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 4.4 and 4.5). Concomitant administration of clarithromycin and oral midazolam is contraindicated (see section 4.5). Concomitant administration of clarithromycin and lomitapide 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, ivabradine 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 with electrolyte disturbances (hypokalaemia or hypomagnesaemia, due to the risk of prolongation of the QT interval). 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 life-threatening. Clostridioides difficileassociated
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 electrolyte disturbances such as
hypomagnesaemia or hypokalaemia; and in patients with a history of QT prolongation or
ventricular cardiac arrhythmia (see section 4.3).
Carefully consider the balance of benefits and risks before prescribing clarithromycin for any
patients taking hydroxychloroquine or chloroquine, because of the potential for an increased
risk of cardiovascular events and cardiovascular mortality (see section 4.5).
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 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 coadministered
with warfarin (see section 4.5). INR and prothrombin times should be frequently
monitored while patients are receiving clarithromycin and oral anticoagulants concurrently.
Caution should be exercised when clarithromycin is co-administered with direct acting oral
anticoagulants such as dabigatran, rivaroxaban, apixaban and edoxaban, particularly to
patients at high risk of bleeding (see section 4.5).
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 XL 500mg Tablets contains lactose. Patients with rare hereditary problems of
galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should
not take these medicines
Klacid XL 500mg Tablets contain 15.3 mg (0.665mmol) of sodium. If patients receive two
Klacid XL 500mg tablets once daily, the resulting sodium amount (in total 30.6 mg per dose)
is equivalent to 1.5% of the WHO recommended maximum daily intake of 2 g sodium for an
adult.

Clarithromycin use in patients who are receiving theophylline may be associated with an
increase of serum theophylline concentrations. Monitoring of serum theophylline
concentrations should be considered for patients receiving high doses of theophylline or with
baseline concentrations in the upper therapeutic range. In two studies in which theophylline
was administered with clarithromycin (a theophylline sustained-release formulation was
dosed at either 6.5 mg/kg or 12 mg/kg together with 250 or 500 mg q12h clarithromycin), the
steady-state levels of Cmax, Cmin, and the area under the serum concentration time curve
(AUC) of theophylline increased about 20%.
Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased
plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations
(48%), and increased 14-hydroxy-clarithromycin plasma concentrations (31%). These effects
are clinically insignificant.
Spontaneous reports in the post-marketing period suggest that concomitant administration of
clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants.
Prothrombin times should be carefully monitored while patients are receiving clarithromycin
and oral anticoagulants simultaneously.
The concomitant use of strong CYP3A4 inhibitors is contraindicated with ivabradine.
Examples of strong CYP3A4 inhibitor include macrolide antibiotics (e.g., clarithromycin,
telithromycin).
The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such as
clarithromycin) may result in an increase in fentanyl plasma concentrations, which could
increase or prolong adverse drug effects and may cause potentially fatal respiratory
depression. Carefully monitor patients receiving Fentanyl and any CYP3A4 inhibitor for
signs of respiratory depression for an extended period of time and adjust the dosage if
warranted.
CYP3A inhibitors such as clarithromycin may result in increased exposure to nifedipine when
co-administered. Careful monitoring and dose adjustment may be necessary; consider
initiating nifedipine at the lowest dose available if given concomitantly.
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 subtherapeutic
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-OHclarithromycin,
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, Bi-directional 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, ivabradine and ranolazine (see section 4.3).
Concomitant administration of clarithromycin with lomitapide is contraindicated due to the
potential for markedly increased transaminases (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, methadone, methylprednisolone, midazolam (intravenous), omeprazole, oral anticoagulants (e.g. warfarin,
rivaroxaban, apixaban), 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.
Corticosteroids
Caution should be exercised in concomitant use of clarithromycin with systemic and inhaled
corticosteroids that are primarily metabolised by CYP3A due to the potential for increased
systemic exposure to corticosteroids. If concomitant use occurs, patients should be closely
monitored for systemic corticosteroid undesirable effects.
Antiarrhythmics
There have been post-marketing reports of torsades de pointes occurring with the concurrent
use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be
monitored for QT prolongation during co-administration 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 hypoglycaemia 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.
Direct acting oral anticoagulants (DOACs)
The DOACs dabigatran and edoxaban are substrates for the efflux transporter P-gp.
Rivaroxaban and apixaban are metabolised via CYP3A4 and are also substrates for P-gp.
Caution should be exercised when clarithromycin is co-administered with these agents
particularly to patients at high risk of bleeding (see section 4.4).
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 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.
Hydroxychloroquine and Chloroquine
Clarithromycin should be used with caution in patients receiving these medicines known to
prolong the QT interval due to the potential to induce cardiac arrhythmia and serious adverse
cardiovascular events.
Observational data have shown that co-administration of azithromycin with
hydroxychloroquine in patients with rheumatoid arthritis is associated with an increased risk
of cardiovascular events and cardiovascular mortality. Because of the potential for a similar
risk with other macrolides when used in combination with hydroxychloroquine or
chloroquine, careful consideration should be given to the balance of benefits and risks before
prescribing clarithromycin for any patients taking hydroxychloroquine or chloroquine.
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 animal studies and experience in humans, the possibility of
adverse effects on embryofoetal development cannot be excluded. Some observational studies
evaluating exposure to clarithromycin during the first and second trimester have reported an
increased risk of miscarriage compared to no antibiotic use or other antibiotic use during the
same period. The available epidemiological studies on the risk of major congenital
malformations with use of macrolides including clarithromycin during pregnancy provide
conflicting results. Therefore, use during pregnancy is not advised without carefully weighing
the benefits against risks (see section 5.3).
Breast-feeding
The safety of clarithromycin for using during breast-feeding of infants has not been
established. Clarithromycin is excreted into human breast milk in small amounts. It has been
estimated that an exclusively breastfed infant would receive about 1.7% of the maternal
weight-adjusted dose of clarithromycin.
Fertility
In the rat, fertility studies have not shown any evidence of harmful effects (see section 5.3).

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 postmarketing
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, neutropenia, thrombocythaemia, eosinophilia	Agranulocytosis, thrombocytopenia
Immune system disorders			Anaphylactoid reaction1, hypersensitivity	Anaphylactic reaction. angioedema
Metabolism and nutrition disorders			Anorexia, decreased appetite
Psychiatric disorders		Insomnia	Anxiety, nervousness,	Psychotic disorder, confusional state, depersonalisation, depression, disorientation, hallucination, abnormal dreams, mania
Nervous system disorders		Dysgeusia, headache	Loss of consciousness, dyskinesia, dizziness, somnolence, tremor	Convulsion, ageusia, parosmia, anosmia, paraesthesia
Ear and labyrinth disorders			Vertigo, hearing impaired, tinnitus	Deafness
Cardiac disorders			Cardiac arrest, atrial fibrillation, electrocardiogram QT prolonged, extrasystoles, palpitations	Torsades de pointes, ventricular tachycardia, Ventricular fibrillation
Vascular disorders		Vasodilation		Haemorrhage
Respiratory, thoracic and mediastinal disorder			Asthma, epistaxis, pulmonary embolism
Gastrointestinal disorders		Diarrhoea, vomiting, dyspepsia, nausea, abdominal pain	Oesophagitis, gastrooesophageal reflux disease, gastritis, proctalgia, stomatitis, glossitis, abdominal distension, constipation, dry mouth, eructation, flatulence	Pancreatitis acute, tongue discolouration, tooth discolouration
Hepatobiliary disorders		Liver function test abnormal	Cholestasis, hepatitis, alanine aminotransferase increased, aspartate aminotransferase increased, gammaglutamyltransferase increased4	Hepatic failure, jaundice hepatocellular
Skin and subcutaneous tissue disorders		Rash, hyperhidrosis	Dermatitis bullous, pruritus, urticaria, rash maculo-papular	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 spasms, musculoskeletal stiffness, myalgia	Rhabdomyolysis, myopathy
Renal and urinary disorders			Blood creatinine increased, blood urea increased	Renal failure, nephritis interstitial
General disorders and administration site conditions	Injection site phlebitis	Injection site pain, injection site inflammation	Malaise, pyrexia, asthenia, chest pain, chills, fatigue
Investigations			Albumin globulin ratio abnormal, blood alkaline phosphatase increased, blood lactate dehydrogenase increased	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.
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 via:



To report any side effect(s):
-National Pharmacovigilance Center (NPC)
o SFDA Call Center: 19999
o E-mail: npc.drug@sfda.gov.sa
o Website: https://ade.sfda.gov.sa

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.

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 activated 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 two-fold more active than the parent compound.
Clarithromycin is usually active against the following organisms in vitro:
Gram-positive Bacteria: Staphylococcus aureus (methicillin susceptible); Streptococcus
pyogenes (Group A beta-hemolytic streptococci); alpha-hemolytic streptococci (viridans
group); Streptococcus (Diplococcus) pneumoniae; Streptococcus agalactiae; Listeria
monocytogenes.
Gram-negative Bacteria: Haemophilus 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.
Susceptibility testing breakpoints
MIC (minimum inhibitory concentration) interpretive criteria for susceptibility testing have
been established by the European Committee on Antimicrobial Susceptibility Testing
(EUCAST) for clarithromycin and are listed here:
https://www.ema.europa.eu/documents/other/minimum-inhibitory-concentration-micbreakpoints_en.xlsx.

 

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 - 4.5g/ml. A decrease in
binding to 41% at 45.0g/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 0.48g/mL, respectively. When
the dosage was increased to 1000mg daily, these steady-state values were 2.4g/mL and
0.67g/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, Reproduction and Teratogenicity
Studies performed in rats at oral doses up to 500 mg/kg/day (highest dose associated with
overt renal toxicity) demonstrated no evidence for clarithromycin-related adverse effects on
male fertility. This dose corresponds to a human equivalent dose (HED) of approximately 5
times the maximum recommended human dose (MRHD) on a mg/m2 basis for a 60-kg
individual.

Fertility and reproduction studies in female rats have shown that a daily dosage of
150mg/kg/day (highest dose tested) caused no adverse effects on the oestrus cycle, fertility,
parturition and number and viability of offspring. Oral teratogenicity studies in rats (Wistar
and Sprague-Dawley), rabbits (New Zealand White) and cynomolgous monkeys failed to
demonstrate any teratogenicity from clarithromycin at the highest doses tested up to 1.5, 2.4
and 1.5 times the MRHD on a mg/m2 basis in the respective species. However, a 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 at ~5 times the MRHD on a mg/m2 basis
for a 60-kg individual. Embryonic loss was seen in monkeys 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.

Tablet Core
Citric acid
Sodium alginate
Lactose
Povidone
Talc
Stearic acid
Magnesium stearate
Coating Solution
Hypromellose
Macrogols
Titanium dioxide
Sorbic acid

None known.

The shelf-life is 36 months when stored in PVC/PVdC blisters.

Store below 30°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.