Consideration should be given to official guidance on the appropriate use of
antibacterial agents.
Klacid XL 500 mg Tablets are indicated in adults and children 12 years and
older.
Klacid XL 500 mg Tablets are 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.
Klacid XL 500 mg Tablets are also indicated in skin and soft tissue infections
of mild to moderate severity, for example folliculitis, cellulitis and erysipelas
(see section 4.4 and 5.1 regarding Sensitivity Testing).

Adults: The usual recommended dosage of Klacid XL 500 mg Tablets in
adults is one 500mg modified-release tablet daily to be taken with food. In
more severe infections, the dosage can be increased to two 500mg modifiedrelease
tablets daily. The usual duration of treatment is 6 to 14 days.

Children older than 12 years: As for adults.
Do not crush or chew Klacid XL 500 mg Tablets.
Klacid XL 500 mg Tablets should not be used in patients with significant renal
impairment (creatinine clearance less than 30 ml/min), as appropriate
clarithromycin dosage reduction is not possible when administering this
product. Clarithromycin immediate release tablets may be utilized in this
patient population (see section 4.3). 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. For patients with moderate renal function (creatinine clearance 30 to
60 ml/min), a 50% dosage reduction should be implemented resulting in a
maximum dose of one Klacid XL 500 mg Tablet per day.
Children younger than 12 years: Use of Klacid XL 500 mg Tablets are not
recommended for children younger than 12 years. Clinical trials have been
conducted using clarithromycin peadiatric suspension in children 6 months to
12 years of age. Therefore, children under 12 years of age should use
clarithromycin peadiatric suspension (granules for oral suspension).

Hypersensitivity to macrolide antibiotic drugs or to any of the excipients listed in section 6.1. In the case of Klacid XL 500 mg Tablets, as the dose cannot be reduced from 500mg daily, Klacid 500 mg Tablets are contraindicated in patients with creatinine clearance less than 30 mL/min. All other formulations may be used in this patient population. 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, pimozide and terfenadine as this may result in QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see section 4.5). 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.

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 lifethreatening.
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:
Prolonged cardiac repolarisation and QT interval, imparting a risk of
developing cardiac arrhythmia and torsades de pointes, have been seen in
treatment with macrolides including clarithromycin (see section 4.8).
Therefore, as the following situations may lead to an increased risk for
ventricular arrhythmias (including torsades de pointes), clarithromycin should
be used with caution in the following patients;
• Patients with coronary artery disease, severe cardiac insufficiency,
conduction disturbances or clinically relevant bradycardia
• Patients with electrolyte disturbances such as hypomagnesaemia.
Clarithromycin must not be given to patients with hypokalaemia (see
section 4.3).
• Patients concomitantly taking other medicinal products associated with
QT prolongation (see section 4.5).
• Concomitant administration of clarithromycin with astemizole,
cisapride, pimozide and terfenadine is contraindicated (see section 4.3).
Clarithromycin must not be used in patients with congenital or
documented acquired QT prolongation or history of ventricular
arrhythmia (see section 4.3).

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 hospitalacquired
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
Klacid Modified Release contains lactose. Patients with rare hereditary
problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose
malabsorption should not take these medicines
Klacid XL 500mg Tablets contain 15.3 mg sodium per tablet. If patients
receive two Modified Release tablets once daily, the resulting sodium amount
(in total 30.6 mg per dose) should be taken into consideration for patients on a
controlled sodium diet.

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.

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-
OH-clarithromycin 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 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, see 4.4), atypical antipsychotics (e.g. quetiapine), pimozide,
quinidine, rifabutin, sildenafil, simvastatin, sirolimus, tacrolimus, terfenadine,
triazolam and vinblastine but this list is not exhaustive. 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, Pglycoprotein
(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
HIV-infected 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 coadministered
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

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		Haemorrhage8
Respiratory, thoracic and mediastinal disorder			Asthma1, epistaxis2, pulmonary embolism1
Gastrointestinal 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
Hepatobiliary 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 maculo-papular3	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
Musculoskeleta l 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 administration site conditions	Injection site phlebitis1	Injection site pain1, injection site inflammation1	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 for Infusion
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
5,6 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.

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 subunit
of susceptible bacteria preventing translocation of activitate amino acids.
It inhibits the intracellular protein synthesis of susceptible bacteria.
The 14-(R)-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 twofold
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 influenza; Haemophilus
parainfluenza; Moraxella (Branhamella) catarrhalis; Neisseria gonorrhoeae;
Legionella pneumophila; Bordetella pertussis; Campylobacter jejuni.
Mycoplasma: Mycoplasma pneumoniae; Ureaplasma urealyticum.
Other Organisms: Chlamydia trachomatis; Mycobacterium avium;
Mycobacterium leprae; Mycobacterium kansasii; Mycobacterium chelonae;
Mycobacterium fortuitum; Mycobacterium intracellularis; Chlamydia
pneumoniae.
Anaerobes: 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 and Campylobacter spp.
Breakpoints
The following breakpoints have been established by the European Committee
for Antimicrobial Susceptibility Testing (EUCAST).

Breakpoints (MIC, mg/L)
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.

 

 

The kinetics of orally administered modified-release clarithromycin have been
studied in adult humans and compared with clarithromycin 250mg and 500mg
immediate release tablets. The extent of absorption was found to be
equivalent when equal total daily doses were administered. The absolute
bioavailability is approximately 50%. Little or no unpredicted accumulation
was found and the metabolic disposition did not change in any species
following multiple dosing. Based upon the finding of equivalent absorption
the following in vitro and in vivo data are applicable to the modified-release
formulation.
In vitro: Results of in vitro studies showed that the protein binding of
clarithromycin in human plasma averaged about 70 % at concentrations of
0.45 - 4.5μg/mL. A decrease in binding to 41% at 45.0μg/mL suggested that
the binding sites might become saturated, but this only occurred at
concentrations far in excess of therapeutic drug levels.

In vivo: Clarithromycin levels in all tissues, except the central nervous system,
were several times higher than the circulating drug levels. The highest
concentrations were found in the liver and lung tissue, where the tissue to
plasma ratios reached 10 to 20.
The pharmacokinetic behaviour of clarithromycin is non-linear. In fed
patients given 500mg clarithromycin modified-release daily, the peak steady
state plasma concentration of clarithromycin and 14 hydroxy clarithromycin
were 1.3 and 0.48μg/mL, respectively. When the dosage was increased to
1000mg daily, these steady-state values were 2.4μg/mL and 0.67μg/mL
respectively. Elimination half-lives of the parent drug and metabolite were
approximately 5.3 and 7.7 hours respectively. The apparent half-lives of both
clarithromycin and its hydroxylated metabolite tended to be longer at higher
doses.

Urinary excretion accounted for approximately 40% of the clarithromycin
dose. Faecal elimination accounts for approximately 30%.

In repeated dose studies, clarithromycin toxicity was related to dose and
duration of treatment. The primary target organ was the liver in all species,
with hepatic lesions seen after 14 days in dogs and monkeys. Systemic
exposure levels associated with this toxicity are not known but toxic mg/kg
doses were higher than the dose recommended for patient treatment.
No evidence of mutagenic potential of clarithromycin was seen during a range
of in vitro and in vivo tests.
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 in monkeys embryonic loss was seen
but only at dose levels which were clearly toxic to the mothers.
No other toxicological findings considered to be of relevance to the dose level
recommended for patient treatment have been reported.

6.1 List of excipients
Tablet Core:
Citric acid
Sodium alginate
Sodium calcium alginate
Lactose
Povidone
Talc
Stearic acid
Magnesium stearate
Coating Solution
Hypromellose
Polyethylene glycol
Titanium dioxide
Quinoline Yellow (E104 aluminium lake)
Sorbic acid

None known.

36 Months

Do not store above 25°C. Store in the original package.
Keep this medicine out of sight and reach of children.

7 or 14 tablets in a blister original pack or in bottles. The blisters, of
PVC/PVdC, are heat sealed with 20 micron hard tempered aluminium foil and
packaged in a cardboard carton with a pack insert.
Not all pack sizes may be marketed.

No special requirements for disposal.