4.1 Therapeutic indications:
Consideration should be given to official guidance on the appropriate use of
antibacterial agents.
Clarithromycin tablets are indicated in adults and children 12 years and older. (Adult
only formulations, e.g. tablets, IV)
Clarithromycin Tablets are indicated for treatment of the following infections caused
by susceptible organisms Indication include:
Lower respiratory tract infections for example: acute and chronic bronchitis, and
pneumonia.
Upper respiratory tract infections for example: sinusitis and pharyngitis.
Clarithromycin is appropriate for initial therapy in community acquired respiratory
infections and has been shown to be active in vitro against common and atypical
respiratory pathogens as listed in the microbiology section.
Clarithromycin is also indicated in skin and soft tissue infections of mild to moderate
severity.
Clarithromycin in the presence of acid suppression effected by omeprazole or
lansoprazole is also indicated for the eradication of H. pylori in patients with
duodenal ulcers. See Dosage and Administration section.

Clarithromycin is usually active against the following organisms in vitro:
Gram-positive Bacteria: Staphylococcus aureus (methicillin susceptible);
Streptococcus pyogenes (Group A beta-hemolytic streptococci); alpha-hemolytic
streptococci (viridans group); Streptococcus (Diplococcus) pneumoniae;
Streptococcus agalactiae; Listeria monocytogenes.
Gram-negative Bacteria: Haemophilus influenzae; Haemophilus parainfluenzae;
Moraxella (Branhamella) catarrhalis; Neisseria gonorrhoeae; Legionella
pneumophila; Bordetella pertussis; Helicobacter pylori; Campylobacter jejuni.
Mycoplasma: Mycoplasma pneumoniae; Ureaplasma urealyticum.
Other Organisms: Chlamydia trachomatis; Mycobacterium avium; Mycobacterium
leprae
Anaerobes: Macrolide-susceptible Bacteroides fragilis; Clostridium perfringens;
Peptococcus species; Peptostreptococcus species; Propionibacterium acnes.
Clarithromycin has bactericidal activity against several bacterial strains. The
organisms include Haemophilus influenzae; Streptococcus pneumoniae;
Streptococcus pyogenes; Streptococcus agalactiae; Moraxella (Branhamella)
catarrhalis; Neisseria gonorrhoeae; H. pylori and Campylobacter spp.
The activity of clarithromycin against H. pylori is greater at neutral pH than at acid
pH.

 

Dosing:
A. One tablet contain 500 mg.
B. Half a tablet contain 250 mg.
Note: to split tablet place it on a hard surface and press down with one thumb on the
left of the dividing groove and the other thumb on the right. The tablet can thus be
readily split into halves.
Patients with respiratory tract/skin and soft tissue infections
Adults: The usual dose is 250 mg twice daily although this may be increased to
500mg twice daily in severe infections. The usual duration of treatment is 6 to 14
days. (Adult only formulation)
Children older than 12 years: As for adults.
Children younger than 12 years: Use of clarithromycin tablets are not recommended
for children younger than 12 years. Clinical trials have been conducted using clarithromycin paediatric suspension in children 6 months to 12 years of age.
Therefore, children under 12 years of age should use clarithromycin paediatric
suspension (granules for oral suspension).

Eradication of H. pylori in patients with duodenal ulcers (Adults)
The usual duration of treatment is 6 to 14 days.
Triple Therapy:
Clarithromycin 500mg twice daily and lansoprazole 30mg twice daily should be given
with amoxycillin 1000mg twice daily.
Triple Therapy:
Clarithromycin 500mg twice daily and lansoprazole 30mg twice daily should be given
with metronidazole 400mg twice daily.
Triple Therapy:
Clarithromycin 500mg twice daily and omeprazole 40mg daily should be given with
amoxycillin 1000mg twice daily or metronidazole 400mg twice daily.
Triple Therapy:
Clarithromycin 500mg twice daily should be given with amoxycillin 1000mg twice
daily and omeprazole 20mg daily.
Dual Therapy:
The usual dose of clarithromycin is 500 mg three times daily for 14 days.
Clarithromycin should be administered with oral omeprazole 40 mg once daily. The
pivotal study was conducted with omeprazole 40 mg once daily for 28 days.
Supportive studies have been conducted with omeprazole 40 mg once daily.
Elderly
As for adults.
Renal impairment
Dosage adjustments are not usually required except in patients with severe renal
impairment (creatinine clearance < 30 ml/min). If adjustment is necessary, the total
daily dosage should be reduced by half, e.g. 250 mg once daily or 250 mg twice daily
in more severe infections. Treatment should not be continued beyond 14 days in
these patients.
Clarithromycin may be given without regard to meals as food does not affect the
extent of bioavailability.

 

Clarithromycin is contraindicated in patients with known hypersensitivity to clarithromycin, to any other macrolide antibiotic drug, or to any of the other ingredients in the tablets. Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is contraindicated, as this may result in ergot toxicity. Concomitant administration of clarithromycin and any of the following drugs is contraindicated : astemizole, cisapride, pimozide and terfenadine as this may result in QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointe (see section 4.5). 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 metabolized by CYP3A4 (lovastatin or simvastatin), due to increased risk of myopathy, including rhabdomyolysis. Treatment with these agents should be discontinued during clarithromycin treatment (see section 4.4). Colchicine is contraindicated in patients with renal or hepatic impairment who are taking P-glycoprotein or a strong CYP3A4 inhibitor. 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.

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).
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 this antibiotic to patients with impaired hepatic function.
Caution should also be exercised when administering clarithromycin 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 difficile- associated diarrhoea (CDAD) has been reported with use of
nearly all antibacterial agents including clarithromycin, and may range in severity
from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the
normal flora of the colon, which may lead to overgrowth of C. difficile. CDAD must be
considered in all patients who present with diarrhoea following antibiotic use. Careful
medical history is necessary since CDAD has been reported to occur over two
months after the administration of antibacterial agents. Therefore, discontinuation of
clarithromycin therapy should be considered regardless of the indication. Microbial
testing should be performed and adequate treatment initiated. Drugs inhibiting
peristalsis should be avoided.
Exacerbation of symptoms of myasthenia gravis has been reported in patients
receiving clarithromycin therapy.
There have been post-marketing reports of colchicine toxicity with concomitant use of
clarithromycin and colchicine, especially in the elderly, some of which occurred in
patients with renal insufficiency. Deaths have been reported in some such patients
(see section 4.5). If concomitant administration of colchicine and clarithromycin is
necessary, patients should be monitored for clinical symptoms of colchicine toxicity
(see section 4.3).
Caution is advised regarding concomitant administration of clarithromycin and
triazolobenzodiazepines, such as triazolam, and midazolam (see section 4.5).
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.

Due to the risk for QT prolongation, clarithromycin 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). Clarithromycin
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
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.
In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-
Johnson Syndrome, and toxic epidermal necrolysis, DRESS and Henoch-Schonlein
purpura, clarithromycin therapy should be discontinued immediately and appropriate
treatment should be urgently initiated.
Clarithromycin should be used with caution when administered concurrently with
medications that induce the cytochrome CYP3A4 enzyme (see section 4.5).
HMG-CoA reductase inhibitors: Concomitant use of clarithromycin with lovastatin or
simvastatin is contraindicated (see section 4.3) as these statins are extensively
metabolized by CYP3A4 and concomitant treatment with clarithromycin increases
their plasma concentration, which increases the risk of myopathy, including
rhabdomyolysis. Rare reports of rhabdomyolysis have been reported in patients
taking these drugs concomitantly with these statins.
If treatment with clarithromycin cannot be avoided, therapy with lovastatin or
simvastatin must be suspended during the course of treatment.
Caution should be exercised when prescribing clarithromycin with statins.

In situations where the concomitant use of clarithromycin with statins cannot be
avoided, it is recommended to prescribe the lowest registered dose of the statin. Use
of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin or
pravastatin) should be considered.
Oral hypoglycaemic agents/Insulin: The concomitant use of clarithromycin and oral
hypoglycaemic agents and/or insulin can result in significant hypoglycaemia. With
certain hypoglycaemic drugs such as nateglinide, pioglitazone, repaglinide and
rosiglitazone, inhibition of CYP3A enzyme by clarithromycin may be involved and
could cause hypolgycemia when used concomitantly. Careful monitoring of glucose is
recommended.
Oral anticoagulants: There is a risk of serious haemorrhage and significant elevations
in International Normalized Ratio (INR) and prothrombin time when clarithromycin is
co-administered with warfarin (see section 4.5). INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral
anticoagulants concurrently.
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 colonisation with increased
numbers of non-susceptible bacteria and fungi. If superinfections occur, appropriate
therapy should be instituted.
Attention should also be paid to the possibility of cross resistance between
clarithromycin 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 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).
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 clarithromycin and terfenadine resulted in 2- to 3-fold
increase in the serum level of the acid metabolite of terfenadine and in prolongation
of the QT interval which did not lead to any clinically detectable effect. Similar effects
have been observed with concomitant administration of astemizole and other
macrolides.
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 ischaemia 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).
Effects of Other Medicinal Products on Clarithromycin
Drugs that are inducers of CYP3A (e.g. rifampicin, phenytoin, carbamazepine,
phenobarbital, St John's wort) may induce the metabolism of clarithromycin. This may
result in sub-therapeutic levels of clarithromycin leading to reduced efficacy.
Furthermore, it might be necessary to monitor the plasma levels of the CYP3A

inducer, which could be increased owing to the inhibition of CYP3A by clarithromycin
(see also the relevant product information for the CYP3A4 inhibitor administered).
Concomitant administration of rifabutin and clarithromycin resulted in an increase in
rifabutin, and decrease in clarithromycin serum levels together with an increased risk
of uveitis.
The following drugs are known or suspected to affect circulating concentrations of
clarithromycin; clarithromycin dosage adjustment or consideration of alternative
treatments may be required.
Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine
Strong inducers of the cytochrome P450 metabolism system such as efavirenz,
nevirapine, rifampicin, rifabutin, and rifapentine may accelerate the metabolism of
clarithromycin and thus lower the plasma levels of clarithromycin, while increasing
those of 14-OH-clarithromycin, a metabolite that is also microbiologically active.
Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are
different for different bacteria, the intended therapeutic effect could be impaired
during concomitant administration of clarithromycin and enzyme inducers.
Etravirine
Clarithromycin exposure was decreased by etravirine; however, concentrations of the
active metabolite, 14-OHclarithromycin, were increased. Because 14-OHclarithromycin
has reduced activity against Mycobacterium avium complex (MAC),
overall activity against this pathogen may be altered; therefore alternatives to
clarithromycin should be considered for the treatment of MAC.
Fluconazole
Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg
twice daily to 21 healthy volunteers led to increases in the mean steady-state
minimum clarithromycin concentration (Cmin) and area under the curve (AUC) of
33% and 18% respectively. Steady state concentrations of the active metabolite 14-
OH-clarithromycin were not significantly affected by concomitant administration of
fluconazole. No clarithromycin dose adjustment is necessary.

Ritonavir
A pharmacokinetic study demonstrated that the concomitant administration of
ritonavir 200 mg every eight hours and clarithromycin 500 mg every 12 hours resulted
in a marked inhibition of the metabolism of clarithromycin. The clarithromycin Cmax
increased by 31%, Cmin increased 182% and AUC increased by 77% with
concomitant administration of ritonavir. An essentially complete inhibition of the
formation of 14-OH-clarithromycin was noted. Because of the large therapeutic
window for clarithromycin, no dosage reduction should be necessary in patients with
normal renal function. However, for patients with renal impairment, the following
dosage adjustments should be considered: For patients with CLCR 30 to 60 mL/min
the dose of clarithromycin should be reduced by 50%. For patients with CLCR <30

mL/min the dose of clarithromycin should be decreased by 75%. Doses of
clarithromycin greater than 1 gm/day should not be co-administered with ritonavir.
Similar dose adjustments should be considered in patients with reduced renal
function when ritonavir is used as a pharmacokinetic enhancer with other HIV
protease inhibitors including atazanavir and saquinavir (see section below, Bidirectional
drug interactions)
Effect of Clarithromycin on Other Medicinal Products
CYP3A-based interactions
Co-administration of clarithromycin, known to inhibit CYP3A, and a drug primarily
metabolised by CYP3A may be associated with elevations in drug concentrations that
could increase or prolong both therapeutic and adverse effects of the concomitant
drug. Clarithromycin should be used with caution in patients receiving treatment with
other drugs known to be CYP3A enzyme substrates, especially if the CYP3A
substrate has a narrow safety margin (e.g. carbamazepine) and/or the substrate is
extensively metabolised by this enzyme.
Dosage adjustments may be considered, and when possible, serum concentrations
of drugs primarily metabolised by CYP3A should be monitored closely in patients
concurrently receiving clarithromycin.
The following drugs or drug classes are known or suspected to be metabolised by the
same CYP3A isozyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride,
ciclosporin, disopyramide, ergot alkaloids, lovastatin, methylprednisolone,
midazolam, omeprazole, oral anticoagulants (e.g. warfarin), 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 post-marketed reports of torsade de points occurring with the
concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms
should be monitored for QTc prolongation during co-administration of clarithromycin
with these drugs. Serum levels of quinidine and disopyramide should be monitored
during clarithromycin therapy.
Omeprazole
Clarithromycin (500 mg every 8 hours) was given in combination with omeprazole (40
mg daily) to healthy adult subjects. The steady-state plasma concentrations of
omeprazole were increased (Cmax, AUC0-24, and t1/2 increased by 30%, 89%, and
34%, respectively), by the concomitant administration of clarithromycin. The mean
24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7
when omeprazole was co-administered with clarithromycin.

Sildenafil, tadalafil and vardenafil

Each of these phosphodiesterase inhibitors is metabolised, at least in part, by
CYP3A, and CYP3A may be inhibited by concomitantly administered clarithromycin.
Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil would likely
result in increased phosphodiesterase inhibitor exposure. Reduction of sildenafil,
tadalafil and vardenafil dosages should be considered when these drugs are coadministered
with clarithromycin.
Theophylline, carbamazepine
Results of clinical studies indicate that there was a modest but statistically significant
(p≤ 0.05) increase of circulating theophylline or carbamazepine levels when either of
these 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 as
clarithromycin in the CYP2D6 poor metaboliser population.

Triazolobenzodiazepines (e.g., alprazolam, midazolam, triazolam)
When midazolam was co-administered with clarithromycin tablets (500 mg twice
daily), midazolam AUC was increased 2.7-fold after intravenous administration of
midazolam and 7-fold after oral administration. Concomitant administration of oral
midazolam and clarithromycin should be avoided. If intravenous midazolam is coadministered
with clarithromycin, the patient must be closely monitored to allow dose
adjustment. The same precautions should also apply to other benzodiazepines that
are metabolised by CYP3A, including triazolam and alprazolam. For benzodiazepines
which are not dependent on CYP3A for their elimination (temazepam, nitrazepam,
lorazepam), a clinically important interaction with clarithromycin is unlikely.
There have been post-marketing reports of drug interactions and central nervous
system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of
clarithromycin and triazolam. Monitoring the patient for increased CNS
pharmacological effects is suggested.
Other drug interactions
Colchicine
Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein
(Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp.
When clarithromycin and colchicine are administered together, inhibition of Pgp
and/or CYP3A by clarithromycin may lead to increased exposure to colchicine.

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.
Zidovudine
Simultaneous oral administration of clarithromycin tablets and zidovudine to HIVinfected
adult patients may result in decreased steady-state zidovudine
concentrations. Because clarithromycin appears to interfere with the absorption of
simultaneously administered oral zidovudine, this interaction can be largely avoided
by staggering the doses of clarithromycin and zidovudineto 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 metabolised 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-OHclarithromycin,
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 coadministered 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.
Saquinavir
Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and there
is evidence of a bi-directional drug interaction. Concomitant administration of
clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg
three times daily) to 12 healthy volunteers resulted in steady-state AUC and Cmax
values of saquinavir which were 177% and 187% higher than those seen with
saquinavir alone. Clarithromycin AUC and Cmax values were approximately 40%
higher than those seen with clarithromycin alone. No dose adjustment is required
when the two 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 4.5: Ritonavir).
Verapamil
Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients
taking clarithromycin and verapamil concomitantly.
Clarithromycin has been shown not to interact with oral contraceptives.

pregnancy category: C
The safety of clarithromycin during pregnancy and breast feeding of infants 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. Clarithromycin is excreted into
human breast milk.

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

a. Summary of the safety profile
The most frequent and common adverse reactions related to clarithromycin therapy
for both adult and peadiatric populations are abdominal pain, diarrhoea, 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 clarithromycin immediate-release tablets, granules for oral
suspension, powder for solution for injection, extended-release tablets and modifiedrelease
tablets.
The reactions considered at least possibly related to clarithromycin are displayed by
system organ class and frequency using the following convention: very common
(≥1/10), common (≥ 1/100 to < 1/10), uncommon (≥1/1,000 to < 1/100) and not
known (adverse reactions from post-marketing experience; cannot be estimated from
the available data). Within each frequency grouping, adverse reactions are presented
in order of decreasing seriousness when the seriousness could be assessed.

1 ADRs reported only for the Powder for Solution for Injection formulation
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
5,8,10,11,12See section a)
6,7,9See section c)

* Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure. Patient exposure is estimated to be greater than 1
billion patient treatment days for clarithromycin.
**In some of the reports of rhabdomyolysis, clarithromycin was administered
concomitantly with other drugs known to be associated with rhabdomyolysis (such as
statins, fibrates, colchicine or allopurinol).
c. Description of selected adverse reactions
Injection site phlebitis, injection site pain, vessel puncture site pain, and injection site
inflammation are specific to the clarithromycin intravenous formulation.
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 diarrhoea should be paid as Clostridium difficile-associated
diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents
including clarithromycin, and may range in severity from mild diarrhoea to fatal colitis.
(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).
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
diarrhoea subsequent to the administration of antibacterial agents (see section 4.4).
In some of the reports of rhabdomyolysis, clarithromycin was administered
concomitantly with statins, fibrates, colchicine or allopurinol (see section 4.3 and 4.4).
There have been post-marketing reports of 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 hypoglycaemia, some of which have occurred in
patients on concomitant oral hypoglycaemic 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 haemorrhage 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).
There have been rare reports of clarithromycin ER tablets in the stool, many of which
have occurred in patients with anatomic (including ileostomy or colostomy) or
functional gastrointestinal disorders with shortened GI transit times. In several
reports, tablet residues have occurred in the context of diarrhoea. It is recommended
that patients who experience tablet residue in the stool and no improvement in their
condition should be switched to a different clarithromycin formulation (e.g.
suspension) or another antibiotic.
Special population: Adverse Reactions in Immunocompromised Patients (see section
e)

d. Paediatric populations
Clinical trials have been conducted using clarithromycin paediatric suspension in
children 6 months to 12 years of age. Therefore, children under 12 years of age
should use clarithromycin paediatric suspension. There are insufficient data to
recommend a dosage regimen for use of the clarithromycin 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
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 2000mg of clarithromycin were: nausea,
vomiting, taste perversion, abdominal pain, diarrhoea, rash, flatulence, headache,
constipation, hearing disturbance, Serum Glutamic Oxaloacetic Transaminase
(SGOT) and Serum Glutamic Pyruvate Transaminase (SGPT) elevations. Additional
low-frequency events included dyspnoea, insomnia and dry mouth. The incidences
were comparable for patients treated with 1000mg and 2000mg, but were generally
about 3 to 4 times as frequent for those patients who received total daily doses of
4000mg 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 1000mg or 2000mg 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 4000mg daily for all parameters except
White Blood Cell.

Reports indicate that the ingestion of large amounts of clarithromycin can be
expected to produce gastro-intestinal symptoms. One patient who had a history of
bipolar disorder ingested 8 grams of clarithromycin and showed altered mental
status, paranoid behaviour, hypokalemia and hypoxemia. Adverse reactions
accompanying overdose should be treated by the prompt elimination of unabsorbed
drug and supportive measures. As with other macrolides, clarithromycin serum
levels are not expected to be appreciably affected by haemodialysis or peritoneal
dialysis.

5.1 Pharmacodynamics properties:
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 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. influenzae where the 14-hydroxy metabolite is two-fold more active than
the parent compound.
Clarithromycin is usually active against the following organisms in vitro:-
Gram-positive Bacteria: Staphylococcus aureus (methicillin susceptible);
Streptococcus pyogenes (Group A beta-hemolytic streptococci); alpha-hemolytic
streptococci (viridans group); Streptococcus (Diplococcus)pneumoniae;
Streptococcus agalactiae; Listeria monocytogenes.
Gram-negative Bacteria: Haemophilus influenzae; Haemophilus parainfluenzae;
Moraxella (Branhamella) catarrhalis; Neisseria gonorrhoeae; Legionella pneumophila;
Bordetella pertussis; Helicobacter pylori; Campylobacter jejuni.
Mycoplasma: Mycoplasma pneumoniae; Ureaplasma urealyticum.
Other Organisms: Chlamydia trachomatis; Mycobacterium avium; Mycobacterium
leprae;
Anaerobes: Macrolide-susceptible Bacteroides fragilis; Clostridium perfringens;
Peptococcus species; Peptostreptococcus species; Propionibacterium acnes.
Clarithromycin has bactericidal activity against several bacterial strains. The
organisms include Haemophilus influenzae, Streptococcus pneumoniae,
Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella)
catarrhalis, Neisseria gonorrhoeae, H. pylori and Campylobacter spp.

H. pylori is associated with acid peptic disease including duodenal ulcer and gastric
ulcer in which about 95% and 80% of patients respectively are infected with the
agent. H. pylori is also implicated as a major contribution factor in the development of
gastric and ulcer recurrence in such patients.
Clarithromycin has been used in small numbers of patients in other treatment
regimens. Possible kinetic interactions have not been fully investigated. These
regimens include:
Clarithromycin plus tinidazole and omeprazole; clarithromycin plus tetracycline,
bismuth subsalicylate and ranitidine; clarithromycin plus ranitidine alone.
Clinical studies using various different H. pylori eradication regimens have shown that
eradication of H. pylori prevents ulcer recurrence.
Clarithromycin is rapidly and well absorbed from the gastro-intestinal tract after oral
administration of Clarithromycin tablets. The microbiologically active metabolite 14-

hydroxyclarithromycin is formed by first pass metabolism. Clarithromycin may be
given without regard to meals as food does not affect the extent of bioavailability of
Clarithromycin tablets. Food does slightly delay the onset of absorption of
clarithromycin and formation of the 14-hydroxymetabolite. The pharmacokinetics of
clarithromycin are non linear; however, steady-state is attained within 2 days of
dosing. At 250 mg b.i.d. 15-20% of unchanged drug is excreted in the urine. With 500
mg b.i.d. daily dosing urinary excretion is greater (approximately 36%). The 14-
hydroxyclarithromycin is the major urinary metabolite and accounts for 10-15% of the
dose. Most of the remainder of the dose is eliminated in the faeces, primarily via the
bile. 5-10% of the parent drug is recovered from the faeces.
When clarithromycin 500 mg is given three times daily, the clarithromycin plasma
concentrations are increased with respect to the 500 mg twice daily dosage.
Clarithromycin provides tissue concentrations that are several times higher than the
circulating drug levels. Increased levels have been found in both tonsillar and lung
tissue. Clarithromycin is 80% bound to plasma proteins at therapeutic levels.
Clarithromycin also penetrates the gastric mucus. Levels of clarithromycin in gastric
mucus and gastric tissue are higher when clarithromycin is co-administered with
omeprazole than when clarithromycin is administered alone.

In acute mouse and rat studies, the median lethal dose was greater than the highest
feasible dose for administration (5g/kg).
In repeated dose studies, toxicity was related to dose, duration of treatment and
species. Dogs were more sensitive than primates or rats. The major clinical signs at
toxic doses included emesis, weakness, reduced food consumption and weight gain,
salivation, dehydration and hyperactivity. In all species the liver was the primary
target organ at toxic doses. Hepatotoxicity was detectable by early elevations of liver
function tests. Discontinuation of the drug generally resulted in a return to or toward
normal results. Other tissues less commonly affected included the stomach, thymus
and other lymphoid tissues and the kidneys. At near therapeutic doses, conjunctival
injection and lacrimation occurred only in dogs. At a massive dose of 400mg/kg/day,
some dogs and monkeys developed corneal opacities and/or oedema.
Fertility and reproduction studies in rats have shown no adverse effects.
Teratogenicity studies in rats (Wistar (p.o.) and Spraque-Dawley (p.o. and i.v.)), New
Zealand White rabbits and cynomolgous monkeys failed to demonstrate any
teratogenicity from clarithromycin. However, a further similar study in Sprague-
Dawley rats indicated a low (6%) incidence of cardiovascular abnormalities, which
appeared to be due to spontaneous expression of genetic changes. Two mouse
studies revealed a variable incidence (3-30%) of cleft palate and embryonic loss was
seen in monkeys but only at dose levels, which were clearly toxic to the mothers.

Klare 500 mg film-coated tablets contain the following excipients
Material Name : Qty/unit (mg/ Tablet)
Tablet core:
Croscarmellose Sodium 70.00
Microcrystalline Cellulose 170.60
Povidone K 30 40.00
Pregelatinized Maize Starch 130.00
Colloidal Anhydrous Silica 14.40
Talc Powder 35.00
Stearic Acid 25.00
Magnesium Stearate 15.00
Tablet coating:
Opadry OYS-32924 Yellow 30.00

Not Applicable.
 

The shelf life is 2 years.

Store below 30°C.
This medicinal product does not require any special storage conditions

-The immediate packaging material is PVC/PVDC/Alu Blister.
-Pack size: 14 Film-Coated Tablets.

No special requirements.