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Clarithromycin Actavis 250 mg Film-coated Tablets V007 – Safety Update (CSP Update) SUMMARY OF PRODUCT CHARACTERISTICS
NAME OF THE MEDICINAL PRODUCT

Clarithromcyin Actavis 250 mg Film-coated Tablets
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains Clarithromycin 250 mg.
Excipients: Contains 0.11 mg glucose per tablet
For a full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM

Film coated tablets.
Yellow, oval-shaped, convex film-coated tablets, scored on one side.
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4.
CLINICAL PARTICULARS
Therapeutic Indications
Consideration should be given to official guidance on the appropriate use of antibacterial agents. Clarithromycin is indicated in adults and children 12 years and older. Clarithromcyin Actavis is indicated in the treatment of infections due to susceptible organisms. Such infections include: 1. Lower respiratory tract infections (e.g. bronchitis, pneumonia). Upper respiratory tract infections (e.g. pharyngitis, sinusitis). Skin and soft tissue infections (e.g. folliculitis, cellulitis, erysipelas). Disseminated or localised mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare. Localised infections due to Mycobacterium chelonae, Mycobacterium fortuitum, or Mycobacterium kansasii. Clarithromycin is indicated for the prevention of disseminated Mycobacterium avium complex infection in HIV-infected patients with CD4 lymphocyte counts less than or equal to 100/mm3. Clarithromycin in the presence of acid suppression is indicated for the eradication of H. pylori, resulting in decreased recurrence of duodenal ulcer. Further information
H. pylori
is strongly associated with peptic ulcer disease. Ninety to 100% of patients with duodenal
ulcers are infected with this agent.
Eradication of H. pylori has been shown to markedly reduce the rate of duodenal ulcer recurrence,
thereby reducing the need for maintenance anti-secretory therapy.
In a well-controlled double-blind study, H. pylori infected patients with duodenal ulcer received
clarithromycin 500 mg TID for 14 days with omeprazole 40 mg daily for 28 days.
Clarithromycin has been used in other treatment regimens for the eradication of H. pylori. These
regimens include: clarithromycin plus tinidazole and omeprazole; and clarithromycin plus tetracycline,
bismuth subsalicylate, and ranitidine.
Clarithromycin Actavis 250 mg Film-coated Tablets V007 – Safety Update (CSP Update)
As with other antibiotics, it is recommended that guidelines on the prevalence of local resistance, and
associated medical practice regarding the prescription of anitibiotics, be consulted before prescribing
Clarithromycin.
4.2.
Posology and Method of Administration

Adults and children older than 12 years
The usual recommended dose of clarithromycin in adults is one 250 mg tablet twice daily. In more
severe infections, the dosage can be increased to 500 mg twice daily.
The usual duration of therapy is 6 to 14 days.
Children younger than 12 years: Use of clarithromycin is not recommended for children younger than
12 years. Use clarithromycin paediatric suspension.
Clinical trials have been conducted using clarithromycin paediatric suspension in children 6 months to
12 years. Therefore, children under 12 years should use clarithromycin paediatric suspension (granules
for oral suspension).
In patients with renal impairment with creatinine clearance less than 30ml/min, the dosage of
clarithromycin should be reduced by one-half, i.e.: 250mg once daily or 250 mg twice daily in more
severe infections. Treatment should not be continued beyond 14 days in these patients.
Dosage in patients with mycobacterial infections
The recommended starting dose is 500 mg BID (twice daily). If no clinical or bacteriological response
is observed in 3 to 4 weeks, the dose may be increased to 1000 mg BID.
Treatment of disseminated Mycobacterium Avium Complex (MAC) infections in AIDS patients
should be continued, as long as clinical microbiological benefit is demonstrated.
Clarithromycin should be used in conjunction with other anti-mycobacterial agents.
Treatment of other non-tuberculous mycobacterial infections should continue at the discretion of the
physician.
Dosage for MAC prophylaxis
The recommended dosage of clarithromycin is adults is 500 mg twice daily.
Eradication of H. pylori
- Dual Therapy
The recommended dose of clarithromycin is 500 mg TID (three times a day) for 14 days (see
pharmacological properties).
- Triple Therapy (7 days)
Clarithromycin (500 mg) twice daily and a proton pump inhibitor (at the approved daily dose)* should
be given with amoxicillin 1000 mg twice daily for 7 days.
- Triple Therapy (7 days)
Clarithromycin (500 mg) twice daily and a proton pump inhibitor (at the approved daily dose)* should
be given with metronidazole 400 mg twice daily for 7 days.
- Triple Therapy (7-10 days)
Clarithromycin (500 mg) twice daily should be given with amoxicillin 1000 mg twice daily and
omeprazole 20 mg daily for 7-10 days.
* see individual data sheets/SPCs for the dose recommendations for H. pylori eradication.
Clarithromycin Actavis 250 mg Film-coated Tablets V007 – Safety Update (CSP Update)
Clarithromycin Actavis 250 mg, film-coated tablets may be given without regard to meals as food
does not affect the extent of bioavailability.
4.3.
Contraindications

Clarithromcyin Actavis 250 mg Film-coated tablets are contraindicated in patients with known
hypersensitivity to macrolide antibiotic drugs or any of its excipients.
Concomitant administration of clarithromycin and any of the following drugs is contraindicated:
astemizole, cisapride, pimozide,terfenadine as this may result in QT prolongation and cardiac
arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointe (see
section 4.5). Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is
contraindicated, as this may result in ergot toxicity.
Clarithromcyin should not be given to patients with history of QT prolongation or ventricular cardiac
arrhythmia, including torsades de pointe (see sections 4.4 and 4.5).
Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins),
lovastatin or simvastatin, due to the risk of rhabdomyolysis. Treatment with these agents should be
discontinued during clarithromycin (see section 4.4).
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.
4.4.
Special warnings and precautions for use
The physician should not prescribe clarithromycin to pregnant women without carefully weighing the benefits against risk; particularly during the first three months of pregnancy (see section 4.6). Caution is advised in patients with severe renal insufficiency (see section 4.2). Clarithromycin is principally excreted by the liver. Therefore, caution should be exercised in administering the antibiotic to patients with impaired hepatic function. Caution should also be exercised when administering clarithromcyin to patients with moderate to severe renal impairment. Cases of fatal hepatic failure (see section 4.8) have been reported. Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products. Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop, such as anorexia, jaundice, dark urine, pruritus, or tender abdomen. Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, and may range in severity from mild to life threatening. Clostridium difficile-associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents including clarithromycin, and may range in severity from mild diarrhoea to fatal colitis. Treatment with anti bacterial 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 anti bacterial 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. Clarithromycin Actavis 250 mg Film-coated Tablets V007 – Safety Update (CSP Update) Exacerbation of symptoms of myasthenia gravis has been reported in patients receiving clarithromycin therapy. There have been post-marketing reports of colchine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see section 4.5). If concomitant administration of colchicine and clarithromycin is necessary, patients should be monitored for clinical symptoms of colchicine toxicity. Caution triazolobenzodiazepines, such as triazolam and midazolam (see section 4.5). Caution is advised regarding concomitant administration of clarithromycin with other ototoxic drugs, especially with aminoglycosides. Monitoring of vestibular and auditory function should be carried out during and after treatment Due to the risk for QT prolongation, clarithromycin should be used with caution in patients with coronary artery disease, severe cardiac insufficiency, hypomagnesemia, bradycardia (<50 bpm), or when co-administered with other medicinal products associated with QT prolongation (see section 4.5). Clarithromycin must not be used in patients with congenital or documented acquired QT prolongation or history of ventricular arrhythmia (see section 4.3). Pneumonia: In view of the emerging resistance of Streptococcus pneumoniae to macrolides, it is important that sensitivity testing be performed when prescribing clarithromycin for community-acquired pneumonia. In hospital-acquired pneumonia, clarithromycin should be used in combination with additional appropriate antibiotics. Skin and soft tissue infections of mild to moderate severity: These infections are most often caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Therefore, it is important that sensitivity testing be performed. In cases where beta–lactam antibiotics cannot be used (e.g. allergy), other antibiotics, such as clindamycin, may be the drug of first choice. Currently, macrolides are only considered to play a role in some skin and soft tissue infections, such as those caused by Corynebacterium minutissimum (erythrasma), acne vulgaris, and erysipelas and in situations where penicillin treatment cannot be used. In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome, and toxic epidermal necrolysis, clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated. Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see section 4.5). HMG-CoA reductase inhibitors: Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section 4.3). As with other macrolides, clarithromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors (see section 4.5). Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly. Patients should be monitored for signs and symptoms of myopathy. Rare reports of rhabdomyolysis have also been reported in patients taking atorvastatin or rosuvastatin concomitantly with clarithromycin. When used with clarithromycin, atorvastatin or rosuvastatin should be administered in the lowest possible doses. Adjustment of the statin dose or use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin or pravastatin) should be considered. Oral hypoglycemic agents/Insulin: The concomitant use of clarithromycin and oral hypoglycemic agents and/or insulin can result in significant hypoglycemia. With certain hypoglycemic drugs such as Clarithromycin Actavis 250 mg Film-coated Tablets V007 – Safety Update (CSP Update) nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypolgycemia when used concomitantly. Careful monitoring of glucose is recommended. Oral anticoagulants: There is a risk of serious hemorrhage and significant elevations in International Normalized Ratio (INR) and prothrombin time when clarithromycin is co-administered with warfarin (see section 4.5). INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently. Use of any antimicrobial therapy, such as clarithromycin, to treat H. pylori infection may select for drug-resistant organisms. Long-term use may, as with other antibiotics, result in colonization 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. This product contains glucose. Patients with rare glucose-galactose malabsorption should not take this
medicine.
4.5.
Interactions with other medicinal products and other forms of interaction

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
a two to three fold increase in the serum level of the acid metabolite of terfenadine and in prolongation
of the QT interval which did not lead to any clinically detectable effect. Similar effects have been
observed with concomitant administration of astemizole and other macrolides.
Ergotamine/dihydroergotamine
Postmarketing reports indicate that co-administration of clarithromycin with ergotamine or
dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm, and
ischemia of the extremities and other tissues including the central nervous system. Concomitant
administration of clarithromycin and these medicinal products is contraindicated (see section 4.3).
Effects of other medicinal products on clarithromycin

Drugs that are inducers of CYP3A (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St
John’s wort) may induce the metabolism of clarithromycin. This may result in sub-therapeutic levels
of clarithromycin leading to reduced efficacy. Furthermore, it might be necessary to monitor the
plasma levels of the CYP3A inducer, which could be increased owing to the inhibition of CYP3A by
clarithromycin (see also the relevant product information for the CYP3A4 inhibitor administered).
Clarithromycin Actavis 250 mg Film-coated Tablets V007 – Safety Update (CSP Update)
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.
Fluconazole
Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21
healthy volunteers led to increases in the mean steady-state minimum clarithromycin concentration
(Cmin) and area under the curve (AUC) of 33% and 18% respectively. Steady state concentrations of
the active metabolite 14-OH-clarithromycin were not significantly affected by concomitant
administration of fluconazole. No clarithromycin dose adjustment is necessary.
Ritonavir
A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200 mg every
eight hours and clarithromycin 500 mg every 12 hours resulted in a marked inhibition of the
metabolism of clarithromycin. The clarithromycin Cmax increased by 31%, Cmin increased 182% and
AUC increased by 77% with concomitant administration of ritonavir. An essentially complete
inhibition of the formation of 14-OH-clarithromycin was noted. Because of the large therapeutic
window for clarithromycin, no dosage reduction should be necessary in patients with normal renal
function. However, for patients with renal impairment, the following dosage adjustments should be
considered: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by
50%. For patients with CLCR <30 ml/min the dose of clarithromycin should be decreased by 75%.
Doses of clarithromycin greater than 1 gm/day should not be 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, Bi-directional drug interactions)
Effect of clarithromycin on other medicinal products

CYP3A-based interactions
Co-administration of clarithromycin, known to inhibit CYP3A, and a drug primarily metabolized 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 metabolized by this enzyme.
Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily
metabolized by CYP3A should be monitored closely in patients concurrently receiving clarithromycin.

The following drugs or drug classes are known or suspected to be metabolized by the same CYP3A
isozyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide,
ergot alkaloids, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g.
warfarin), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, tacrolimus, terfenadine,
Clarithromycin Actavis 250 mg Film-coated Tablets V007 – Safety Update (CSP Update) triazolam and vinblastine. Drugs interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate. Antiarrhythmics There have been postmarketing reports of torsades de pointes occurring with 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. 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 metabolized, 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. 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 metabolizer population. Triazolobenzodiazepines (e.g. alprazolam, midazolam, triazolam)
When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam
AUC was increased 2.7-fold after intravenous administration of midazolam and 7-fold after oral
administration. Concomitant administration of oral midazolam and clarithromycin should be avoided.
If intravenous midazolam is co-administered with clarithromycin, the patient must be closely
monitored to allow dose adjustment. The same precautions should also apply to other benzodiazepines
that are metabolized 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
Clarithromycin Actavis 250 mg Film-coated Tablets V007 – Safety Update (CSP Update) colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine. Patients should be monitored for clinical symptoms of colchicine toxicity (see section 4.4). Digoxin Digoxin is thought to be a substrate for the efflux transporter, P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are administered together, inhibition of Pgp by clarithromycin may lead to increased exposure to digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have also been reported in post marketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored while patients are receiving digoxin and clarithromycin simultaneously. Zidovudine
Simultaneous oral administration of clarithromycin tablets and zidovudine to 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 metabolized 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.
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 Clarithromycin Actavis 250 mg Film-coated Tablets V007 – Safety Update (CSP Update)
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.
Verapamil
Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients taking
clarithromycin and verapamil concomitantly.
4.6.
Fertility, pregnancy and lactation

The safety of clarithromycin for use during pregnancy and breast feeding of infants has not been
established. Based on variable results obtained from studies in mice, rats, rabbits and monkeys, the
possibility of adverse effects on embryofoetal development cannot be excluded. Therefore, use in
pregnancy is not advised without carefully weighing the benefits against the risk. Clarithromycin is
excreted into human breast milk.
4.7.
Effects on ability to drive and use machines

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.
4.8.
Undesirable Effects

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 preexisting 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, 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.
Clarithromycin Actavis 250 mg Film-coated Tablets V007 – Safety Update (CSP Update) (cannot be estimated from the available data) Leukopenia, neutropenia4, Agranulocytosis, confusional state, depersonalisation, depression, disorientation, hallucination, abnormal dreams Electrocardiogram QT prolonged8, extrasystoles1, palpitations stomatitis, glossitis, abdominal distension4, constipation, dry mouth, eructation, flatulence, increased, aspartate aminotransferase increased, gamma-glutamyltransferase Clarithromycin Actavis 250 mg Film-coated Tablets V007 – Safety Update (CSP Update) epidermal necrolysis5, drug rash with eosinophilia and systemic symptoms (DRESS), acne 1 ADRs reported only for the Powder for Solution for Injection formulation
2 ADRs reported only for the Extended-Release Tablets formulation
3 ADRs reported only for the Granules for Oral Suspension formulation
4 ADRs reported only for the Immediate-Release Tablets formulation
5, 8,10,11,12 See section a)
6, 7,9 See section c)
c. Description of selected adverse reactions

Injection site phlebitis, injection site pain, vessel puncture site pain, and injection site inflammation
are specific to the clarithromycin intravenous formulation.
In very rare instances, hepatic failure with fatal outcome has been reported and generally has been
associated with serious underlying diseases and/or concomitant medications (see section 4.4).
Special attention to diarrhoea should be paid as Clostridium difficile-associated diarrhoea (CDAD) has
been reported with use of nearly all antibacterial agents including clarithromycin, and may range in
severity from mild diarrhoea to fatal colitis. (see section 4.4)
In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson
Syndrome and toxic epidermal necrolysis, clarithromycin therapy should be discontinued immediately
and appropriate treatment should be urgently initiated (see section 4.4).
As with other macrolides, QT prolongation, ventricular tachycardia, and torsade de pointes have rarely
been reported with clarithromycin (see section 4.4 and 4.5).
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including
clarithromycin, and may range in severity from mild to life threatening. Therefore, it is important to
consider this diagnosis in patients who present with diarrhea subsequent to the administration of
antibacterial agents (see section 4.4).
Clarithromycin Actavis 250 mg Film-coated Tablets V007 – Safety Update (CSP Update)
In some of the reports of rhabdomyolysis, clarithromycin was administered concomitantly with statins,
fibrates, colchicine or allopurinol (see section 4.3 and 4.4).
There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin
and colchicine, especially in elderly and/or patients with renal insufficiency, some with a fatal
outcome. (see sections 4.4 and 4.5).
There have been rare reports of hypoglycemia, some of which have occurred in patients on
concomitant oral hypoglycemic agents or insulin (see section 4.4 and 4.5).
There have been post-marketing reports of drug interactions and central nervous system (CNS) effects
(e.g. somnolence and confusion) with the concomitant use of clarithromycin and triazolam.
Monitoring the patient for increased CNS pharmacological effects is suggested (see section 4.5).
There is a risk of serious hemorrhage and significant elevations in INR and prothrombin time when
clarithromycin is co-administered with warfarin. INR and prothrombin times should be frequently
monitored while patients are receiving clarithromycin and oral anticoagulants concurrently (see
section 4.4 and 4.5).
There have been rare reports of clarithromycin extended release 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 2000 mg of clarithromycin were: nausea, vomiting, taste perversion, abdominal
pain, diarrhea, 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 1000 mg and 2000 mg, but were generally about 3 to 4 times as
frequent for those patients who received total daily doses of 4000 mg 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.
Clarithromycin Actavis 250 mg Film-coated Tablets V007 – Safety Update (CSP Update)
On the basis of these criteria, about 2% to 3% of those patients who received 1000 mg or 2000 mg 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 4000 mg daily for all parameters except White Blood Cell.
4.9.
Overdose

Reports indicate that the ingestion of large amounts of clarithromycin can be expected to produce gastrointestinal symptoms. One patient who had a history of bipolar disorder ingested 8 grams of clarithromycin and showed altered mental status, paranoid behaviour, hypokalemia and hypoxemia . Adverse reactions accompanying overdosage should be treated by prompt elimination of unabsorbed
drug and supportive measures. As with other macrolides, clarithromycin serum levels are not expected
to be appreciably affected by hemodialysis or peritoneal dialysis.
5.
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic Properties
Pharmacotherapeutic group: Macrolides, ATC code: J01F A09 Clarithromycin is a semi-synthetic derivative of erythromycin A. It exerts its antibacterial action by
binding to the 50s ribosomal sub-unit of susceptible bacteria and suppresses protein synthesis. It is
highly potent against a wide variety of aerobic and anaerobic gram-positive and gram-negative
organisms. The minimum inhibitory concentrations (MICs) of clarithromycin are generally two-fold
lower than the MICs of erythromycin.
The 14-hydroxy metabolite of clarithromycin also has anti-microbial activity. The MICs of its
metabolite are equal or two-fold higher than the MICs of the parent compound, except for H.
influenzae
where the 14-hydroxy metabolite is two-fold more active than the parent compound.
Clarithryomcyin is usually active against the following organisms in vitro: Please see below for table
of MIC breakpoints.

Gram-positive bacteria:
Staphylococcus aureus (methicillin susceptible); Streptococcus pyogenes
(Group A -haemolytic streptococci),
-haemolytic streptococci (viridans group), Streptococcus (Diplococcus) pneumoniae, Streptococcus agalactiae, Listeria monocytogenes.

Gram-negative bacteria: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella
(Branhamella) catarrhalis, Neisseria gonorrhoeae, Legionella pneumophila, Bordetella pertussis,
Helicobacter pylori, Campylobacter jejuni.

Mycoplasma: Mycoplasma pneumoniae, Ureaplasma urealyiticum.
Other organisms: Chlamydia trachomatis, Mycobacterium avium, Mycobacterium leprae.
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 (Branhamella) catarrhalis, Neisseria gonorrhoeae, Helicobacter pylori
and Campylobacter
species.
Clarithromycin Actavis 250 mg Film-coated Tablets V007 – Safety Update (CSP Update)
H. pylori is associated with acid peptic disease including duodenal ulcer and gastric ulcer in which
about 95% and 80% of patients respectively are infected with the agent. H. pylori is also implicated as
a major contribution factor in the development of gastric and ulcer recurrence in such patients.
Clarithromycin has been used in small numbers of patients in other treatment regimens. Possible
kinetic interactions have not been fully investigated. These regimens include:
Clarithromycin plus tinidazole and omeprazole; clarithromycin plus tetracycline, bismuth subsalicylate
and ranitidine; clarithromycin plus ranitidine alone.
Clinical studies using various different H. pylori eradication regimens have shown that eradication of
H. pylori prevents ulcer recurrence.
Breakpoints
The following breakpoints for clarithromycin, separating susceptible organisms from resistant
organisms, have been established by the European Committee for Antimicrobial Susceptibility Testing
(EUCAST).

Clarithromycin is used for the eradication of H. pylori ; minimum inhibitory concentration (MIC)
0.25 μg/ml which has been established as the susceptible breakpoint by the Clinical and Laboratory
Standards Institute (CLSI).
5.2.
Pharmacokinetic Properties
H. Pylori is associated with acid peptic disease including duodenal ulcer and gastric ulcer in which about 95% and 80% of patients respectively are infected with the agent. H. Pylori is also implicated as a major contribution factor in the development of gastric and ulcer recurrence in such patients. Clarithromycin has been used in small numbers of patients in other treatment regimens. Possible kinetic interactions have not been fully investigated. These regimens include: Clarithromycin plus tinidazole and omeprazole; clarithromycin plus tetracycline, bismuth subsalicylate and ranitidine; clarithromycin plus ranitidine alone. Clinical studies using various different H.Pylori eradication regimens have shown that eradication of H.Pylori prevents ulcer recurrence. Clarithromycin is rapidly and well absorbed from the gastrointestinal tract after oral administration. The microbiologically active metabolite 14-hydrocyclarithromycin is formed by first pass metabolism. Clarithromycin may be given without regards 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. The pharmacokinetics of clarithromycin are non linear, however, steady state is attained within 2 days of dosing. At 250 mg b.i.d. 15-20% of unchanged drug is excreted in the urine. With 500 mg b.i.d. daily dosing urinary excretion is greater (approximately 36%). The 14- Clarithromycin Actavis 250 mg Film-coated Tablets V007 – Safety Update (CSP Update)
hydroxyclarithromycin is the major urinary metabolite and accounts for 10-15% of the dose. Most of
the remainder of the dose is eliminated in faeces, primarily via bile. 5-10% of the parent drug is
recovered from faeces.
When clarithromycin 500 mg is given three times daily, the clarithromycin plasma concentrations are
increased with respect to the 500 mg twice daily dosage.
Clarithromycin provides tissue concentrations that are several times higher than the circulating drug
levels. Increased levels have been found in tonsillar and lung tissue. Clarithromycin is 80% bound to
plasma protein at therapeutic levels.
Clarithromycin also penetrates the gastric mucus. Levels of clarithromycin in gastric mucus and
gastric tissue are higher when clarithromycin is co-administered with omeprazole than when
clarithromycin is administered alone.
Clarithromycin Actavis 250 mg, film-coated tablets do not contain tartrazine or other azodyes, lactose
or gluten.
5.3.
Preclinical Safety Data

In acute mouse and rats studies, the median lethal dose was greater than the highest feasible dose for
administration (5 g/kg).
In repeated doses studies, toxicity was related to dose, duration of treatment and species. Dogs were
more sensitive than primates or rats. The major clinical signs at toxic doses included emesis,
weakness, reduced food consumption and weight gain, salivation, dehydration and hyperactivity. In all
species the liver was the primary target organ at toxic doses. Hepatotoxicity was detectable by early
elevations of liver function tests. Discontinuation of the drug generally resulted in a return to or
toward normal results. Other tissues less commonly affected included the stomach, thymus and other
lymphoid tissues and the kidneys. At near therapeutic doses, conjunctival injection and lacrimation
occurred only in dogs. At a massive dose of 400 mg/kg/day, some dogs and monkeys developed
corneal opacities and/or oedema.
Fertility and reproduction studies in rats have shown not adverse effects. Teratogenicity studies in rats
(Wistar (p.o.) and Spraque-Dawley (p.o. and i.v.)), New Zealand white rabbits and cynomologous
monkeys failed to demonstrate any teratogenicity from clarithromycin. However, a further similar
study in Sprague-Dawley rats indicated a low (6%) incidence of cardiovascular abnormalities which
appeared to be due to spontaneous expression of genetic changes. Two mouse studies revealed a
variable incidence (3-30%) of cleft palate and embryonic loss was seen in monkeys but only at dose
levels which were clearly toxic to the mothers.
6.
PHARMACEUTICAL PARTICULARS
List of Excipients
Microcrystalline cellulose (E460) Colloidal anhydrous silica Croscarmellose sodium Povidone Stearic acid Talc Magnesium stearate (E470) Hypromellose(E464) Propylene glycol Clarithromycin Actavis 250 mg Film-coated Tablets V007 – Safety Update (CSP Update)
Sorbitan monooleate (E494)
Vanilla dry flavour (contains artificial vanilla flavour, glucose, palm oils and coconut oils)
Titanium dioxide (E171)
Quinolline yellow lake (E104)
Hypromellose (E463)
Sorbic acid (E200-E201)
6.2.
Incompatibilities

Not applicable.
6.3.
Shelf Life

2 years.

6.4.

Special Precautions for Storage

Do not store above 25oC.
6.5.
Nature and Contents of Container

14 film-coated tablets in a PVC/PVdC-Aluminium blister.
6.6.
Special precautions for disposal

No special requirements.

7.

MARKETING AUTHORISATION HOLDER

Actavis Group PTC ehf.
Reykjavikurvegi 76-78
220 Hafnarfjordur
Iceland
8.
MARKETING AUTHORISATION NUMBER

PA 1380/109/1
9.
DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

Date of first Authorisation: 07 July 2006
Date of last Renewal: 07 July 2011
10.
DATE OF REVISION OF THE TEXT

Source: http://www.actavis.ie/NR/rdonlyres/6E272E82-C2A2-4C2C-9970-AE21F505ED93/25002/IEClarithromycin250mgFCtabletsv4020120605.pdf

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