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Claritromycine Sandoz 250 mg, filmomhulde tabletten

RegistratienummerRVG 107884
ProcedurenummerNL/H/2088/001
Farmaceutische vormFilmomhulde tablet
ToedieningswegOraal gebruik
ATCJ01FA09 - Clarithromycin
AfleverstatusUitsluitend recept
Registratiedatum23 september 2011
Registratiehouder
Veluwezoom 22
1327 AH ALMERE
Werkzame stof(fen)
Hulpstof(fen)CELLULOSE, MICROKRISTALLIJN (E 460)
CHINOLINEGEEL (E 104)

HYPROLOSE (E 463)

MAGNESIUMSTEARAAT (E 572)
POVIDON K 30 (E 1201)
PROPYLEENGLYCOL (E 1520)
SILICIUMDIOXIDE (E 551)
SORBITANMONOOLEAAT (E 494)
TALK (E 553 B)
TITAANDIOXIDE (E 171)
VANILLINE
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1.3.1.1 Summary of Product Characteristics 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 

Claritromycine Sandoz 500 mg, filmomhulde tabletten 
 
 
2. 
QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Claritromycine Sandoz 250 mg 
Each film-coated tablet contains 250 mg Clarithromycin 
Claritromycine Sandoz 500 mg 
Each film-coated tablet contains 500 mg Clarithromycin 
 
For a full list of excipients, see section 6.1 
 
 
3. PHARMACEUTICAL 
FORM 
 
Film-coated tablet 
Claritromycine Sandoz 250 mg 
Dark yellow, film-coated, capsule shaped tablets (15.6 x 7.9 mm). 
Claritromycine Sandoz 500 mg 
Light yellow, film-coated, oval shaped tablets. (18.8 x 8.8 mm) 
 
 
4. CLINICAL 
PARTICULARS 
 
4.1 Therapeutic 
indications 
 
Clarithromycin is indicated in adults and adolescents 12 years and older for the treatment of the 
following infections, when caused by clarithromycin-susceptible bacteria (see sections 4.4 and 5.1). 
 
• 
Bacterial pharyngitis 
• 
Acute bacterial sinusitis 
• 
Acute bacterial exacerbation of chronic bronchitis 
• 
Mild to moderate community acquired pneumonia 
• 
Skin infections and soft tissue infections of mild to moderate severity, for example folliculitis, 
cellulitis and erysipelas. 
 
[nationally completed name, 250 mg/ 500 mg, film-coated tablets] can also be used in appropriate 
combination with antibacterial therapeutic regimens and an appropriate ulcer healing agent for the 
eradication of H. pylori in 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 depends on the clinical condition of the patient and has to be defined in 
any case by the physician. 
 
Adults and adolescents (12 years and older): 
 
• 
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. 
 
Children younger than 12 years: 
 
Clarithromycin tablets are not suitable for children younger than 12 years of age with weight less than 
30 kg. For these patients other pharmaceutical forms (e.g. suspensions) are available. Clinical trials 
have been conducted using clarithromycin paediatric suspension in children 6 months to 12 years of 
age. 
 
For children with weight more than 30 kg, dosage for adults and adolescents is applicable. 
 
Elderly: 
 
As for adults. 
 

 
In patients with gastro-duodenal ulcers due to H. pylori infection clarithromycin can be used in a dose 
of 500 mg twice daily during the eradication therapy in combination with amoxicillin 1000 mg twice 

 
Dosage in renal functional impairment: 
 
In patients with renal impairment with creatinine clearance less than 30 mL/min, the dosage of 
clarithromycin should be reduced by one-half, i.e. 250 mg once daily, or 250 mg twice daily in more 
severe infections. Treatment should not be continued beyond 14 days in these patients.  
 
Patients with hepatic impairment: 
 
Caution should be exercised when administrating clarithromycin in patients with hepatic impairment 
(see section 4.3 and 4.4). 
 
Duration of therapy: 
 
The duration of therapy with clarithromycin 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 is 6 to 14 days. 
• 
Therapy should be continued at least for 2 days after symptoms have subsided. 

• 
In ß-haemolytic streptococcal infections the duration of therapy should be at least 10 days in 
order to prevent complications such as rheumatic fever and glomerulonephritis. 
• 
Combination therapy for the eradication of H. pylori infection, e.g. clarithromycin 500 mg (two 
250 mg tablets or one 500 mg tablet) twice daily in combination with amoxicillin 1000 mg twice 
daily and omeprazole 20 mg twice daily should be continued for 7 days. 
 
Method of administration: 
 
Clarithromycin may be given irrespective of food intake (see section 5.2).  
 
4.3 Contraindications 
 
Clarithromycin should not be used in patients with hypersensitivity to clarithromycin, to other 
macrolides or to any of the other tablet ingredients. 
 
Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is 
contraindicated, as this may result in ergot toxicity (see section 4.5). 
 
Concomitant administration of clarithromycin and any of the following active substances is 

and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and Torsade de 
Pointes (see section 4.5).  
 
Clarithromycin 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). 
 


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 selection of clarithromycin to treat an individual patient should take into account the 
appropriateness of using a macrolide antibacterial agent based on adequate diagnosis to ascertain the 
bacterial etiology of the infection in the approved indications and the prevalence of resistance to 
clarithromycin or other macrolides. 
In areas with a high incidence of erythromycin A resistance, it is especially important to take into 
consideration the evolution of the pattern of susceptibility to clarithromycin and other antibiotics. As 
for other macrolides, high resistance rates of Streptococcus pneumoniae have been reported for 
clarithromycin in some European countries (see section 5.1). This should be taken into account when 
treating infections caused by Streptococcus pneumoniae

In bacterial pharyngitis the use of clarithromycin is recommended only in cases where first line 

 
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, especially in patients with impaired renal 
function (see also section 4.3).  
 
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. 
 
As with other antibiotics 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. 
 
Attention should be paid to patients who have been treated with lincomycin or clindamycin before 
because cross-hypersensitivity reactions can occur and the possibility of cross-resistance exists. 
 
Prolonged or repeated use of clarithromycin may result in an overgrowth of non-susceptible bacteria 
or fungi. If superinfection occurs, clarithromycin should be discontinued and appropriate therapy 
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 (see section 4.8). 
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). 
 


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 is an inhibitor of CYP3A4, and concomitant use with an inducer of CYP3A4 or 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 reports of rhabdomyolysis have also been 


Adjustment of the statin dose or use of a statin that is not dependent on CYP3A metabolism (e.g. 

 

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

clarithromycin may be involved and could cause hypolgycemia when used concomitantly. Careful 

 
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. 
 
As known for other macrolides, clarithromycin may cause exacerbation or aggravation of myasthenia 
gravis and should therefore be used with caution in patients with myasthenia gravis (see section 4.8). 
 
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. 
 
 
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). 
 

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 
Post-marketing reports indicate that co-administration of clarithromycin with ergotamine or 
dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm, and 
ischemia of the extremities and other tissues including the central nervous system. Concomitant 
administration of clarithromycin and 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 tablets 
 


pointes, cardiac arrest). 
 
Medicinal 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. 
 


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 t.i.d) have been shown to inhibit the metabolism of clarithromycin (500 mg b.i.d.), 
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 atazanavir and 

 
The effect of Clarithromycin tablets 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 

extensively metabolized by this 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 CYP3A 



triazolam and vinblastine. Drugs interacting by similar mechanisms through other isozymes within the 
cytochrome P450 system include phenytoin, theophylline and valproate.  
 
There are no in-vivo human data available describing an interaction between clarithromycin and the 
in vitro data 
suggest these drugs are CYP3A substrates, caution should be used when they are co-administered with 
clarithromycin. 
 
Antiarrhythmics 
Cases with torsades de pointes have 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). 
 
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 of clarithromycin 


drugs are co-administered with clarithromycin. 
 

Results of clinical studies indicate there was a modest but statistically significant (p â‰¤ ï€ 0.05) increase of 
circulating theophylline or carbamazepine levels when either of these drugs was 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. 
 
Benzodiazepines 

When midazolam was co-administered with clarithromycin tablets (250 mg b.i.d.), 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 


clarithromycin is unlikely. 
 

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 

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. 
 
Anticoagulants 
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). 
 
Anti-diabetic products 
After concomitant administration of Clarithromycin with insulin and other anti-diabetic medicinal 
products hypoglycaemia has been observed (see section 4.4). 
 
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. Patients should be monitored for clinical symptoms of colchicine 
toxicity (see section 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.  
 

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 (see section above, “Effect of other medicinal products on Clarithromycin 
tabletsâ€). 
 

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 or on the health of and 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 given to pregnant women 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 
paediatric 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 
candidiasis* 

Uncommon 
Candidiasis*, vaginal infection* 
Not known 
Erysipelas, erythrasma 
 
 
Blood and lymphatic system disorders 
Uncommon  
Leucopenia, neutropenia, eosinophilia 
Very rare 
Thrombocytopenia 
Not known 
Agranulocytosis 
 
 
Immune system disorders 
Uncommon Allergic 
reactions** 
 
 
Metabolism and nutrition disorders 
Uncommon 
Anorexia, decreased appetite 
Very rare 
Hypoglycaemia$
 
 
Psychiatric disorders 
Common Insomnia 
Uncommon Anxiety 
Very rare 
Hallucinations, psychotic disorder, disorientation, 
depersonalisation, abnormal dreams, confusional state 
Not known 
Depression 
 
 
Nervous system disorders 
Common 
Headache, smell alteration, dysgeusia, taste perversion, i.e. metallic 
or bitter taste 
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, QT prolongation 
Very rare  
Ventricular tachycardia and Torsades de Pointes 
 
 
Vascular disorders 
 
Not known 
Hemorrhage 
 
 
Gastrointestinal disorders 
Common 
Nausea, diarrhoea, vomiting, abdominal pain, dyspepsia, stomatitis, 
glossitis, reversible tooth and tongue discoloration 
Uncommon 
Gastritis, abdominal distension, constipation, dry mouth, eructation, 
flatulence 
Very rare 
Pancreatitis, Pseudomembranous colitis*** (see section 4.4)  

 
 
Hepatobiliary disorders 
Uncommon Hepatic 
dysfunction#, hepatitis and cholestasis with or without 
jaundice 
Very rare  
Fatal hepatic failure§  
 
 
Skin and subcutaneous tissue disorders 
Common Rash, 
hyperhidrosis 
Uncommon Pruritus, 
urticaria 
Very rare  
Stevens-Johnson syndrome, toxic epidermal necrolysis 
Not known 
Drug rash with eosinophilia and systemic symptoms (DRESS), acne
 
 
Musculoskeletal and connective tissue disorders 
Uncommon Arthralgia, 
myalgia 
Not known 
Myopathy 
 
 
Renal and urinary disorders 
Very rare  
Interstitial nephritis, renal failure 
 
 
General disorders and administration site conditions 
Uncommon 
Malaise, asthenia, chest pain, chills, fatigue 
 
 
Investigations 
Common 
Elevated blood urea nitrogen (BUN), liver function test abnormal 
Uncommon 
Prolongation of prothrombin time, international normalised ratio 
 
increased, elevated serum creatinine, alanine aminotransferase 
increased, aspartate aminotransferase increased, gamma-
glutamyltransferase increased, blood alkaline phosphatase 
increased, blood lactate dehydrogenase increased 
Not known 
Urine color abnormal 
* As with other antibiotics, prolonged use may result in the overgrowth of non-susceptible organisms. 
** Ranging from urticaria and mild skin eruptions to anaphylaxis. 
*** May range in severity from mild to life threatening. 
# Which is usually transient and reversible. 
§ Has been reported particularly in patients with pre-existing liver disease or taking other hepatotoxic 
medicinal products. 
$ Especially after concomitant administration with antidiabetic medicinal products and insulin 
 
 
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 with statins, 

 
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 overdosage 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. 
 
 
5. 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 antibacterial 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 
influenzae
 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‰¤ (mg/L) 
Resistant > (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 

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. 
 
Commonly susceptible species 
Aerobic Gram-positive microorganisms 
Corynebacterium diphteriae 
Streptococcus 
Group F 
Aerobic Gram-negative microorganisms 
Bordetella pertussis 
Legionalla 
spp. 
Moraxella catarrhalis 
Pasteurella multocida 

Anaerobes 
Clostridum spp. other than C. difficile 
Other microorganisms 

Chlamydia trachomatis 
Chlamydia pneumoniae 
Clamydophilapsitacci 
Mycoplasma pneumoniae 
Mycobacterium
 spp. 
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 infuenzae§ 
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 agent should be taken into the 
considerations for a new treatment 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%. Food slightly delays the absorption but does 
not affect the extent of bioavailability. Therefore, clarithromycin tablets 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 . 
 
After administration of 250 mg clarithromycin twice daily the microbiologically active 14-hydroxy 
metabolite attains peak plasma concentrations of 0.6 Âµg/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 drug levels. 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. 
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 been estimated to approximately 700 mL/min (11.7 mL/s), with a renal 
clearance of approximately 170 mL/min (2.8 mL/s). 
 
Special populations: 
 


Renal impairment: Reduced renal insufficiency function results in increased plasma levels of 
clarithromycin and the active metabolite levels in plasma. 
 



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