Klacid Granules for Oral Suspension 125mg/5ml is indicated in children 6 months
to 12 years.
Klacid Granules for Oral Suspension 125mg/5ml is indicated for the treatment of
infections caused by susceptible organisms. Indications include:
- Lower respiratory tract infections (e.g. bronchitis, pneumonia) (see section 4.4
and 5.1 regarding Sensitivity Testing).
- Upper respiratory tract infections (e.g. pharyngitis, sinusitis).
- Skin and soft tissue infections (e.g. folliculitis, cellulitis, erysipelas) (see
section 4.4 and 5.1 regarding Sensitivity Testing).
- Acute otitis media.
Consideration should be given to official guidance on the appropriate use of
antibacterial agents.

Paediatric patients under 12 years of age
Clinical trials have been conducted using Klacid Granules for Oral Suspension in
children 6 months to 12 years of age. Therefore, children under 12 years of age
should use Klacid Granules for Oral Suspension.
Recommended doses and dosage schedules:
The usual duration of treatment is for 5 to 10 days depending on the pathogen
involved and the severity of the condition. The recommended daily dosage of
Klacid Granules for Oral Suspension 125mg/5ml in children is given in the
following table and is based on a 7.5mg/kg b.i.d. dosing regime up to a maximum
dose of 500 mg b.i.d. The prepared suspension can be taken with or without meals
and can be taken with milk.
KLACID GRANULES FOR ORAL SUSPENSION 125mg/5ml DOSAGE IN CHILDREN

 

Dosage Based on Body Weight (kg)
Weight* (kg)	Approx Age (yrs)	Dosage (ml) bid
8-11	1 -2	2.50
12-19	3 - 6	5.00
20-29	7 - 9	7.50
30-40	10 - 12	10.00

* Children < 8 kg should be dosed on a per kg basis (approx. 7.5 mg/kg bid)

Renal Impairment
In children with creatinine clearance less than 30 ml/min/1.73m2, the dosage of
clarithromycin should be reduced by half to 7.5mg/kg per day.
Dosage should not be continued beyond 14 days in these patients.
Preparation for use: see section 6.6

 

Hypersensitivity to macrolide antibiotic drugs or to any of the excipients listed in section 6.1. Concomitant administration of clarithromycin and ergot alkaloids (e.g. ergotamine or dihydroergotamine) is contraindicated, as this may result in ergot toxicity (see section 4.5). Concomitant administration of clarithromycin and oral midazolam is contraindicated (see section 4.5). Concomitant administration of clarithromycin and any of the following drugs is contraindicated: astemizole, cisapride, 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 life-threatening.
Clostridium difficile- associated diarrhoea (CDAD) has been reported with use of
nearly all antibacterial agents including clarithromycin, and may range in severity
from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the
normal flora of the colon, which may lead to overgrowth of C. difficile. CDAD
must be considered in all patients who present with diarrhoea following antibiotic
use. Careful medical history is necessary since CDAD has been reported to occur
over two months after the administration of antibacterial agents. Therefore,
discontinuation of clarithromycin therapy should be considered regardless of the
indication. Microbial testing should be performed and adequate treatment
initiated. Drugs inhibiting peristalsis should be avoided.
There have been post-marketing reports of colchicine toxicity with concomitant
use of clarithromycin and colchicine, especially in the elderly, some of which
occurred in patients with renal insufficiency. Deaths have been reported in some
such patients (see section 4.5). Concomitant administration of clarithromycin and
colchicine is contraindicated (see section 4.3).
Caution is advised regarding concomitant administration of clarithromycin and
triazolobenzodiazepines, such as triazolam, and intravenous or oromucosal
midazolam (see section 4.5).

Cardiovascular Events:
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 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 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
Patients with rare hereditary problems of fructose intolerance, glucose-galactose
malabsorption or sucrase-isomaltase insufficiency should not take Klacid Granules
for Oral Suspension 125mg/5ml or Klacid Granules for Oral Suspension
250mg/5ml. When prescribing to diabetic patients, the sucrose content should be
taken into account.

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-OHclarithromycin
has reduced activity against Mycobacterium avium complex
(MAC), overall activity against this pathogen may be altered; therefore
alternatives to clarithromycin should be considered for the treatment of MAC.
Fluconazole
Concomitant administration of fluconazole 200 mg daily and clarithromycin 500
mg twice daily to 21 healthy volunteers led to increases in the mean steady-state
minimum clarithromycin concentration (Cmin) and area under the curve (AUC) of
33% and 18% respectively. Steady state concentrations of the active metabolite
14-OH-clarithromycin were not significantly affected by concomitant
administration of fluconazole. No clarithromycin dose adjustment is necessary.

Ritonavir
A pharmacokinetic study demonstrated that the concomitant administration of
ritonavir 200 mg every eight hours and clarithromycin 500 mg every 12 hours
resulted in a marked inhibition of the metabolism of clarithromycin. The
clarithromycin Cmax increased by 31%, Cmin increased 182% and AUC
increased by 77% with concomitant administration of ritonavir. An essentially
complete inhibition of the formation of 14-OH-clarithromycin was noted. Because
of the large therapeutic window for clarithromycin, no dosage reduction should be
necessary in patients with normal renal function. However, for patients with renal
impairment, the following dosage adjustments should be considered: For patients
with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.
For patients with CLCR <30 mL/min the dose of clarithromycin should be
decreased by 75%. Doses of clarithromycin greater than 1 g/day should not be coadministered
with ritonavir.

Similar dose adjustments should be considered in patients with reduced renal
function when ritonavir is used as a pharmacokinetic enhancer with other HIV
protease inhibitors including atazanavir and saquinavir (see section below, Bidirectional
drug interactions).

Effect of Clarithromycin on Other Medicinal Products
CYP3A-based interactions
Co-administration of clarithromycin, 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 HIVinfected
adult patients may result in decreased steady-state zidovudine
concentrations. Because clarithromycin appears to interfere with the absorption of
simultaneously administered oral zidovudine, this interaction can be largely
avoided by staggering the doses of clarithromycin and zidovudine to allow for a 4-
hour interval between each medication. This interaction does not appear to occur
in paediatric HIV-infected patients taking clarithromycin suspension with
zidovudine or dideoxyinosine. This interaction is unlikely when clarithromycin is
administered via intravenous infusion.
Phenytoin and Valproate
There have been spontaneous or published reports of interactions of CYP3A
inhibitors, including clarithromycin with drugs not thought to be metabolised by
CYP3A (e.g. phenytoin and valproate). Serum level determinations are
recommended for these drugs when administered concomitantly with
clarithromycin. Increased serum levels have been reported.

 

Bi-directional drug interactions
Atazanavir
Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and
there is evidence of a bi-directional drug interaction. Co-administration of
clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily) resulted
in a 2-fold increase in exposure to clarithromycin and a 70% decrease in exposure
to 14-OH-clarithromycin, with a 28% increase in the AUC of atazanavir. Because
of the large therapeutic window for clarithromycin, no dosage reduction should be
necessary in patients with normal renal function. For patients with moderate renal
function (creatinine clearance 30 to 60 mL/min), the dose of clarithromycin should
be decreased by 50%. For patients with creatinine clearance <30 mL/min, the dose
of clarithromycin should be decreased by 75% using an appropriate clarithromycin
formulation. Doses of clarithromycin greater than 1000 mg per day should not be
co-administered with protease inhibitors.
Calcium Channel Blockers
Caution is advised regarding the concomitant administration of clarithromycin and
calcium channel blockers metabolized by CYP3A4 (e.g. verapamil, amlodipine,
diltiazem) due to the risk of hypotension. Plasma concentrations of clarithromycin

as well as calcium channel blockers may increase due to the interaction.
Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients
taking clarithromycin and verapamil concomitantly.
Itraconazole
Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A,
leading to a bidirectional drug interaction. Clarithromycin may increase the
plasma levels of itraconazole, while itraconazole may increase the plasma levels of
clarithromycin. Patients taking itraconazole and clarithromycin concomitantly
should be monitored closely for signs or symptoms of increased or prolonged
pharmacologic effect.
Saquinavir
Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and
there is evidence of a bi-directional drug interaction. Concomitant administration
of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules,
1200 mg three times daily) to 12 healthy volunteers resulted in steady-state AUC
and Cmax values of saquinavir which were 177% and 187% higher than those seen
with saquinavir alone. Clarithromycin AUC and Cmax values were approximately
40% higher than those seen with clarithromycin alone. No dose adjustment is
required when the two drugs are co-administered for a limited time at the
doses/formulations studied. Observations from drug interaction studies using the
soft gelatin capsule formulation may not be representative of the effects seen using
the saquinavir hard gelatin capsule. Observations from drug interaction studies
performed with saquinavir alone may not be representative of the effects seen with
saquinavir/ritonavir therapy. When saquinavir is co-administered with ritonavir,
consideration should be given to the potential effects of ritonavir on
clarithromycin (see section 4.5: Ritonavir).
Patients taking oral contraceptives should be warned that if diarrhoea, vomiting or
breakthrough bleeding occur there is a possibility of contraceptive failure.

Pregnancy
The safety of clarithromycin for use during pregnancy has not been established.
Based on variable results obtained from studies in mice, rats, rabbits and monkeys,
the possibility of adverse effects on embryofoetal development cannot be
excluded. Therefore, use during pregnancy is not advised without carefully
weighing the benefits against risk.
Breast-feeding
The safety of clarithromycin for using during breast-feeding of infants has not
been established. Clarithromycin is excreted into human breast milk.

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

a. Summary of the safety profile
The most frequent and common adverse reactions related to clarithromycin
therapy for both adult and paediatric populations are abdominal pain, diarrhoea,
nausea, vomiting and taste perversion. These adverse reactions are usually mild in
intensity and are consistent with the known safety profile of macrolide antibiotics
(see section b of section 4.8).
There was no significant difference in the incidence of these gastrointestinal
adverse reactions during clinical trials between the patient population with or
without pre-existing mycobacterial infections.

b. Tabulated summary of adverse reactions
The following table displays adverse reactions reported in clinical trials and from
post-marketing experience with clarithromycin immediate-release tablets,
Granules for Oral Suspension, powder for solution for injection, extended-release
tablets and modified-release tablets.
The reactions considered at least possibly related to clarithromycin are displayed
by system organ class and frequency using the following convention: very
common (≥1/10), common (≥ 1/100 to < 1/10), uncommon (≥1/1,000 to < 1/100)
and not known (adverse reactions from post-marketing experience; cannot be
estimated from the available data). Within each frequency grouping, adverse
reactions are presented in order of decreasing seriousness when the seriousness
could be assessed.

System Organ Class	Very common ≥1/10	Common ≥ 1/100 to < 1/10	Uncommon ≥1/1,000 to < 1/100	Not Known* (cannot be estimated from the available data)
Infections and infestations			Cellulitis1, candidiasis, gastroenteritis2, infection3, vaginal infection	Pseudomembranous colitis, erysipelas,
Blood and lymphatic system			Leukopenia, neutropenia4, thrombocythaemia3, eosinophilia4	Agranulocytosis, thrombocytopenia
Immune system disorders			Anaphylactoid reaction1, hypersensitivity	Anaphylactic reaction. angioedema
Metabolism and nutrition disorders			Anorexia, decreased appetite
Psychiatric disorders		Insomnia	Anxiety, nervousness3,	Psychotic disorder, confusional state5, depersonalisation, depression, disorientation, hallucination, abnormal dreams, mania
Nervous system disorders		Dysgeusia, headache	Loss of consciousness1, dyskinesia1, dizziness, somnolence5, tremor	Convulsion, ageusia, parosmia, anosmia, paraesthesia
Ear and labyrinth disorders			Vertigo, hearing impaired, tinnitus	Deafness
Cardiac disorders			Cardiac arrest1, atrial fibrillation1, electrocardiogram QT prolonged, extrasystoles1, palpitations	Torsades de pointes, ventricular tachycardia, ventricular fibrillation
Vascular disorders		Vasodilation1		Haemorrhage
Respiratory, thoracic and mediastinal disorder			Asthma1, epistaxis2, pulmonary embolism1
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,, 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 Granules for Oral
Suspension in children 6 months to 12 years of age. Therefore, children under 12
years of age should use clarithromycin Granules for Oral 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: +966-11-205-7662

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 anti-bacterial 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-hydroxy metabolite of clarithromycin, a product of parent drug metabolism
also has anti-microbial 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 also bactericidal against several bacterial strains.
Clarithromycin is usually active against the following organisms in vitro:-
Gram-positive Bacteria: Staphylococcus aureus (methicillin susceptible);
Streptococcus pyogenes (Group A beta-haemolytic streptococci); alphahaemolytic
streptococci (viridans group); Streptococcus (Diplococcus)
pneumoniae; Streptococcus agalactiae; Listeria monocytogenes.
Gram-negative Bacteria: Haemophilus influenzae, Haemophilus parainfluenzae,
Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae; Legionella
pneumophila, Bordetella pertussis, Helicobacter pylori; Campylobacter jejuni.
Mycoplasma: Mycoplasma pneumoniae; Ureaplasma urealyticum.

Other Organisms: Chlamydia trachomatis; Mycobacterium avium;
Mycobacterium leprae; Chlamydia pneumoniae.
Anaerobes: Macrolide-susceptible Bacteroides fragilis; Clostridium perfringens;
Peptococcus species; Peptostreptococcus species; Propionibacterium acnes.
Clarithromycin also has bactericidal activity against several bacterial strains.
These organisms include H. influenzae, Streptococcus pneumoniae, Streptococcus
pyogenes, Streptococcus agalactiae, Moraxella (Brahamella) catarrhalis, Neisseria
gonorrhoeae, Helicobacter pylori and Campylobacter species.

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.

 

 

Clarithromycin is rapidly and well absorbed from the gastro-intestinal tract after
oral administration. The microbiologically active 14(R)-hydroxyclarithromycin is
formed by first pass metabolism. Clarithromycin, may be given without regard to
meals as food does not affect the extent of bioavailability. Food does slightly
delay the onset of absorption of clarithromycin and formation of the 14-hydroxy
metabolite. Although the pharmacokinetics of clarithromycin are non linear,

steady state is attained within 2 days of dosing. 14-Hydroxyclarithromycin is the
major urinary metabolite and accounts for 10-15% of the dose. Most of the
remainder of the dose is eliminated in the faeces, primarily via the bile. 5-10% of
the parent drug is recovered from the faeces.
Clarithromycin provides tissue concentrations that are several times higher than
circulating drug level. Increased levels of clarithromycin have been found in both
tonsillar and lung tissue. Clarithromycin penetrates into the middle ear fluid at
concentrations greater than in the serum. Clarithromycin is 80% bound to plasma
proteins at therapeutic levels.
Klacid Granules for Oral Suspension 125mg/5ml does not contain tartrazine or
other azo dyes, lactose or gluten.

The acute oral LD50 values for a clarithromycin suspension administered to 3-day
old mice were 1290 mg/kg for males and 1230 mg/kg for females. The LD50
values in 3-day old rats were 1330 mg/kg for males and 1270 mg/kg for females.
For comparison, the LD50 of orally-administered clarithromycin is about 2700
mg/kg for adult mice and about 3000 mg/kg for adult rats. These results are
consistent with other antibiotics of the penicillin group, cephalosporin group and
macrolide group in that the LD50 is generally lower in juvenile animals than in
adults.
In both mice and rats, body weight was reduced or its increase suppressed and
suckling behaviour and spontaneous movements were depressed for the first few
days following drug administration. Necropsy of animals that died disclosed darkreddish
lungs in mice and about 25% of the rats; rats treated with 2197 mg/kg or
more of a clarithromycin suspension were also noted to have a reddish - black
substance in the intestines, probably because of bleeding. Deaths of these animals
were considered due to debilitation resulting from depressed suckling behaviour or
bleeding from the intestines.
Pre-weaning rats (5 days old) were administered a clarithromycin suspension
formulation for two weeks at doses of 0, 15, 55 and 200 mg/kg/day. Animals from
the 200 mg/kg/day group had decreased body-weight gains, decreased mean
haemoglobin and haematocrit values, and increased mean relative kidney weights
compared to animals from the control group. Treatment-related minimal to mild
multifocal vacuolar degeneration of the intrahepatic bile duct epithelium and an
increased incidence of nephritic lesions were also observed in animals from this
treatment group. The "no-toxic effect" dosage for this study was 55 mg/kg/day.
An oral toxicity study was conducted in which immature rats were administered a
clarithromycin suspension (granules for suspension) for 6 weeks at daily dosages of
0, 15, 50 and 150 mg base/kg/day. No deaths occurred and the only clinical sign
observed was excessive salivation for some of the animals at the highest dosage
from 1 to 2 hours after administration during the last 3 weeks of treatment. Rats

from the 150 mg/kg dose group had lower mean body weights during the first three
weeks, and were observed to have decreased mean serum albumin values and
increased mean relative liver weight compared to the controls. No treatment-related
gross or microscopic histopathological changes were found. A dosage of 150
mg/kg/day produced slight toxicity in the treated rats and the "no effect dosage" was
considered to be 50 mg/kg/day.
Juvenile beagle dogs, 3 weeks of age, were treated orally daily for four weeks with
0, 30, 100, or 300 mg/kg of clarithromycin, followed by a 4-week recovery period.
No deaths occurred and no changed in the general condition of the animals were
observed. Necropsy revealed no abnormalities. Upon histological examination,
fatty deposition of centrilobular hepatocytes and cell infiltration of portal areas were
observed by light microscopy and an increase in hepatocellular fat droplets was
noted by electron microscopy in the 300 mg/kg dose group. The toxic dose in
juvenile beagle dogs was considered to be greater than 300 mg/kg and the "no effect
dose" 100 mg/kg.
Fertility, Reproduction and Teratogenicity
Fertility and reproduction studies have shown daily dosages of 150-160 mg/kg/day
to male and female rats caused no adverse effects on the oestrus cycle, fertility,
parturition and number and viability of offspring. Two teratogenicity studies in
both Wistar (p.o.) and Sprague-Dawley (p.o. and i.v.) rats, one study in New
Zealand white rabbits and one study in cynomolgus monkeys failed to demonstrate
any teratogenicity from clarithromycin.

Granule component and coating:
Carbopol Carbomers
Povidone
Hypromellose
Castor Oil
Other ingredients:
Silicon dioxide
Sucrose
Xanthan gum
Flavour - fruit punch
Potassium sorbate
Citric acid
Titanium dioxide
Maltodextrin

None known.

The recommended shelf life is 24 months. Once reconstituted, Klacid Granules for Oral Suspension 125mg/5ml should be used within 14 days.

Do not store above 30°C.
After reconstitution you can store at room temperature (15 - 30 °C) for 14 days

Granules for reconstitution in a HDPE bottle with a PS-measuring spoon. Pack sizes
of 60 and 100 ml are available.
Not all pack sizes may be marketed.

100ml bottle: 53ml of water should be added to the granules in the bottle and
shaken until all of the particles are suspended. Avoid vigorous and/ or lengthy
shaking. Shake prior to each subsequent use to ensure re-suspension. The
concentration of clarithromycin in the reconstituted suspension is 125mg per 5ml.

60ml bottle: 31ml of water should be added to the granules in the bottle and shaken
until all of the particles are suspended. Avoid vigorous and/ or lengthy shaking.
Shake prior to each subsequent use to ensure re-suspension. The concentration of
clarithromycin in the reconstituted suspension is 125mg per 5ml.

Administration
Several devices can be used to dose and administer Clarithromycin Pediatric
Suspension.