.
The activity of 14(R)-hydroxyclarithromycin is greater than clarithromycin against Haemophilus influenzae. In vitro studies suggest that 14(R)-hydroxyclarithromycin -and its parent molecule have additive activity against H. influenzae.
Commonly susceptible species
Aerobic, Gram-positive microorganisms
Streptococcus agalactiae
Streptococcus pyogenes (Group A beta-haemolytic streptococci) Streptococcus viridans
Streptococcus pneumoniae
Staphylococcus aureus (methicillin susceptible)
Listeria monocytogenes
Aerobic, Gram-negative microorganisms
Bordetella pertusis
Haemophilus influenzae
Haemophilus parainfluenzae
Helicobacter pylori
Campylobacter jejuni
Moraxella catarrhalis
Neisseria gonorrhoeae
Legionella spp.
Anaerobic microorganisms
Clostridium perfrigens
Bacterioides fragilis
Peptococcus/Peptostreptococcus spp.
Propionibacterium acnes
Other microorganisms
Mycoplasma pneumoniae
Chlamydia trachomatis
Chlamydia pneumoniae
Ureaplasma urealyticum
Mycobacterium spp.
Other information
Susceptibility and resistance of Streptococcus pneumoniae and Streptococcus spp. to clarithromycin can be predicted by testing erythromycin.
5.2 Pharmacokinetic properties
| Distribution |
| Following IV administration, the blood levels of clarithromycin achieved are well in |
| excess of the MIC 90s for the common pathogens and the levels of 14- |
| hydroxyclarithromycin exceed the necessary concentrations for important pathogens, |
| e.g. H. influenzae. The microbiologically active metabolite 14-hydroxyclarithromycin |
| is formed by first pass metabolism as indicated by lower bioavailability of the |
| metabolite following IV administration. |
Clarithromycin gives good penetration into different compartments. Clarithromycin provides tissue concentrations that are several times higher than the circulating active substance levels. Increased levels have been found in both tonsillar and lung tissue. Clarithromycin also penetrates the gastric mucus.
Clarithromycin is 80% bound to plasma proteins at therapeutic levels.
Serum half-life
The serum half-life of the active 14-(R)-hydroxy metabolite ranges between 5 to 6 hours.
Biotransformation and elimination
| Clarithromycin is rapidly and extensively metabolised in the liver. Metabolism |
| involves mainly N-dealkylation, oxidation and stereospecific hydroxylation at |
| position C-14. |
| Linearity |
| The pharmacokinetics of clarithromycin and the 14-hydroxy metabolite are non- |
| linear; steady state is achieved by day 3 of IV dosing. Following a single 500 mg IV |
| dose over 60 minutes, about 33% clarithromycin and 11% 14-hydroxyclarithromycin |
| is excreted in the urine at 24 hours. |
5.3 Preclinical safety data
| In 4-week-studies in animals, toxicity of clarithromycin was found to be related to the |
| dose and to the duration of the treatment. In all species, the first signs of toxicity were |
| observed in the liver, in which lesions were seen within 14 days in dogs and monkeys. |
| The systemic levels of exposure, related to this toxicity, are not known in detail, but |
| toxic doses (300 mg/kg/day) were clearly higher than the therapeutic doses |
| recommended for humans. Other tissues affected included the stomach, thymus and |
| other lymphoid tissues as well as the kidneys. At near therapeutic doses conjunctival |
| injection and lacrimation occurred only in dogs. At a dose of 400mg/kg/day some |
| dogs and monkeys developed corneal opacities and/or oedema. |
| In vitro and in vivo studies showed that clarithromycin did not have genotoxic |
| potential. |
| No mutagenic effects were found in in vitro- and in vivo -studies with clarithromycin. |
| Studies on reproduction toxicity showed that administration of clarithromycin at |
| doses 2x the clinical dose in rabbit (i.v.) and 10x the clinical dose in monkey (p.o.) |
| resulted in an increased incidence of spontaneous abortions. These doses were related |
| to maternal toxicity. No embryotoxicity or teratogenicity was generally noted in rat |
| studies. However, cardiovascular malformations were observed in two studies in rats |
| treated with doses of 150 mg/kg/d. |
| In mice at doses 70x the clinical dose, cleft palate occurred at varying incidence (3- |
| 30%). |
| Clarithromycin has been found in the milk of lactating animals. |
| In 3-day old mice and rats, the LD50 values were approximately half those in adult |
| animals. Juvenile animals presented similar toxicity profiles to mature animals |
| although enhanced nephrotoxicity in neonatal rats has been reported in some studies. |
| Slight reductions in erythrocytes, platelets and leukocytes have also been found in |
| juvenile animals. |
| Clarithromycin has not been tested for carcinogenicity. |
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium hydroxide (pH adjuster)
6.2 Incompatibilities
None known.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
- 6. PHARMACEUTICAL PARTICULARS
6.3 Shelf life
Unopened: 5 years
After reconstitution:
Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C / 48 hours at 2-8°C for the reconstituted solution.
After dilution:
Chemical and physical in-use stability has been demonstrated 6 hours at 25°C / 48 hours at 2-8°C for the final infusion solution.
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 would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution / dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
For storage conditions after reconstitution/dilution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
Uncoloured clear glass vial type I (15 ml), sealed with bromobutyl rubber stopper and aluminium cap with plastic flip-off seal.
The following pack sizes are available for Clarithromycin 500 mg powder for concentrate for solution for infusion:
1, 5 or 10 vial(s) containing 500 mg of clarithromycin.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Clarithromycin 500 mg powder for concentrate for solution for infusion should be administered into one of the larger proximal veins as an IV infusion over 60 minutes, using a solution concentration of about 2 mg/ml. Clarithromycin should not be given as a bolus or an intramuscular injection.
Preparation for use
Prepare all solutions using aseptic techniques.
Reconstitution (Step 1)
Clarithromycin 500 mg powder for concentrate for solution for infusion is reconstituted with 10 ml of sterile water for injections, a solution with a concentration of 50 mg/ml is obtained. Shake until the vial contents have dissolved. The reconstitution time is not more than 7 minutes and the solution is clear to slightly opalescent, colourless to slightly yellow. Use only water for injections, as other diluents may cause precipitation during reconstitution. Do not use diluents containing preservatives or inorganic salts.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
Dilution (Step 2)
The reconstituted solution should be added to 250 ml of a suitable intravenous diluent prior to infusion: 0.9% Sodium chloride, 5% Dextrose, 5% Dextrose in 0.3% Sodium chloride, 5% Dextrose in 0.45% Sodium chloride, 5% Dextrose in Ringer’s lactate solution and Ringer’s lactate solution. The solution after dilution is clear to slightly opalescent, colourless to slightly yellow.
The concentration of Clarithromycin for the final solution for infusion is 2 mg/ml.
For storage conditions after dilution of the medicinal product, see section 6.3.
IMPORTANT: BOTH DILUENT STEPS (1 and 2) SHOULD BE COMPLETED BEFORE USE.
For single use only.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
hameln pharma ltd
Nexus, Gloucester Business Park
Gloucester, GL3 4AG
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 01502/0135
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
15/12/2022
10 DATE OF REVISION OF THE TEXT
22/07/2026