CLAREX 500 mg film-coated tablets are indicated in adults and adolescents 12 years and
older for the treatment of the following bacterial infections, when caused by clarithromycinsusceptible bacteria (see section 4.4 and 5.1).
• Acute bacterial exacerbation of chronic bronchitis
• Mild to moderate community acquired pneumonia.
• Acute bacterial sinusitis
• Bacterial pharyngitis.
• Skin infections and soft tissue infections of mild to moderate severity, such as folliculitis,
cellulitis and erysipelas
CLAREX 500 mg can also be used in appropriate combination with antibacterial therapeutic
regimens and an appropriate ulcer healing agent for the eradication of Helicobacter pylori in
patients with Helicobacter pylori associated ulcers (see section 4.2).
Consideration should be given to official guidance on the appropriate use of antibacterial
agents.
 

The dosage of CLAREX 500 mg depends on the clinical condition of the patient and has to be
defined in any case by the physician.
Children older than 12 years and adults:
• 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.
• Clinical trials have been conducted using CLAREX pediatric suspension in children 6 months
to 12 years of age. Therefore, children under 12 years of age should use CLAREX pediatric
suspension (granules for oral suspension).
Elimination of Helicobacter pylori in adults:
In patients with gastro-duodenal ulcers due to H. pylori infection CLAREX can be used in a
dose of 500 mg twice daily during the eradication therapy in combination with amoxicillin
1000 mg twice daily and omeprazole 20 mg twice daily*.
Dosage in renal functional impairment:
The maximum recommended dosages should be reduced proportionately to renal
impairment. In patients with renal impairment with creatinine clearance less than 30
mL/min, the dosage of CLAREX 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.
Duration of therapy:
The duration of therapy with CLAREX 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.
• 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.CLAREX500 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 film-coated tablets 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
CLAREX and formation of the 14-hydroxy metabolite.
* according the publication in Gastroenterology. 1999 Feb; 116(2): 248-53
 

Clarithromycin is contraindicated in patients with known hypersensitivity to the active substance clarithromycin, to other macrolides or to any of the excipients listed in section 6.1. Concomitant administration of CLAREX and any of the following active substances is contraindicated: astemizole, cisapride, pimozide and terfenadine as this may result in QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and Torsade de Pointes (see section 4.5). Concomitant administration with ticagrelor or renolazine is contraindicated. Concomitant administration of CLAREX and ergotamine or dihydroergotamine is contraindicated, as this may result in ergot toxicity.Clarithromycin should 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). Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolosed by CYP3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see section 4.5). Clarithromycin should not be given to patients with hypokalaemia (risk of prolongation of QT-time). Clarithromycin should not be used in patients who suffer from severe hepatic failure in combination with renal impairment. As with other strong CYP3A4 inhibitors, CLAREX should not be used in patients taking colchicine.

The physician should not prescribe CLAREX to pregnant women without carefully weighing
the benefits against risk, particularly during the first three months of pregnancy (see section
4.6).
Caution is advised in patients with severe renal insufficiency (see section 4.2).
Clarithromycin is principally excreted by the liver. Therefore, caution should be exercised in
administering the antibiotic to patients with impaired hepatic function. Caution should also
be exercised when administering CLAREX to patients with moderate to severe renal
impairment.
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.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including
macrolides, and may range in severity from mild to life-threatening. Clostridium difficileassociated 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 CLAREX therapy should be considered regardless of the indication.
Microbial testing should be performed and adequate treatment initiated. Drugs inhibiting
peristalsis should be avoided.
There have been post-marketing reports of colchicine toxicity with concomitant use of
CLAREX and colchicine, especially in the elderly, some of which occurred in patients with
renal insufficiency. Deaths have been reported in some such patients (see section 4.5).
Concomitant administration of CLAREX and colchicines is contraindicated (see section 4.3).
Caution is advised regarding concomitant administration of CLAREX and
triazolobenzodiazepines, such as triazolam, and midazolam (see section 4.5).
Caution is advised regarding concomitant administration of CLAREX with other ototoxic
drugs, especially with aminoglycosides. Monitoring of vestibular and auditory function
should be carried out during and after treatment.
Due to the risk for QT prolongation, CLAREX should be used with caution in patients with
coronary artery disease, severe cardiac insufficiency, hypomagnesaemia, bradycardia (<50
bpm), or when co-administered with other medicinal products associated with QT
prolongation (see section 4.5).CLAREX must not be used in patients with congenital or
documented acquired QT prolongation or history of ventricular arrhythmia (see section 4.3).
Pneumonia: In view of the emerging resistance of Streptococcus pneumoniae to macrolides,
it is important that sensitivity testing be performed when prescribing CLAREX for
community-acquired pneumonia. In hospital-acquired pneumonia, CLAREX 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, acne vulgaris, and erysipelas and in situations where penicillin treatment
cannot be used.
In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson
Syndrome, and toxic epidermal necrolysis,CLAREXtherapy should be discontinued
immediately and appropriate treatment should be urgently initiated.
Clarithromycin should be used with caution when administered concurrently with
medications that induce the cytochrome CYP3A4 enzyme (see section 4.5).
HMG-CoARreductase Inhibitors (statins): Concomitant use of CLAREX with lovastatin or
simvastatin is contraindicated (see section 4.3). Caution should be exercised when
prescribing clarithromycinwith other statins. Rhabdomyolysis has been reported in patients
taking CLAREX and statins. Patients should be monitored for signs and symptoms of
myopathy. In situations where the concomitant use of CLAREX with statins cannot be
avoided, it is recommended to prescribe the lowest registered dose of statin. Use of a statin
that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered.
Oral hypoglycemic agents/Insulin: The concomitant use of CLAREX and oral hypoglycemic
agents (such as sulfonylurias) and/or insulin can result in significant hypoglycemia. Careful
monitoring of glucose is recommended.
Oral anticoagulants: There is a risk of serious hemorrhage and significant elevations in
International Normalized Ratio (INR) and prothrombin time when CLAREX is co-administered
with warfarin (see section 4.5). INR and prothrombin times should be frequently monitored
while patients are receiving CLAREX and oral anticoagulants concurrently.
Use of any antimicrobial therapy, such as clarithromycin, to treat H. pylori infection may
select for drug-resistant organisms.
Long-term use may, as with other antibiotics, result in colonization with increased numbers
of non-susceptible bacteria and fungi. If super-infection occur,appropriate therapy should be
instituted.
Attention should also be paid to the possibility of cross resistance between CLAREX and
other macrolide drugs, as well as lincomycin and clindamycin.
 

The use of the following drugs is strictly contraindicated due to the potential for severe
drug interaction effects:
Cisapride, pimozide, astemizole and terfenadine
Elevated cisapride levels have been reported in patients receiving CLAREX 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 takingCLAREX and pimozide concomitantly (see section 4.3).
Macrolides have been reported to alter the metabolism of terfenadine resulting in increased
levels of terfenadine which has occasionally been associated with cardiac arrhythmias such
as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsades de pointes
(see section 4.3). In one study in 14 healthy volunteers, the concomitant administration of
CLAREX 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 CLAREX 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 CLAREX and these medicinal products is
contraindicated (see section 4.3).
HMG-CoA Reductase Inhibitors (statins)
Concomitant use of CLAREX with lovastatin or simvastatin is contraindicated (see 4.3) as
these statins are extensively metabolized by CYP3A4 and concomitant treatment with
CLAREX increases their plasma concentration, which increases the risk of myopathy,
including rhabdomyolysis. Reports of rhabdomyolysis have been received for patients taking
CLAREX concomitantly with these statins. If treatment with CLAREX cannot be avoided,
therapy with lovastatin or simvastatin must be suspended during the course of treatment.
Caution should be exercised when prescribing CLAREX with statins. In situations where the
concomitant use of CLAREX with statins cannot be avoided, it is recommended to prescribe
the lowest registered dose of the statin.Use of a statin that is not dependent on CYP3A
metabolism (e.g.fluvastatin) can be considered. Patients should be monitored for signs and
symptoms of myopathy.
Effects of other medicinal products on clarithromycin
Drugs that are inducers of CYP3A (e.g. rifampicin, phenytoin, carabamazepin, phenobarbital,
St. Johns wort) may induce the metabolism of clarithromycin. This may result in sub-
therapeutic levels of CLAREX leading to a reduced efficacy. Furthermore it might be
necessary to monitor the plasma levels of the CYP3A inducer, which could be increased
owing to the inhibition of CYP3A byCLAREX(see also the relevant product information for the
CYP3A4 inhibitor administered). Concomitant administration of rifabutin andCLAREXresulted
in an increase in rifabutin, and decrease in CLAREX serum levels together with an increased
risk of uveitis.
The following drugs are known or suspected to affect circulating concentrations of
clarithromycin; CLAREX dosage adjustment or consideration of alternative treatments may
be required.
Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine
Strong inducers of the cytochrome P450 metabolism system such as efavirenz, nevirapine,
rifampicin, rifabutin, and rifapentine may accelerate the metabolism of CLAREX 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 CLAREX
and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic
effect could be impaired during concomitant administration of CLAREX and enzyme
inducers.
Etravirine
Clarithromycin exposure was decreased by etravirine; however, concentrations of the active
metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has
reduced activity against Mycobacterium avium complex (MAC), overall activity against this
pathogen may be altered; therefore alternatives toCLAREXshould be considered for the
treatment of MAC.
Fluconazole
Concomitant administration of fluconazole 200 mg daily andCLAREX500 mg twice daily to 21
healthy volunteers led to increases in the mean steady-state minimumCLAREXconcentration
(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. NoCLAREXdose adjustment is necessary.
Ritonavir
A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200
mg every eight hours andCLAREX500 mg every 12 hours resulted in a marked inhibition of
the metabolism of clarithromycin. TheCLAREXCmax increased by 31%, Cmin increased 182%
and AUC increased by 77% with concomitant administration of ritonavir. An essentially
complete inhibition of the formation of 14-OH-clarithromycin was noted. Because of the
large therapeutic window for clarithromycin, no dosage reduction should be necessary in
patients with normal renal function. However, for patients with renal impairment, the
following dosage adjustments should be considered: For patients with CLCR 30 to 60 mL/min
the dose of CLAREX should be reduced by 50%. For patients with CLCR <30 mL/min the dose
of CLAREX should be decreased by 75%. Doses of CLAREX greater than 1 g/day should not be
coadministered with ritonavir.
Similar dose adjustments should be considered in patients with reduced renal
function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease
inhibitors including atazanavir and saquinavir (see section below, Bi-directional drug
interactions).
Effect ofCLAREXon 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. CLAREX
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 safety margin (e.g.
carbamazepine) and/or the substrate is 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 isozyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine,
disopyramide, ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral
anticoagulants (e.g. warfarin, see section 4.4), pimozide, quinidine, rifabutin, sildenafil,
simvastatin, sirolimus, tacrolimus, terfenadine, triazolam and vinblastine. Drugs interacting
by similar mechanisms through other isozymes within the cytochrome P450 system include
phenytoin, theophylline and valproate.
Antiarrhythmics
There have been postmarketing reports of torsades de pointes occurring with concurrent
use of CLAREX and quinidine or disopyramide. Electrocardiograms should be monitored for
QT prolongation during co-administration ofCLAREXwith these drugs. Serum levels of
quinidine and disopyramide should be monitored during CLAREX therapy.
There have been post marketing reports of hypoglycemia with the concomitant
administration of CLAREX and disopyramide. Therefore blood glucose levels should be
monitored during concomitant administration of CLAREX and disopyramide.
Oral hypoglycemic agents/Insulin
With certain hypoglycemic drugs such as nateglinide, and repaglinide, inhibition of CYP3A
enzyme by CLAREX may be involved and could cause hypolgycemia when used
concomitantly. Careful monitoring of glucose is recommended.
Omeprazole
Clarithromycin (500 mg every 8 hours) was given in combination with omeprazole (40 mg
daily) to healthy adult subjects. The steady-state plasma concentrations of omeprazole were
increased (Cmax, AUC0-24, and t1/2 increased by 30%, 89%, and 34%, respectively), by the
concomitant administration of clarithromycin. The mean 24-hour gastric pH value was 5.2
when omeprazole was administered alone and 5.7 when omeprazole was co-administered
with clarithromycin.
Sildenafil, tadalafil, and vardenafil
Each of these phosphodiesterase inhibitors is metabolized, at least in part, by CYP3A, and
CYP3A may be inhibited by concomitantly administered clarithromycin. Co-administration of
CLAREX with sildenafil, tadalafil or vardenafil would likely result in increased
phosphodiesterase inhibitor exposure. Reduction of sildenafil, tadalafil and vardenafil
dosages should be considered when these drugs are co-administered with clarithromycin.
Theophylline, carbamazepine
Results of clinical studies indicate there was a modest but statistically significant (p≤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.
Tolterodine
The primary route of metabolism for tolterodine is via the 2D6 isoform of cytochrome P450
(CYP2D6). However, in a subset of the population devoid of CYP2D6, the identified pathway
of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in
significantly higher serum concentrations of tolterodine. A reduction in tolterodine dosage
may be necessary in the presence of CYP3A inhibitors, such asCLAREXin the CYP2D6 poor
metabolizer population.
Triazolobenzodiazepines (e.g. alprazolam, midazolam, triazolam)
When midazolam was co-administered with CLAREX tablets (500 mg twice daily), midazolam
AUC was increased 2.7-fold after intravenous administration of midazolam and 7-fold after
oral administration. Concomitant administration of oral midazolam and CLAREX 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 metabolized by CYP3A, including triazolam and alprazolam.
For benzodiazepines which are not dependent on CYP3A for their elimination (temazepam,
nitrazepam, lorazepam), a clinically important interaction with CLAREX is unlikely.
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 CLAREX and
triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.
Other drug interactions
Aminoglycosides
Caution is advised regarding concomitant administration of CLAREX with other ototoxic
drugs, especially with aminoglycosides. See 4.4
Colchicine
Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein
(Pgp).CLAREXand other macrolides are known to inhibit CYP3A and Pgp. WhenCLAREXand
colchicine are administered together, inhibition of Pgp and/or CYP3A byCLAREXmay 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).CLAREXis
known to inhibit Pgp. WhenCLAREXand digoxin are administered together, inhibition of Pgp
byCLAREXmay lead to increased exposure to digoxin. Elevated digoxin serum concentrations
in patients receivingCLAREXand 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 andCLAREXsimultaneously.
Zidovudine
Simultaneous oral administration ofCLAREXtablets and zidovudine to HIV-infected adult
patients may result in decreased steady-state zidovudine concentrations.
BecauseCLAREXappears to interfere with the absorption of simultaneously administered oral
zidovudine, this interaction can be largely avoided by staggering the doses ofCLAREXand
zidovudine to allow for a 4-hour interval between each medication. This interaction does not
appear to occur in paediatric HIV-infected patients takingCLAREXsuspension with zidovudine
or dideoxyinosine. This interaction is unlikely whenCLAREXis administered via intravenous
infusion.
Phenytoin and Valproate
There have been spontaneous or published reports of interactions of CYP3A inhibitors,
including CLAREX 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 CLAREX and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of
a bi-directional drug interaction. Co-administration of CLAREX (500 mg twice daily) with
atazanavir (400 mg once daily) resulted in a 2- fold increase in exposure to CLAREX 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 CLAREX should be decreased by
50%. For patients with creatinine clearance <30 mL/min, the dose of CLAREX should be
decreased by 75% using an appropriateCLAREXformulation.
Doses of CLAREX greater than 1000 mg per day should not be co-administered with protease
inhibitors.
Calcium Channel Blockers
Caution is advised regarding the concomitant administration of CLAREX and calcium channel
blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem) due to the risk of
hypotension. Plasma concentrations of CLAREX as well as calcium channel blockers may
increase due to the interaction. Hypotension, bradyarrhythmias and lactic acidosis have
been observed in patients taking CLAREX and verapamil concomitantly.
Itraconazole
Both CLAREX and itraconazole are substrates and inhibitors of CYP3A, leading to a
bidirectional drug interaction. CLAREX may increase the plasma levels of itraconazole, while
itraconazole may increase the plasma levels of clarithromycin. Patients taking itraconazole
and CLAREX concomitantly should be monitored closely for signs or symptoms of increased
or prolonged pharmacologic effect.
Saquinavir
Both CLAREX and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of
a bi-directional drug interaction. Concomitant administration of CLAREX (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. CLAREX AUC and Cmax values were
approximately 40% higher than those seen with CLAREX 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
 

Pregnancy
The safety of CLAREX for use during pregnancy has not been established. Based on variable
results obtained from studies in mice, rats, rabbits and monkeys, the possibility of adverse
effects on embryofoetal development cannot be excluded. Therefore, use during pregnancy
is not advised without carefully weighing the benefits against risk.
Breast-feeding
The safety of CLAREX for use during breast feeding of infants has not been established.
CLAREX is excreted into human breast milk.
Fertility
There is no data available on the effect of CLAREX on fertility in humans. In rats, the limited
data available do not indicate any effects on fertility
 

There are no data on the effect of CLAREX on the ability to drive or use machines. The
potential for dizziness, vertigo, confusion and disorientation, which may occur with the
medication, should be taken into account before patients drive or use machines.
 

Summary of the safety profile
The most frequent and common adverse reactions related to CLAREX 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
The following table displays adverse reactions reported in clinical trials and from postmarketing experience with CLAREX immediate-release tablets, granules for oral suspension,
powder for solution for injection, extended release tablets and modified-release tablets.
The reactions considered at least possibly related to CLAREX are displayed by system organ
class and frequency using the following convention: very common (≥1/10), common (≥1/100
to <1/10), uncommon (≥1/1,000 to <1/100) and not known (adverse reactions from postmarketing experience; cannot be estimated from the available data). Within each frequency
grouping, adverse reactions are presented in order of decreasing seriousness when the
seriousness could be assessed.

2ADRs reported only for the Extended-Release Tablets formulation
3 ADRs reported only for the Granules for Oral Suspension formulation
4 ADRs reported only for the Immediate-Release Tablets formulation
5
,
7, 9, 10, See section a)
6, 8, 11 See section c)
c. Description of selected adverse reactions
Injection site phlebitis, injection site pain, vessel puncture site pain, and injection site
inflammation are specific to the CLAREX intravenous formulation.
In some of the reports of rhabdomyolysis, CLAREX was administered concomitantly with
statins, fibrates, colchicine or allopurinol (see section 4.3 and 4.4).
There have been post-marketing reports of colchicine toxicity with concomitant use of
CLAREX 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 post-marketing reports of drug interactions and central nervous system
(CNS) effects (e.g. somnolence and confusion) with the concomitant use of CLAREX and
triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested
(see section 4.5).
There have been rare reports of CLAREXER tablets in the stool, many of which have occurred
in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal
disorders with shortened GI transit times. In several reports, tablet residues have occurred
in the context of diarrhea. It is recommended that patients who experience tablet residue in
the stool and no improvement in their condition should be switched to a different CLAREX
formulation (e.g. suspension) or another antibiotic.
Special population: Adverse Reactions in Immunocompromised Patients (see section e)
d. Paediatric populations
Clinical trials have been conducted using CLAREX paediatric suspension in children 6 months
to 12 years of age. Therefore, children under 12 years of age should use CLAREX paediatric
suspension. There are insufficient data to recommend a dosage regimen for use of the
CLAREX IV formulation in patients less than 18 years of age.
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 CLAREX
over long periods of time for mycobacterial infections, it was often difficult to distinguish
adverse events possibly associated with CLAREX 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 1,000 mg and 2,000 mg of CLAREX 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 1,000 mg and 2,000 mg, but were generally about 3 to 4 times as frequent for those
patients who received total daily doses of 4,000 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 1,000 mg or 2,000 mg of CLAREX 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
4,000 mg daily for all parameters except White Blood Cell.

Symptoms of intoxication:
Reports indicate that the ingestion of large amounts of CLAREX can be expected to produce
gastrointestinal symptoms. One patient who had a history of bipolar disorder ingested eight
grams of CLAREX and showed altered mental status, paranoid behaviour, hypokalaemia and
hypoxemia.
Therapy of intoxication:
Adverse reactions accompanying overdosage should be treated by the prompt elimination of
unabsorbed drug and supportive measures. As with other macrolides, CLAREX serum levels
are not expected to be appreciably affected by hemodialysis or peritoneal dialysis.
In the case of overdosage ,CLAREX IV (powder for solution for injection) should be
discontinued and all other appropriate supportive measures should be instituted.
 

Pharmacotherapeutic group: Macrolides
ATC code: J01FA09
Mode of action:
Clarithromycin is a semi-synthetic derivative of erythromycin A. It 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 grampositive and gram-negative organisms. The minimum inhibitory concentrations (MICs) of
CLAREX are generally two-fold lower than the MICs of erythromycin.
The 14-hydroxy metabolite of CLAREX also has antimicrobial activity. The MICs of this
metabolite are equal or twofold higher than the MICs of the parent compound, except for H.
influenzae where the 14-hydroxy metabolite is two-fold more active than the parent
compound.
PK/PD relationship
Clarithromycin is extensively distributed into body tissues and fluids. Due to the high tissue
penetration, intracellular concentrations higher than serum concentrations. The main
pharmacodynamic parameters to predict macrolidenactiviteit are unconvincing established.
The time above the MIC (T / MIC) is the best determinant for the efficacy of clarithromycin.
Because the concentrations of CLAREX in the lung tissues and epithelial tissue fluid reaches
the plasma concentrations exceed, the use of plasma concentrations based parameters are
insufficient to accurately predict response for respiratory infections.
Mechanisms of resistance:
Resistance mechanisms against macrolide antibiotics include alteration of the target site of
the antibiotic or are based on modification and/or the active efflux of the antibiotic.
Resistance development can be mediated via chromosomes or plasmids, be induced or exist
constitutively. Macrolideresistant 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. CLAREX 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 crossresistance exists among clarithromycin, erythromycin and azithromycin. Methicillin-resistant
staphylococci and penicillin-resistant Streptococcus pneumoniae are resistant to 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) 2010-04-27 (v 1.1)

§ 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
CLAREX can be predicted by testing erythromycin.
Most available clinical experience from controlled randomised clinical trials indicate
thatCLAREX500 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-duodenal 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 retreatment regimen.
 

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-mgCLAREXtablet is approximately 50%. Food slightly delays
the absorption but does not affect the extent of bioavailability. Therefore,CLAREXtablets
may be given without regard to food. Due to its chemical structure (6-OMethylerythromycin)CLAREX is quite resistant to degradation by stomach acid. Peak plasma
levels of 1 – 2 μg/ml CLAREX were observed in adults after oral administration of 250 mg
twice daily. After administration of 500 mgCLAREXtwice daily the peak plasma level was 2.8
μg/ml. After administration of 250 mg CLAREX 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.CLAREXprovides 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.CLAREXalso 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, decladinosylCLAREXand 14-hydroxy clarithromycin. The pharmacokinetics
ofCLAREXis non-linear due to saturation of hepatic metabolism at high doses. Elimination
half-life increased from 2-4 hours following administration of 250 mgCLAREXtwice daily to 5
hours following administration of 500 mgCLAREXtwice daily. The half-life of the active 14-
hydroxy metabolite ranges between 5 to 6 hours following administration of 250 mg CLAREX
twice daily.
Approximately 20 -40% ofCLAREXis 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 CLAREX 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
CLAREX and the active metabolite levels in plasma.
 

In 4-week-studies in animals, toxicity of CLAREX was found to be related to the dose and to
the duration of the treatment. In all species, the first signs of toxicity were observed in the
liver, in which lesions were seen within 14 days in dogs and monkeys. The systemic levels of
exposure, related to this toxicity, are not known in detail, but toxic doses were clearly higher
than the therapeutic doses recommended for humans. Other tissues affected included the
stomach, thymus and other lymphoid tissues as well as the kidneys. At near therapeutic
doses conjunctival injection and lacrimation occurred only in dogs. At a dose of 400
mg/kg/day some dogs and monkeys developed corneal opacities and/or oedema.
No mutagenic effects were found in in vitro- and in vivo -studies with clarithromycin
Studies on reproduction toxicity showed that administration of CLAREX at doses 2x the
clinical dose in rabbit (i.v.) and x10 the clinical dose in monkey (p.o.) resulted in an increased
incidence of spontaneous abortions. These doses were related to maternal toxicity. No
embryotoxicity or teratogenicity was noted in rat studies. Cardiovascular malformations
were observed in rats treated with doses of 150 mg/kg/d. In mouse at doses x70 the clinical
dose cleft palate occurred at varying incidence (3-30%).
Clarithromycin has been found in the milk of lactating animals.
In 3-day old mice and rats, the LD50 values were approximately half those in adult animals.
Juvenile animals presented similar toxicity profiles to mature animals although enhanced
nephrotoxicity in neonatal rats has been reported in some studies. Slight reductions in
erythrocytes, platelets and leukocytes have also been found in juvenile animals.
Clarithromycin has not been tested for carcinogenicity
 

Avicel 102, Sodium starch, Povidone, Maize Starch,Aerosol, Croscarmellose Sodium), Talc,
Magnesium Stearate, Opadry, .
 

Not applicable.
 

2 years

Store below 30°C.
 

PVC-PVDC / Aluminium blister
Packs of 14 Film coated tablets
 

No special requirements.