4.1 Therapeutic indications
Consideration should be given to official guidance on the appropriate use of
antibacterial agents.
Klacid 500mg Tablets are indicated in adults and children 12 years and older.
Clarithromycin is indicated for treatment of infections caused by susceptible
organisms. Indications include:
Lower respiratory tract infections for example, acute and chronic bronchitis, and
pneumonia (see section 4.4 and 5.1 regarding Sensitivity Testing).
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 (e.g. folliculitis, cellulitis, erysipelas) (see section 4.4 and
5.1 regarding Sensitivity Testing).
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-haemolytic streptococci); alpha- haemolytic
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.

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.
Children older than 12 years: As for adults. Children
younger than 12 years:
Use of Klacid 500mg 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).
Clarithromycin may be given without regard to meals as food does not affect the
extent of bioavailability.

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 and omeprazole 20mg daily should be given
with amoxycillin 1000mg twice daily.

Elderly: As for adults.
Renal 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.

Hypersensitivity to macrolide antibiotic drugs or to any of the excipients listed in section 6.1. Concomitant administration of clarithromycin and ergot alkaloids (e.g. ergotamine or dihydroergotamine) is contraindicated, as this may result in ergot toxicity (see section 4.5). Concomitant administration of clarithromycin and oral midazolam is contraindicated (see section 4.5). Concomitant administration of clarithromycin and any of the following drugs is contraindicated: astemizole, cisapride, domperidone, pimozide and terfenadine as this may result in QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see section 4.4 and 4.5). Clarithromycin should not be given to patients with history of QT prolongation (congenital or documented acquired QT prolongation) or ventricular cardiac arrhythmia, including torsades de pointes (see sections 4.4 and 4.5). Concomitant administration with ticagrelor or ranolazine is contraindicated. Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4, (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see section 4.5). As with other strong CYP3A4 inhibitors, Clarithromycin should not be used in patients taking colchicine (see sections 4.4 and 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.

Use of any antimicrobial therapy, such as clarithromycin, to treat H. pylori
infection may select for drug-resistant organisms.
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).
Clarithromycin is principally metabolised 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 (see section 4.2).
Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or
cholestatic hepatitis, with or without jaundice, has been reported with
clarithromycin. This hepatic dysfunction may be severe and is usually reversible.
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.

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). Concomitant administration of clarithromycin and
colchicine is contraindicated (see section 4.3).
Caution is advised regarding concomitant administration of clarithromycin and
triazolobenzodiazepines, such as triazolam, and intravenous or oromucosal
midazolam (see section 4.5).

Cardiovascular Events:
Prolongation of the QT interval, reflecting effects on cardiac repolarisation
imparting a risk of developing cardiac arrhythmia and torsades de pointes, have
been seen in patients treated with macrolides including clarithromycin (see section
4.8). Due to increased risk of QT prolongation and ventricular arrhythmias
(including torsades de pointes), the use of clarithromycin is contraindicated: in
patients taking any of astemizole, cisapride, domperidone, pimozide and
terfenadine; in patients who have hypokalaemia; and in patients with a history of
QT prolongation or ventricular cardiac arrhythmia (see section 4.3).
Furthermore, clarithromycin should be used with caution in the following:
• Patients with coronary artery disease, severe cardiac insufficiency,
conduction disturbances or clinically relevant bradycardia;
• Patients with hypomagnesaemia;
• Patients concomitantly taking other medicinal products associated with QT
prolongation other than those which are contraindicated
Epidemiological studies investigating the risk of adverse cardiovascular outcomes
with macrolides have shown variable results. Some observational studies have
identified a rare short-term risk of arrhythmia, myocardial infarction and cardiovascular mortality associated with macrolides including clarithromycin.
Consideration of these findings should be balanced with treatment benefits when
prescribing clarithromycin.
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, acne
vulgaris, and erysipelas and in situations where penicillin treatment cannot be
used.

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, severe
cutaneous adverse reactions (SCAR) (e.g. Acute generalised exanthematous
pustulosis (AGEP), Stevens-Johnson Syndrome, toxic epidermal necrolysis and
drug rash with eosinophilia and systemic symptoms (DRESS)), 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 (statins): Concomitant use of clarithromycin with
lovastatin or simvastatin is contraindicated (see section 4.3). Caution should be
exercised when prescribing clarithromycin with other statins.
Rhabdomyolysis has been reported in patients taking clarithromycin and statins.
Patients should be monitored for signs and symptoms of myopathy.
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) can
be considered (see section 4.5).

Oral hypoglycaemic agents/Insulin: The concomitant use of clarithromycin and
oral hypoglycaemic agents (such as sulphonylurias) and/or insulin can result in
significant hypoglycaemia. Careful monitoring of glucose is recommended (see
section 4.5).
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.
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.
Excipients
This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to
say essentially ‘sodium-free’.

The use of the following drugs is strictly contraindicated due to the potential
for severe drug interaction effects:
Astemizole, cisapride, domperidone, pimozide, 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.

Ergot alkaloids:
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 ergot alkaloids is contraindicated (see section 4.3).
Oral Midazolam
When midazolam was co-administered with clarithromycin tablets (500 mg twice
daily), midazolam AUC was increased 7-fold after oral administration of
midazolam. Concomitant administration of oral midazolam and clarithromycin is contraindicated (see section 4.3).
HMG-CoA Reductase Inhibitors (statins)
Concomitant use of clarithromycin with lovastatin or simvastatin is
contraindicated (see 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.
Reports of rhabdomyolysis have been received for patients taking clarithromycin
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) 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, 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 inducer
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-OH-clarithromycin, 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 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, Bidirectional
drug interactions).

Effect of Clarithromycin on Other Medicinal Products
CYP3A-based interactions
Co-administration of clarithromycin, which is 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.
The use of clarithromycin is contraindicated in patients receiving the CYP3A
substrates astemizole, cisapride, domperidone, pimozide and terfenadine due to the
risk of QT prolongation and cardiac arrhythmias, including ventricular
tachycardia, ventricular fibrillation, and torsades de pointes (see sections 4.3 and
4.4).

The use of clarithromycin is also contraindicated with ergot alkaloids, oral
midazolam, HMG CoA reductase inhibitors metabolised mainly by CYP3A4 (e.g.
lovastatin and simvastatin), colchicine, ticagrelor and ranolazine (see section 4.3).
Caution is required if clarithromycin is co-administered 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. Drugs or drug classes that
are known or suspected to be metabolised by the same CYP3A isozyme include
(but this list is not comprehensive) alprazolam, carbamazepine, cilostazole,
ciclosporin, disopyramide, ibrutinib, methylprednisolone, midazolam (intravenous),
omeprazole, oral anticoagulants (e.g. warfarin), atypical antipsychotics (e.g.
quetiapine), quinidine, rifabutin, sildenafil, sirolimus, tacrolimus, 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 torsades de pointes occurring with the
concurrent use of clarithromycin and quinidine or disopyramide.
Electrocardiograms should be monitored for QT prolongation during coadministration
of clarithromycin with these drugs. Serum levels of quinidine and
disopyramide should be monitored during clarithromycin therapy.

There have been post marketing reports of hypoglycemia with the concomitant
administration of clarithromycin and disopyramide. Therefore blood glucose levels
should be monitored during concomitant administration of clarithromycin and
disopyramide.
Oral hypoglycemic agents/Insulin
With certain hypoglycemic drugs such as nateglinide, and repaglinide, inhibition of
CYP3A enzyme by clarithromycin 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 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 co-administered 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. If intravenous midazolam is co-administered with clarithromycin, the
patient must be closely monitored to allow dose adjustment. Drug delivery of
midazolam via oromucosal route, which could bypass pre-systemic elimination of
the drug, will likely result in a similar interaction to that observed after intravenous
midazolam rather than oral administration. 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 (see
section 4.3 and 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 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 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-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.

Calcium Channel Blockers
Caution is advised regarding the concomitant administration of clarithromycin and
calcium channel blockers metabolized by CYP3A4 (e.g. verapamil, amlodipine,
diltiazem) due to the risk of hypotension. Plasma concentrations
of clarithromycin as well as calcium channel blockers may increase due to the
interaction. Hypotension, bradyarrhythmias and lactic acidosis have been observed
in patients taking clarithromycin and verapamil concomitantly.
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).
Patients taking oral contraceptives should be warned that if diarrhoea, vomiting or
breakthrough bleeding occur there is a possibility of contraceptive failure.

Pregnancy
The safety of clarithromycin 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 clarithromycin for using during breast-feeding of infants has not been
established. 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 paediatric 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 pre- existing mycobacterial infections.

b. Tabulated summary of adverse reactions
The following table displays adverse reactions reported in clinical trials and from
post-marketing experience with clarithromycin 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 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.

System Organ Class	Very common ≥1/10	Common ≥ 1/100 to < 1/10	Uncommon ≥1/1,000 to < 1/100	Not Known* (cannot be estimated from the available data)
Infections and infestations			Cellulitis1, candidiasis, gastroenteritis2, infection3, vaginal infection	Pseudomembranous colitis, erysipelas,
Blood and lymphatic system			Leukopenia, neutropenia4, thrombocythaemia3, eosinophilia4	Agranulocytosis, thrombocytopenia
Immune system disorders			Anaphylactoid reaction1, hypersensitivity	Anaphylactic reaction. angioedema
Metabolism and nutrition disorders			Anorexia, decreased appetite
Psychiatric disorders		Insomnia	Anxiety, nervousness3,	Psychotic disorder, confusional state5, depersonalisation, depression, disorientation, hallucination, abnormal dreams, mania
Nervous system disorders		Dysgeusia, headache	Loss of consciousness1, dyskinesia1, dizziness, somnolence5, tremor	Convulsion, ageusia, parosmia, anosmia, paraesthesia
Ear and labyrinth disorders			Vertigo, hearing impaired, tinnitus	Deafness
Cardiac disorders			Cardiac arrest1, atrial fibrillation1, electrocardiogram QT prolonged, extrasystoles1, palpitations	Torsades de pointes, ventricular tachycardia, ventricular fibrillation
Vascular disorders		Vasodilation1		Haemorrhage
Respiratory, thoracic and mediastinal disorder			Asthma1, epistaxis2, pulmonary embolism1
Gastrointesti nal disorders		Diarrhoea, vomiting, dyspepsia, nausea, abdominal pain	Oesophagitis1, gastrooesophageal reflux disease2, gastritis, proctalgia2, stomatitis, glossitis, abdominal distension4, constipation, dry mouth, eructation, flatulence,	Pancreatitis acute, tongue discolouration, tooth discolouration
Hepatobiliar y disorders		Liver function test abnormal	Cholestasis4, hepatitis4, alanine aminotransferase increased, aspartate aminotransferase increased, gammaglutamyltransferase increased4	Hepatic failure, jaundice hepatocellular
Skin and subcutaneous tissue disorders		Rash, hyperhidrosis	Dermatitis bullous1, pruritus, urticaria, rash maculopapular3	Severe cutaneous adverse reactions (SCAR) (e.g. Acute generalised exanthematous pustulosis (AGEP),Stevens- Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS)), acne
Musculoskel etal and connective tissue disorders			Muscle spasms3, musculoskeletal stiffness1, myalgia2	Rhabdomyolysis2,6, myopathy
Renal and urinary disorders			Blood creatinine increased1, blood urea increased1	Renal failure, nephritis interstitial
General disorders and administratio n site conditions	Injection site phlebitis1	Injection site pain1, injection site inflammation 1	Malaise4, pyrexia3, asthenia, chest pain4, chills4, fatigue4
Investigations			Albumin globulin ratio abnormal1, blood alkaline phosphatase increased4, blood lactate dehydrogenase increased4	International normalised ratio increased, prothrombin time prolonged, urine colour abnormal

1 ADRs reported only for the Powder for Concentrate for Solution 

2 for Infusion formulation

3A DRs reported only for the Extended-Release Tablets formulation

4 ADRs reported only for the Granules for Oral Suspension formulation ADRs reported only for the Immediate-Release Tablets formulation
5, 6, See 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.

 

c. Description of selected adverse reactions
Injection site phlebitis, injection site pain, and injection site inflammation are specific to
the clarithromycin intravenous formulation.
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 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 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.
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.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions.

To report any side effect(s):
-National Pharmacovigilance Center (NPC)
o Fax: +966-1-205-7662
oCall NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
oToll free phone: 8002490000
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc

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, hypokalaemia and hypoxaemia.
Adverse reactions accompanying overdosage 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 Pharmacodynamic properties
ATC Classification:
Pharmacotherapeutic group: Antibacterial for systemic use, macrolide
ATC-Code: J01FA09
Mode of Action:
Clarithromycin is an antibiotic belonging to the macrolide antibiotic group. It
exerts its antibacterial action by selectively binding to the 50s ribosomal sub- unit
of susceptible bacteria preventing translocation of activitate amino acids. It
inhibits the intracellular protein synthesis of susceptible bacteria.
The 14-hydroxy metabolite of clarithromycin, a product of parent drug metabolism
also has antimicrobial activity. The metabolite is less active than
the parent compound for most organisms, including mycobacterium spp. An
exception is Haemophilus influenza 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) alphahemolytic
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; Mycobacterum kansasii; Mycobacterium chelonae; Mycobacterium
fortuitum; Mycobacterium intracellulare.
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.

Breakpoints
The following breakpoints have been established by the European Committee for
Antimicrobial Susceptibility Testing (EUCAST).

Microorganism	Susceptible (≤)	Resistant (>)
Staphylococcus spp	1 mg/L	2 mg/L
Streptococcus A, B, C and G	0.25 mg/L	0.5 mg/L
Streptococcus pneumonia	0.25 mg/L	0.5 mg/L
Viridans group streptococcus	IE	IE
Haemophilus spp.	1 mg/L	32 mg/L
Moraxella catarrhalis	0.25 mg/L	0.5 mg/L 1
Helicobacter pylori	0.25 mg/L1	0.5 mg/L

1 The breakpoints are based on epidemiological cut-off values (ECOFFs),
which distinguish wild-type isolates from those with reduces susceptibility.
“IE" indicates that there is insufficient evidence that the species in
question is a good target for therapy with the drug.

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 gastritis 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 Sprague-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.

Tablet Core Croscarmellose
sodium Cellulose,
microcrystalline Silicon
dioxide
Povidone Stearic
acid
Magnesium stearate Talc
Tablet Coating, Colour and Gloss Coating Hypromellose
Sorbitan oleate Propylene
glycol Titanium dioxide
Vanillin
Quinoline Yellow (E104 aluminium lake)
Hydroxypropylcellulose
Sorbic acid

None known

36 months.

Store below 25° C
Store in a dry place, protected from light.

Tablets in a PVC/ PVdC aluminium foil blister pack. Pack sizes are 14, 20, 28, 42,
84,168 tablets in a carton with a patient leaflet.
Not all pack sizes may be marketed.

No special requirements for disposal.