Claritromycine Sandoz 250 mg, filmomhulde tabletten
|Farmaceutische vorm||Filmomhulde tablet|
|ATC||J01FA09 - Clarithromycin|
|Registratiedatum||23 september 2011|
1327 AH ALMERE
|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)
18.104.22.168 Summary of Product Characteristics
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
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
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).
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.
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
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 ÃŸ-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
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
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including
macrolides, and may range in severity from mild to life-threatening. Clostridium difficile-
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
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
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
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
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.
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 â€“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
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
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
suggest these drugs are CYP3A substrates, caution should be used when they are co-administered with
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).
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.
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.
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).
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 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 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
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.
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, â€œEffect of other medicinal products on Clarithromycin
Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients taking
clarithromycin and verapamil concomitantly.
Fertility, pregnancy and lactation
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
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
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 (â‰¥ 1/10)
Common (â‰¥ 1/100 to < 1/10)
Uncommon (â‰¥ 1/1,000 to < 1/100)
Rare (â‰¥ 1/10,000 to < 1/1,000)
Very rare (< 1/10,000), not known (cannot be estimated from the available data) Infections and infestations
Candidiasis*, vaginal infection*
Blood and lymphatic system disorders
Leucopenia, neutropenia, eosinophilia
Immune system disorders
Metabolism and nutrition disorders
Anorexia, decreased appetite
Hallucinations, psychotic disorder, disorientation,
depersonalisation, abnormal dreams, confusional state
Nervous system disorders
Headache, smell alteration, dysgeusia, taste perversion, i.e. metallic
or bitter taste
Ageusia, parosmia, anosmia
Ear and labyrinth disorders
Vertigo, hearing impaired, tinnitus
Reversible hearing loss
Palpitations, QT prolongation
Ventricular tachycardia and Torsades de Pointes
Nausea, diarrhoea, vomiting, abdominal pain, dyspepsia, stomatitis,
glossitis, reversible tooth and tongue discoloration
Gastritis, abdominal distension, constipation, dry mouth, eructation,
Pancreatitis, Pseudomembranous colitis*** (see section 4.4)
dysfunction#, hepatitis and cholestasis with or without
Fatal hepatic failureÂ§
Skin and subcutaneous tissue disorders
Stevens-Johnson syndrome, toxic epidermal necrolysis
Drug rash with eosinophilia and systemic symptoms (DRESS), acne
Musculoskeletal and connective tissue disorders
Renal and urinary disorders
Interstitial nephritis, renal failure
General disorders and administration site conditions
Malaise, asthenia, chest pain, chills, fatigue
Elevated blood urea nitrogen (BUN), liver function test abnormal
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
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.
Â§ Has been reported particularly in patients with pre-existing liver disease or taking other hepatotoxic
$ 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
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
Frequency, type and severity of adverse reactions in children are expected to be the same as in adults. e. Other special populations
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
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 H
where the 14-hydroxy metabolite is two-fold more active than the parent compound.
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
are resistant to all currently available Beta-lactam antibiotics and macrolides such as
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
Resistant > (mg/L)
groups A, B, C, G
Streptococcus pneumoniae D
Gram-positive anaerobes (except
Non-species related break-points A
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
â€œIE" 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).
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
Aerobic Gram-negative microorganisms
spp. Moraxella catarrhalis
spp. other than C. difficile
Species for which acquired resistance may be a problem
Aerobic Gram-positive microorganisms
(methicillin-susceptible and methicillin-resistant+) Staphylococcus epidermidis+
Streptococcus Group A*, B, C, G
Aerobic Gram-negative microorganisms
spp. Peptococcus / Peptostreptococcus
Inherently resistant organisms
Aerobic Gram-negative microorganisms
Enterobacteriacea Pseudomonas aeruginosa
# 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
Â§ Breakpoints for macrolides and related antibiotics were set to categorise wild type H. influenzae
intermediate Other information
Susceptibility and resistance of Streptococcus pneumoniae
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
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.
Clarithromycin is rapidly and well absorbed from the gastrointestinal tract â€“ primarily in the jejunum
â€“ 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 â€“ 2 Âµg/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 Âµg/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
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.