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Claritromycine Sandoz 125 mg/5 ml, granulaat voor orale suspensie

RegistratienummerRVG 108082
ProcedurenummerNL/H/2100/001
Farmaceutische vormGranulaat voor orale suspensie
ToedieningswegOraal gebruik
ATCJ01FA09 - Clarithromycin
AfleverstatusUitsluitend recept
Registratiedatum20 januari 2012
Registratiehouder
Veluwezoom 22
1327 AH ALMERE
Werkzame stof(fen)
Hulpstof(fen)COPOLYMEER VAN ETHYLACRYLAAT-METHACRYLZUUR (1:1)
FRUIT-PUNCH SMAAKSTOFPOEDER
GLYCEROLMONOSTEARAAT (E 471)

KALIUMSORBAAT (E 202)

MALTODEXTRINE
MALTOL (E 636)
NATRIUMZETMEELOCTENYLSUCCINAAT (E 1450)
POLOXAMEER 188
POLYSORBAAT 80 (E 433)
POVIDON K 30 (E 1201)

SILICIUMDIOXIDE (E 551)
TITAANDIOXIDE (E 171)
TRIETHYLCITRAAT (E 1505)
XANTHAANGOM (E 415)
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1.3.1.1 Summary of Product Characteristics 
 

NAME OF THE MEDICINAL PRODUCT 
 

 
 

QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
After reconstitution 1 ml oral suspension contains 25 mg clarithromycin, 
5 ml oral suspension contain 125 mg clarithromycin. 
 
The product contains 2.4 g sucrose per 5 ml ready- for- use suspension. 
 
For a full list of excipients, see section 6.1. 
 
 

PHARMACEUTICAL FORM 
 
Granules for oral suspension. 
 
White to beige granules. 
 
 

CLINICAL PARTICULARS 
 
4.1  Therapeutic indications 
 
Clarithromycin 25 mg/ml granules for oral suspension is indicated in adults, adolescents and 
children, 6 months to 12 years, for the treatment of the following acute and chronic infections, 
when caused by clarithromycin susceptible organisms. 
 
•  Infections of the upper respiratory tract such as tonsillitis/pharyngitis, as an alternative 

•  Acute otitis media in children. 
•  Infections of the lower respiratory tract such as community acquired pneumonia. 
•  Sinusitis and acute exacerbation of chronic bronchitis in adults and adolescents over 12 
years of age 
•  Skin infections and soft tissue infections of mild to moderate severity. 
 
In appropriate combination with antibacterial therapeutic regimens and an appropriate ulcer 
healing medicinal product for the eradication of  in adult patients with H. 
pylori
 associated ulcers. See section 4.2. 
 

Consideration should be given to official guidance on the appropriate use of antibacterial 
agents. 
 
4.2  Posology and method of administration 
 
The dosage of Clarithromycin 25 mg/ml granules for oral suspension depends on the clinical 
condition of the patient and has to be defined in any case by the physician. 
 
Adults and adolescents: 
Standard dosage: The usual dose is 250 mg twice daily. 
High dosage treatment (severe infections): The usual dose may be increased to 500 mg twice 
daily in severe infections. 
 
Elimination of Helicobacter pylori in adults: 
In patients with gastro-duodenal ulcers due to H. pylori infection clarithromycin as part of the 
first line triple therapy is given in a dosage of 500 mg twice daily. The national 
recommendations for Helicobacter pylori eradication have to be considered. 
 
Dosage in renal functional impairment: 
The maximum recommended dosages should be reduced proportionately to renal impairment. 
 
At creatinine clearance rate of less than 30 ml/min, the dosage should be halved to 250 mg 
daily or in the most severe infections to 250 mg twice daily. The duration of treatment should 
not exceed 14 days in these patients. 
 
Children 6 months to 12 years of age: 
The recommended dose is 7.5 mg/kg twice a day.  
 
Weight 
 
Age   
 
Dosage 
 
 
 
8 – 11 kg 
 
1 – 2 years 
 
2.5 ml twice daily 
12 – 19 kg 
 
2 – 4 years 
 
5.0 ml twice daily 
20 – 29 kg 
 
4 – 8 years 
 
7.5 ml twice daily 
30 – 40 kg 
 
8 – 12 years   
10.0 ml twice daily 
 
Children weighing less than 8 kg should be treated based on their bodyweight. 
Clinical trials have been conducted using clarithromycin pediatric suspension in children 6 
months to 12 years of age. Therefore, children under 12 years of age should use 
clarithromycin pediatric suspension (granules for oral suspension). 
There is limited experience of treatment of children below 6 months of age. 
For the indication community acquired pneumonia effect in children under 3 years of age is 
not documented. 
 

In renal insufficiency, especially if the creatinine clearance is < 30 ml/min, the dose must be 
halved, i.e. 7.5 mg/kg once a day, and the duration of treatment should not exceed 14 days. 
 
Duration of therapy: 
The duration of therapy with Clarithromycin 25 mg/ml granules for oral suspension depends 
on the clinical condition of the patient. The duration of therapy has in any case to be 
determined by the physician.  
 
•  The usual duration of treatment of children up to 12 years of age is 5 to 10 days. 
•  The usual duration of treatment of adults and adolescents is 6 to 14 days. 
•  Therapy should be continued at least for 2 days after symptoms have subsided. 
•  In streptococcus pyogenes (as a beta-haemolytic streptococcal) infections the duration 
of therapy should be at least 10 days.  
•  Combination therapy for the eradication of H. pylori infection, e.g. clarithromycin 500 

20 mg twice daily should be continued for 7 days. 
 
Method of administration: 
Before administration the granules must be reconstituted with water, see section 6.6. For 
administration after reconstitution an oral PE/PP-measuring syringe or a PP-measuring spoon 
are used.  
 
Granules of the oral suspension can cause a bitter aftertaste when remaining in the mouth. 
This can be avoided by eating or drinking something immediately after the intake of the 
suspension 
 
Clarithromycin may be given irrespective of food intake. Food does not affect the extent of 
bioavailability. Food does only slightly delay the onset of absorption of clarithromycin.  
 
4.3  Contraindications 
 
Clarithromycin 25 mg/ml granules for oral suspension must not be used in patients with a 
hypersensitivity to the active substance, other macrolide antibiotics or to any of the 
excipients. 
 
Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is 
contraindicated, as this may result in ergot toxicity. 
Concomitant administration of clarithromycin and any of the following active substances is 

prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular 
fibrillation and Torsade de Pointes (see section 4.5). 
 
Clarithromycin 25 mg/ml granules for oral suspension must not be administered to 
hypokalemic patients (risk of prolongation of QT-time, see section 4.4). 

 
Clarithromycin must not be given to patients with history of QT prolongation or ventricular 
cardiac arrhythmia, including torsades de pointe (see sections 4.4 and 4.5). 
 


agents should be discontinued during clarithromycin treatment (see section 4.4).  
 
Clarithromycin must not be used in patients who suffer from severe hepatic failure in 
combination with renal impairment. 
 
4.4  Special warnings and precautions for use 
 
The physician should not prescribe clarithromycin to pregnant women without carefully 
weighing the benefits against risk, particularly during the first three months of pregnancy (see 
section 4.6). 
 
In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson 
Syndrome, and toxic epidermal necrolysis, clarithromycin therapy should be discontinued 
immediately and appropriate treatment should be urgently initiated. 
 
Clarithromycin is mainly excreted by the liver. Therefore, caution should be taken in 
administering clarithromycin to patients with impaired hepatic function. 
 
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. 
 
When renal function is poor, dosage of clarithromycin should be suitably reduced depending 
on the degree of the impairment (see section 4.2). In elderly patients, the possibility of renal 
impairment should be considered. Caution is advised with severe renal insufficiency. 
 
Clarithromycin therapy for H. pylori may select for drug-resistant organisms. 
 
Patients who are hypersensitive to lincomycin or clindamycin may also be hypersensitive to 
clarithromycin. Therefore, caution is required when prescribing clarithromycin for such 
patients. 
 
Attention should also be paid to the possibility of cross resistance between clarithromycin and 
other macrolide drugs, as well as lincomycin and clindamycin. 
 

Prolonged or repeated use of clarithromycin may result in superinfections with non-
susceptible bacteria or fungi. In case of superinfection, clarithromycin therapy should be 
stopped and appropriate therapy should be instituted.  
 
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including 
macrolides, and may range in severity from mild to life-threatening. Clostridium difficile-
associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents 
including clarithromycin, and may range in severity from mild diarrhea 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 
diarrhea 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. Drugs inhibiting 
peristalsis should be avoided.  
 
Due to a risk of increased QT-interval, clarithromycin should be used with caution in patients 
with a coronary artery disease, severe cardiac insufficiency, non-compensated hypokalemia 
and/or hypomagnesemia, bradycardia (< 50 bpm), or when co-administered with other 
medicinal products with a QT-prolonging effect (see section 4.5). Clarithromycin must not be 
used in patients with congenital or documented acquired QT prolongation or history of 
ventricular arrhythmia (see section 4.3). 
 


with renal insufficiency. Deaths have been reported in some such patients (see section 4.5). If 
concomitant administration of colchicine and clarithromycin is necessary, patients should be 
monitored for clinical symptoms of colchicine toxicity. 
 
Caution is advised regarding concomitant administration of clarithromycin and 

 
Caution is advised regarding concomitant administration of clarithromycin with other 
ototoxic drugs, especially with aminoglycosides. Monitoring of vestibular and auditory 
function should be carried out during and after treatment. 
 
Clarithromycin should be used  with caution whenever indicated for use in patients receiving 
treatment with an inducer of CYP3A4 (see section 4.5). 
 
Clarithromycin is an inhibitor of CYP3A4, and concomitant use with other medicinal 
products that are metabolised to a large extent by this enzyme should be restricted to 
situations where it is clearly indicated (see section 4.5). 
 

HMG-CoA reductase inhibitors: Concomitant use of clarithromycin with lovastatin or 
simvastatin is contraindicated (see section 4.3). As with other macrolides, clarithromycin has 
been reported to increase concentrations of HMG-CoA reductase inhibitors (see section 4.5). 
Rare reports of rhabdomyolysis have been reported in patients taking these drugs 
concomitantly. Patients should be monitored for signs and symptoms of myopathy. Rare 


or rosuvastatin should be administered in the lowest possible doses. Adjustment of the statin 


 

hypoglycemic agents and/or insulin can result in significant hypoglycemia. With certain 

inhibition of CYP3A enzyme by clarithromycin may be involved and could cause 

 
Oral anticoagulants: There is a risk of serious hemorrhage 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. 
 
Exacerbation or aggravation of Myasthenia gravis may occur. 
 
 
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.  
 
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 drug 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
 (erythrasma), acne vulgaris, and erysipelas and in situations where penicillin 
treatment cannot be used. 
 
This medicinal product contains 2.4 g sucrose per 5 ml ready-for-use suspension. This should 
be taken into account in patients with diabetes mellitus.  
 
Patients with rare hereditary problems of fructose intolerance, glucose-galactose 
malabsorption or sucrase-isomaltase insufficiency should not take this medicine. 

 
4.5  Interaction with other medicinal products and other forms of interaction 
 
The use of the following drugs is strictly contraindicated due to the potential for severe 
drug interaction effects: 
 

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). 
 

levels of terfenadine which has occasionally been associated with cardiac arrhythmias such as 
QT prolongation, ventricular tachycardia, ventricular fibrillation and torsades de pointes (see 
section 4.3). In one study in 14 healthy volunteers, the concomitant administration of 
clarithromycin and terfenadine resulted in a two to three 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. 
 
Ergotamine/dihydroergotamine
Postmarketing 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 these medicinal products is contraindicated 
(see section 4.3). 
 
HMG –CoA reductase inhibitors 
Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see 
sections 4.3 and 4.4). 
 
The effect of other medicinal products on clarithromycin 
 
Clarithromycin is an inhibitor of the metabolising enzyme CYP3A4 and the transport protein 
P-glycoprotein. The degree of inhibition with different CYP3A4 substrates is difficult to 
predict. Hence, clarithromycin should not be used during treatment with other medicinal 
products that are substrates for CYP3A4, unless plasma levels, therapeutic effect or adverse 
events of the CYP3A4 substrate can be closely monitored. A dose reduction may be 
necessary for medicinal products that are substrates for CYP3A4 if co-administered with 
clarithromycin. Alternatively, treatment with these products may be interrupted during 
clarithromycin treatment. 
 

Clarithromycin is metabolised by the enzyme CYP3A4. Hence, strong inhibitors of this 
enzyme may inhibit the metabolism of clarithromycin, resulting in increased plasma 
concentrations of clarithromycin. 
 
Products that are inducers of CYP3A4 (e.g. rifampicin, phenytoin, carabamazepin, 
phenobarbital, St. Johns wort) may induce the metabolism of clarithromycin. This may result 
in sub-therapeutic levels of clarithromycin leading to a reduced efficacy. When 
clarithromycin is clearly indicated it might be necessary to increase the dose of 
clarithromycin and monitor the efficacy and safety of clarithromycin carefully. Furthermore 
monitoring the plasma levels of the CYP3A4 inducer might be necessary because the latter 
could be increased owing to the inhibition of CYP3A4 by clarithromycin (see also the 
relevant product information for the CYP3A4 inducer administered). 
Concomitant administration of rifabutin and clarithromycin resulted in an increase and 
decrease, respectively, in serum levels, followed by an increased risk of uveitis. 
 
The following drugs are known or suspected to affect circulating concentrations of 
clarithromycin; clarithromycin dosage adjustment or consideration of alternative treatments 
may be required. 
 


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. 
 

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 (200 mg three times daily) have been shown to inhibit the metabolism of 
clarithromycin (500 mg twice daily), with an increase in Cmax, Cmin and AUC of 31, 182 and 
77%, respectively, when co-administered with ritonavir. Formation of the active 14-OH-
hydroxy metabolite was almost completely inhibited. A general dose reduction is probably 
not required in patients with normal renal function, but the daily dose of clarithromycin 
should not exceed 1 g. Dose reduction should be considered in patients with renal 
impairment. For patients with a creatinine clearance of 30 to 60 ml/min, the clarithromycin 

dose should be reduced with 50%, and at a creatinine clearance of < 30 ml/min the dose 
should be reduced with 75%.  
 
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 

 
Interaction in eradication of H.pylori regimens 
Although the plasma concentrations of clarithromycin and omeprazole may be increased 
when they are administered concurrently, no adjustment to the dosage is necessary. At the 
dosages recommended, there is no clinically significant interaction between clarithromycin 
and lansoprazole. Increased plasma concentrations of clarithromycin may also occur when it 

There are no pharmacokinetic interactions with relevant antibiotics which are used in H. 
pylori
 eradication therapy.   
 
Effect of clarithromycin on other medicinal products 
 
CYP3A-based interactions
Co-administration of clarithromycin, known to inhibit CYP3A, and a drug primarily 
metabolized by CYP3A may be associated with elevations in drug concentrations that could 
increase or prolong both therapeutic and adverse effects of the concomitant drug. 
Clarithromycin should be used with caution in patients receiving treatment with other drugs 
known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow 

enzyme.  
 
Dosage adjustments may be considered, and when possible, serum concentrations of drugs 
primarily metabolized by CYP3A should be monitored closely in patients concurrently 
receiving clarithromycin. 
 
The following drugs or drug classes are known or suspected to be metabolized by the same 




mechanisms through other isozymes within the cytochrome P450 system include phenytoin, 
theophylline and valproate.  
 
Antiarrhythmics
Cases with torsades de pointes has been reported in patients where clarithromycin has been 
co-administered with quinidine or disopyramid. These combinations should therefore be 
avoided, or plasma levels of quinidine or disopyramid closely monitored to allow dose 

adjustment. Electrocardiograms should be monitored for QT prolongation during co-
administration of clarithromycin with these drugs. 
Caution is warranted when clarithromyin is administered to patients treated taking other 
medicinal products with the potential to prolong QT (see section 4.4). 
 

Concomitant use of oral clarithromycin and cyclosporin or tacrolimus have resulted in more 
than a 2-fold increase of the Cmin-levels of both cyclosporin and tacrolimus. Similar effects 
are also expected for sirolimus. When initiating treatment with clarithromycin in patients 
already receiving any of these immunosuppressive agents, cyclosporin, tacrolimus or 
sirolimus plasma levels must be closely monitored and their doses decreased as necessary. 
When clarithromycin is discontinued in these patients, close monitoring of plasma levels of 
cyclosporin, tacrolimus or sirolimus, is again necessary to guide dose adjustment. 
 
Warfarin 
The use of clarithromycin in patients receiving warfarin may result in potentiation of the 
effects of warfarin. Prothrombin time should be frequently monitored in these patients (see 
section 4.4 and 4.8). 
 
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.  
 

Each of these phosphodiesterase inhibitors is metabolized, at least in part, by CYP3A, and 
CYP3A may be inhibited by concomitantly administered clarithromycin. Co-administration 


dosages should be considered when these drugs are co-administered with clarithromycin. 
 

Results of clinical studies indicate there was a modest but statistically significant (p ï€ 0.05) 
increase of circulating theophylline or carbamazepine levels when either of these drugs were 
administered concomitantly with clarithromycin. Dose reduction may need to be considered.  
 


(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 metabolizer population. 
 


midazolam AUC was increased 2.7-fold after intravenous administration of midazolam and 7-
fold after oral administration. Concomitant administration of oral midazolam and 
clarithromycin should be avoided. If intravenous midazolam is co-administered with 
clarithromycin, the patient must be closely monitored to allow dose adjustment. The same 
precautions should also apply to other benzodiazepines that are metabolised by CYP3A4, 
especially triazolam but also alprazolam. For benzodiazepines which are not metabolised by 

 
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 
 
Colchicin 
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. Patients should be monitored for 
clinical symptoms of colchicine toxicity (see section 4.4). 
 
 
Digoxin and other active substances transported by P-glycoprotein 
Claritromycin is a potent inhibitor of the transport protein P-glycoprotein (Pgp). This could 
give rise to increased plasma concentrations of active substances which are transported by 
this transporter and may also increase distribution of such active substances to organs having 
Pgp as an distribution barrier e.g. CNS. The concentration of the Pgp substrate digoxin may 
be increased when co-administered with clarithromycin.  Elevated digoxin serum 
concentrations in patients receiving clarithromycin and digoxin concomitantly have 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. 
 
 

Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV infected 
adult patients may result in decreased steady-state zidovudine levels. 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 drugs not thought to be metabolized by CYP3A (e.g. phenytoin 
and valproate). Serum level determinations are recommended for these drugs when 
administered concomitantly with clarithromycin. Increased serum levels have been reported. 
 
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. 
 
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. 
 
 
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 drugs 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. 
 

Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients taking 
clarithromycin and verapamil concomitantly. 
 
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. 
 
Lactation 
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 born in 
mind. The benefit of treatment of the mother should be weighed against the potential risk for 
the infant. 
 
 
4.7  Effects on ability to drive and use machines 
 
There are no data available on the effect of clarithromycin on the ability to drive or use 
machines. When performing these activities the possible occurrence of the adverse reactions 
dizziness, vertigo, confusion and disorientation should be taken into account. 
 
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 pediatric populations are abdominal pain, diarrhea, nausea, vomiting and taste 
perversion. 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 preexisting mycobacterial 
infections. 
 
b. Tabulated summary of adverse reactions 
 
In this section undesirable effects are defined as follows:  
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 
Common: Oral monilia 
Uncommon: Candidiasis, infection, vaginal infection 
Not known: Erysipelas, erythrasma 
As with other antibiotics, prolonged use may result in the overgrowth of non-susceptible 
organisms. 
 
Blood and lymphatic system disorders 
Uncommon: Leucopenia, thrombocythemia 
Very rare: Thrombocytopenia 
Not known: Agranulocytosis 
 
Immune system disorders 
Uncommon: Allergic reactions ranging from urticaria and mild skin eruptions to anaphylaxis 
 
Metabolism and nutrition disorders 
Uncommon: Anorexia, decreased appetite 
 
Psychiatric disorders 
Common: Insomnia 
Uncommon: Anxiety nervousness, screaming 
Very rare: Hallucinations, psychotic disorder, disorientation, depersonalisation, abnormal 
dreams and confusional state 
Not known: Depression 
 
Nervous system disorders 
Common: Headache, smell alteration, taste perversion, dysgeusia 
Uncommon: Dizziness, tremor 
Very rare: Paraesthesia, convulsions 
Not known: Ageusia, parosmia, anosmia 

 
Ear and labyrinth disorders 
Uncommon: Vertigo, hearing impaired, tinnitus 
Very rare: Reversible hearing loss 
Not known: Deafness 
 
Cardiac disorders 
Uncommon: Palpitations 
Very rare: QT prolongation, ventricular tachycardia and Torsades de Pointes 
 
Gastrointestinal disorders 
Common: Nausea, diarrhoea, vomiting, abdominal pain, dyspepsia, stomatitis, glossitis, 
reversible tooth and tongue discoloration 

Very rare: Pancreatitis. Pseudomembranous colitis has been reported very rarely with 
clarithromycin, and may range in severity from mild to life threatening.  
 
Hepatobiliary disorders 
Uncommon: Hepatic dysfunction, which is usually transient and reversible, hepatitis and 
cholestasis with or without jaundice 
Very rare: Fatal hepatic failure has been reported particularly in patients with pre-existing 
liver disease or taking other hepatotoxic medicinal products. 
 
Skin and subcutaneous tissue disorders 
Common: Rash, hyperhidrosis 
Uncommon: Pruritus, urticaria, rash maculo-papular 
Very rare: Stevens-Johnson syndrome and toxic epidermal necrolysis 
Not known: Drug rash with eosinophilia and systemic symptoms (DRESS), acne 
 
Musculoskeletal, connective tissue and bone disorders 
Uncommon: Arthralgia, myalgia, muscle spasms 
Not known: Myopathy 
 
Renal and urinary disorders 
Very rare: Interstitial nephritis, renal failure. 
 
General disorders and administration site conditions 
Uncommon: Pyrexia, asthenia 
 
Investigations 
Common: Elevated blood urea nitrogen, liver function test abnormal 
Uncommon: Prolongation of prothrombin time, elevated serum creatinine, alanine 
aminotransferase increased, aspartate aminotransferase increased 

Very rare: Hypoglycaemia has been observed especially after concomitant administration 
with antidiabetic medicinal products and insulin 
Not known: Urine color abnormal 
 
 
c. Description of selected adverse reactions 
 
In very rare instances, hepatic failure with fatal outcome has been reported and generally has 
been associated with serious underlying diseases and/or concomitant medications (see section 
4.4). 
 
A special attention to diarrhea should be paid as Clostridium difficile-associated diarrhea 
(CDAD) has been reported with use of nearly all antibacterial agents including 
clarithromycin, and may range in severity from mild diarrhea to fatal colitis (see section 4.4). 
 
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including 
clarithromycin, and may range in severity from mild to life threatening. Therefore, it is 
important to consider this diagnosis in patients who present with diarrhea subsequent to the 
administration of antibacterial agents (see section 4.4). 
 
In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson 
Syndrome and toxic epidermal necrolysis, clarithromycin therapy should be discontinued 
immediately and appropriate treatment should be urgently initiated (see section 4.4). 
 
As with other macrolides, QT prolongation, ventricular tachycardia, and torsade de pointes 
have rarely been reported with clarithromycin (see section 4.4 and 4.5). 
 
In some of the reports of rhabdomyolysis, clarithromycin was administered concomitantly 

 
There have been post-marketing reports of colchicine toxicity with concomitant use of 
clarithromycin and colchicine, especially in elderly and/or patients with renal insufficiency, 
some with a fatal outcome (see sections 4.4 and 4.5). 
 
There have been rare reports of hypoglycemia, some of which have occurred in patients on 
concomitant oral hypoglycemic agents or insulin (see section 4.4 and 4.5). 
 
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 is a risk of serious hemorrhage and significant elevations in INR and prothrombin time 
when clarithromycin is co-administered with warfarin. INR and prothrombin times should be 

frequently monitored while patients are receiving clarithromycin and oral anticoagulants 
concurrently (see section 4.4 and 4.5). 
 
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, diarrhea, 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. 
 
4.9  Overdose 
 

Symptoms of intoxication: 
Reports indicate that the ingestion of large amounts of clarithromycin can be expected to 
produce gastrointestinal symptoms. Symptoms of overdose may largely correspond to the 
profile of adverse reactions. One patient who had a history of bipolar disorder ingested 8 
grams of clarithromycin and showed altered mental status, paranoid behaviour, 
hypokaliaemia and hypoxaemia. 
 
Therapy of intoxication: 
There is no specific antidote on overdose. Serum levels of clarithromycin can not be reduced 
by haemodialysis or peritoneal dialysis. 
 
Adverse reactions accompanying overdose should be treated by gastric lavage and supportive 
measures. Severe acute allergic reactions may be seen very rarely, e.g. anaphylactic shock. At 
first signs of hypersensitivity reactions therapy with clarithromycin must be discontinued and 
the required measures should be initiated immediately. 
 
 

PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
General properties 
 
Pharmacological-therapeutical group: 
Macrolides. ATC Code J01FA09. 
 
Mechanism of action: 
Clarithromycin, a semi-synthetic derivative of erythromycin, exerts its anti-bacterial action by 
binding to the 50s ribosomal sub-unit of susceptible bacteria and suppresses protein synthesis. 
It is highly potent against a wide variety of aerobic and anaerobic gram-positive and gram-
negative organisms. The minimum inhibitory concentrations (MICs) of clarithromycin are 
generally two-fold lower than the MICs of erythromycin. 
 
The 14-hydroxy metabolite of clarithromycin also has antimicrobial activity. The MICs of 
this metabolite are equal or two-fold higher than the MICs of the parent compound, except for 
 where the 14-hydroxy metabolite is two-fold more active than the 
parent compound. 
 
PK/PD relationship 
Clarithromycin is extensively distributed in body tissues and fluids. Because of high tissue 
penetration, intracellular concentrations are higher than serum concentrations. 
The most important pharmacodynamic parameters for predicting macrolide activity are not 
conclusively established. The time above MIC (T/MIC) may correlate best with efficacy for 
clarithromycin, however since clarithromycin concentrations achieved in respiratory tissues 

and epithelial lining fluids exceed those in plasma, using parameters based on plasma 
concentrations may fail to predict accurately the response for respiratory tract infections. 
 
Mechanism of resistance: 
Resistance mechanisms against macrolide antibiotics include alteration of the target site of 
the antibiotic or are based on the modification and/or active efflux of the antibiotic. 
Resistance development can be mediated via chromosomes or plasmids, be induced to exist 
constitutively. Macrolide-resistant bacteria generate enzymes which lead to methylation of 
residual adenine at ribosomal RNA and consequently to inhibition of the antibiotic binding to 
the ribosome. 
Macrolide-resistant organisms are generally cross-resistant to lincosamides and 
streptogramine B based on methylation of the ribosomal binding site. Clarithromycin ranks 
among the strong inducers of this enzyme as well. Furthermore, macrolides have a 
bacteriostatic action by inhibiting the peptidyl transferase of ribosomes. 
A complete cross-resistance exists among clarithromycin, erythromycin and azithromycin. 
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. 
 
Breakpoints 
The following breakpoints for clarithromycin, separating susceptible organisms from resistant 
organisms, have been established by the European Committee for Antimicrobial 
Susceptibility Testing (EUCAST) 2010-12-20 (v 1.2): 
 
 
Species-related breakpoints for 
clarithromycin B,C
Pathogens 
Susceptible â‰¤ 
Resistant > (mg/L) 
(mg/L) 
Enterobacteriaceae 
- - 
Pseudomonas spp. 
- - 
Acinetobacter spp. 
- - 
Staphylococcus spp. 


Enterococcus spp. 
- - 
Streptococcus groups A, B, C, G 
0,25 
0.5 
Streptococcus pneumoniae D
0.25 0.5 
Other streptococci 
IE 
IE 
Haemophilus influenzae 
1 32 
Moraxella catarrhalis 
0.25 0.5 
Neisseria gonorrhoeae 
- - 
Neisseria meningitidis 
- - 
Gram-positive anaerobes (except 
- - 
Clostridium difficile) 
Gram-negative anaerobes 


Non-species related break-points A
IE IE 

A. Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are 
independent of MIC distributions of specific species. They are for use only for species not mentioned in the 
table or footnotes However, pharmacodynamic data for calculation of macrolide, lincosamines and 
streptogramins non-species related breakpoints are not robust, hence IE. 
B. Erythromycin can be used to determine the susceptibility of the listed bacteria to the other macrolides 
(azithromycin, clarithromycin and roxithromycin  
C. Clarithromycin is used for the eradication of H. pylori (MIC â‰¤0.25 mg/L for wild type isolates). 
D. The correlation between H. influenzae macrolide MICs and clinical outcome is weak. Therefore, breakpoints 
for macrolides and related antibiotics were set to categorise wild type H. influenzae as intermediate. 
“IE" indicates that there is insufficient evidence that the species in question is a good target for therapy with the 
drug. 
 
 
Clarithromycin is used for the eradication of H. pylori; minimum inhibitory concentration 
(MIC) â‰¤ 0.25 Î¼g/ml which has been established as the susceptible breakpoint by the Clinical 
and Laboratory Standards Institute (CLSI).  
Susceptibility 
The prevalence of acquired resistance may vary geographically and with time for selected 
species and local information on resistance is desirable, particularly when treating severe 
infections. As necessary, expert advice should be sought when the local prevalence of 
resistance is such that the utility of the agent in at least some types of infections is 
questionable. 
 
Pathogens for which resistance may be a problem: prevalence of resistance is equal to or 
greater than 10% in at least one country in the European Union 
 
Commonly susceptible species 
Aerobic Gram-positive microorganisms 
Corynebacterium diphteriae 
Streptococcus Group F 
Aerobic Gram-negative microorganisms 
Bordetella pertussis 
Legionella spp. 
Moraxella catarrhalis 
Pasteurella multocida 

Anaerobes 
Clostridum spp. other than C. difficile 
Other microorganisms 
Chlamydia trachomatis 
Chlamydia pneumoniae 
Clamydophilapsitacci 

 
 
 
Mycobacterium 
spp. 

Mycoplasma pneumoniae 
Species for which acquired resistance may be a problem 
Aerobic Gram-positive microorganisms 
Enterococcus spp.+ 
Staphylococcus aureus (methicillin-susceptible and 
methicillin-resistant+) 
Staphylococcus epidermidis+ 
Streptococcus Group A*, B, C, G 
Streptococcus viridans 

Streptococcus pneumoniae*+ 
Aerobic Gram-negative microorganisms 
Haemophilus influenzae§ 
Helicobacter pylori 
Anaerobes 
Bacteroides spp. 
Peptococcus / Peptostreptococcus spp. 
Inherently resistant organisms 
Aerobic Gram-negative microorganisms 
Acinetobacter 
Enterobacteriacea 
 
Pseudomonas aeruginosa 
Anaerobes 
Fusobacterium spp. 
Other microorganisms 
Mycobacterium tuberculosis 
# â‰¥ 10% resistance in at least one country of the European Union 
* Species against efficacy has been demonstrated in clinical investigations (if susceptible) 
+ Indicates species for which a high rate of resistance (i.e. greater than 50%) have been observed in one or more 
area/country/region(s) of the EU 
§ Breakpoints for macrolides and related antibiotics were set to categorise wild type H. influenzae as 
intermediate 
 
 
Other information 
 
Susceptibility and resistance of Streptococcus pneumoniae and Streptococcus spp. to 
clarithromycin can be predicted by testing erythromycin. 
Most available clinical experience from controlled randomised clinical trials indicate that 
clarithromycin 500 mg twice daily in combination with another antibiotic e.g. amoxicillin or 
metronidazole and e.g. omeprazole (given at approved levels) for 7 days achieve > 80% H. 
pylori
 eradication rate in patients with gastro-doudenal ulcers. As expected, significantly 

lower eradication rates were observed in patients with baseline metronidazole-resistant H. 
pylori
 isolates. Hence, local information on the prevalence of resistance and local therapeutic 
guidelines should be taken into account in the choice of an appropriate combination regimen 
for H. pylori eradication therapy. Furthermore, in patients with persistent infection, potential 
development of secondary resistance (in patients with primary susceptible strains) to an 
antimicrobial medicinal product should be taken into the considerations for a new retreatment 
regimen. 
 
5.2  Pharmacokinetic properties 
 
Absorption: 
Clarithromycin is rapidly and well absorbed from the gastrointestinal tract – primarily in the 
jejunum - but undergoes extensive first-pass metabolism after oral administration. The 
absolute bioavailability of a 250-mg clarithromycin tablet is approximately 50%. The 
bioavailability of the suspension is identical to or slightly higher than the bioavailability of 
the tablets. The pharmacokinetic profile of the suspension in children corresponds to the 
pharmacokinetic profile of the suspension in adults. Food slightly delays the absorption but 
does not affect the extent of bioavailability. Therefore, clarithromycin may be given without 
regard to food. Due to its chemical structure (6-O-Methylerythromycin) clarithromycin is 
quite resistant to degradation by stomach acid. Peak plasma levels of 1 – 2 µg/ml 
clarithromycin were observed in adults after oral administration of 250 mg twice daily. After 
administration of 500 mg clarithromycin twice daily the peak plasma level was 2.8 µg/ml. In 
children the following steady-state parameters were observed after the ninth dose in a dose 
regimen of 7.5 mg/kg twice daily on average for clarithromycin: Cmax 4.60 µg/ml, AUC 15.7 
µg.hour/ml and Tmax 2.8 hours. The corresponding average values for the 14-OH metabolite 
were respectively: 1.64 µg/ml, 6.69 µg.hour/ml and 2.7 hours. 
 
After administration of 250 mg clarithromycin twice daily the microbiologically active 14-
hydroxy metabolite attains peak plasma concentrations of 0.6 µg/ml. Steady state is attained 
within 2 days of dosing. 
 
Distribution: 
Clarithromycin penetrates well into different compartments, with an estimated volume of 
distribution of 200-400 L. Clarithromycin provides concentrations in some tissues that are 
several times higher than the circulating level of the active substance. Increased levels have 
been found in both tonsils and lung tissue. Clarithromycin also penetrates the gastric mucus. 
 
Clarithromycin is approximately 70% bound to plasma proteins at therapeutic levels. 
 
Biotransformation and elimination: 
Clarithromycin is rapidly and extensively metabolised in the liver. Metabolism is in the liver 
involving the P450 cytochrome system. Three metabolites are described: N-demethyl 
clarithromycin, decladinosyl clarithromycin and 14-hydroxy clarithromycin. 
 

The pharmacokinetics of clarithromycin is non-linear due to saturation of hepatic metabolism 
at high doses. Elimination half-life increased from 2-4 hours following administration of 250 
mg clarithromycin twice daily to 5 hours following administration of 500 mg clarithromycin 
twice daily. With a 250 mg every 12 hours dosing, the half-life of the active 14-hydroxy 
metabolite ranges between 5 to 6 hours following administration of 250 mg clarithromycin 
twice daily. 
 
Approximately 20 -40% of clarithromycin is excreted as the unchanged active substance in 
the urine. This proportion is increased when the dose is increased. An additional 10% to 15% 
is excreted in the urine as 14-hydroxy metabolite. The rest is excreted in the faeces. Renal 
insufficiency increases clarithromycin levels in plasma, if the dose is not decreased. 
Total plasma clearance has bee



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