Klaricid Xl 500 Mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Klaricid XL 500 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
mg/tablet
Active: Clarithromycin 500.00
3 PHARMACEUTICAL FORM
A yellow, ovaloid tablet containing 500mg clarithromycin in a modified-release preparation.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Klaricid XL 500 mg Tablets are indicated in adults and children 12 years and older.
Klaricid XL 500 mg Tablets is indicated for treatment of infections caused by susceptible organisms. Indications include:
Lower respiratory tract infections for example, acute and chronic bronchitis, and pneumonia.
Upper respiratory tract infections for example, sinusitis and pharyngitis.
Klaricid XL 500 mg Tablets is also indicated in skin and soft tissue infections of mild to moderate severity, for example folliculitis, cellulitis and erysipelas.
4.2
Posology and method of administration
Adults: The usual recommended dosage of Klaricid XL 500 mg Tablets in adults is one 500mg modified-release tablet daily to be taken with food. In more severe infections, the dosage can be increased to two 500mg modified-release tablets daily. The usual duration of treatment is 6 to 14 days.
Children older than 12 years: As for adults.
Children younger than 12 years: Use of Klaricid XL 500 mg Tablets are not recommended for children younger than 12 years. Clinical trials have been conducted using clarithromycin peadiatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use clarithromycin peadiatric suspension (granules for oral suspension).
Do not crush or chew Klaricid XL 500 mg Tablets.
Klaricid XL 500 mg Tablets should not be used in patients with significant renal impairment (creatinine clearance less than 30 ml/min), as appropriate clarithromycin dosage reduction is not possible when administering this product. Clarithromycin immediate release tablets may be utilized in this patient population (see section 4.3). The dosage of clarithromycin should be reduced by one-half, i.e. 250 mg once daily, or 250 mg twice daily in more severe infections. Treatment should not be continued beyond 14 days in these patients. For patients with moderate renal function (creatinine clearance 30 to 60 ml/min), a 50% dosage reduction should be implemented resulting in a maximum dose of one Klaricid XL 500 mg Tablet per day.
4.3 Contraindications
Klaricid XL 500 mg Tablets are contra-indicated in patients with known hypersensitivity to macrolide antibiotic drugs or to any of its excipients (see section 6.1).
In the case of Klaricid XL 500 mg Tablets, as the dose cannot be reduced from 500mg daily, Klaricid 500 mg Tablets are contraindicated in patients with creatinine clearance less than 30 mL/min. All other formulations may be used in this patient population.
Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is contraindicated, as this may result in ergot toxicity.
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 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.
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 this antibiotic to patients with impaired hepatic function. Caution should also be exercised when administering clarithromycin 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 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 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, hypomagnesaemia, 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, 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, toxic epidermal necrolysis, DRESS and Henoch-Schonlein purpura, clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.
Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see section 4.5).
HMG-CoA Reductase Inhibitors (statins): Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see section 4.3). Caution should be exercised when prescribing clarithromycin with other statins. Rhabdomyolysis has been reported in patients taking clarithromycin and statins. Patients should be monitored for signs and symptoms of myopathy.
In situations where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered (see section 4.5).
Oral hypoglycaemic agents/Insulin: The concomitant use of clarithromycin and oral hypoglycaemic agents (such as sulphonylurias) and/or insulin can result in significant hypoglycaemia. Careful monitoring of glucose is recommended (see section 4.5).
Oral anticoagulants: There is a risk of serious haemorrhage and significant elevations in International Normalized Ratio (INR) and prothrombin time when clarithromycin is co-administered with warfarin (see section 4.5). INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticoagulants concurrently.
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 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.
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take Klaricid Paediatric Suspension 125 mg/5ml or Klaricid Paediatric Suspension 250mg/5ml.
4.5 Interaction 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 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.
Ergotamine/dihydroergotamine:
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 these medicinal products 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 inhibitor administered). Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis.
The following drugs are known or suspected to affect circulating concentrations of clarithromycin; clarithromycin dosage adjustment or consideration of alternative treatments may be required.
Efavirenz, nevirapine, rifampicin, rifabutin and rifapentine Strong inducers of the cytochrome P450 metabolism system such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine may accelerate the metabolism of clarithromycin and thus lower the plasma levels of clarithromycin, while increasing those of 14-OH-clarithromycin, a metabolite that is also microbiologically active. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers.
Etravirine
Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Fluconazole
Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers led to increases in the mean steady-state minimum clarithromycin concentration (Cmin) and area under the curve (AUC) of 33% and 18% respectively. Steady state concentrations of the active metabolite 14-OH-clarithromycin were not significantly affected by concomitant administration of fluconazole. No clarithromycin dose adjustment is necessary.
Ritonavir
A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200 mg every eight hours and clarithromycin 500 mg every 12 hours resulted in a marked inhibition of the metabolism of clarithromycin. The clarithromycin Cmax increased by 31%, Cmin increased 182% and AUC increased by 77% with concomitant administration of ritonavir. An essentially complete inhibition of the formation of 14-OH-clarithromycin was noted. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. However, for patients with renal impairment, the following dosage adjustments should be considered: For patients with CLcr 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLcr <30 mL/min the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin greater than 1 gm/day should not be co-administered with ritonavir.
Similar dose adjustments should be considered in patients with reduced renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors including atazanavir and saquinavir (see section below, Bi-directional drug interactions).
Effect of Clarithromycin on Other Medicinal Products CYP3A-based interactions
Co-administration of clarithromycin, 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), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, tacrolimus, terfenadine, triazolam and vinblastine. Drugs interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate.
Antiarrhythmics
There have been post-marketed reports of torsades de pointes occurring with the concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QT prolongation during co-administration of clarithromycin with these drugs. Serum levels of quinidine and disopyramide should be monitored during clarithromycin therapy.
There have been post marketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
Oral hypoglycemic agents/Insulin
With certain hypoglycemic drugs such as nateglinide, and repaglinide, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause 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. Coadministration 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 coadministered 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 and 7-fold after oral administration. Concomitant administration of oral midazolam and clarithromycin should be avoided. If intravenous midazolam is coadministered with clarithromycin, the patient must be closely monitored to allow dose adjustment. 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
Aminoglycosides
Caution is advised regarding concomitant administration of clarithromycin with other ototoxic drugs, especially with aminoglycosides. See 4.4.
Colchicine
Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine. 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 metabolised by CYP3A (e.g. phenytoin and valproate). Serum level determinations are recommended for these drugs when administered concomitantly with clarithromycin. Increased serum levels have been reported.
Bi-directional drug interactions
Atazanavir
Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Co-administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily) resulted in a 2-fold increase in exposure to clarithromycin and a 70% decrease in exposure to 14-OH-clarithromycin, with a 28% increase in the AUC of atazanavir. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. For patients with moderate renal function (creatinine clearance 30 to 60 mL/min), the dose of clarithromycin should be decreased by 50%. For patients with creatinine clearance <30 mL/min, the dose of clarithromycin should be decreased by 75% using an appropriate clarithromycin formulation. Doses of clarithromycin greater than 1000 mg per day should not be coadministered with protease inhibitors.
Calcium Channel Blockers
Caution is advised regarding the concomitant administration of clarithromycin and calcium channel blockers metabolized by CYP3A4 (e.g. verapamil, amlodipine, diltiazem) due to the risk of hypotension. Plasma concentrations of clarithromycin as well as calcium channel blockers may increase due to the interaction. Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients taking clarithromycin and verapamil concomitantly.
Itraconazole
Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, leading to a bidirectional drug interaction. Clarithromycin may increase the plasma levels of itraconazole, while itraconazole may increase the plasma levels of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effect.
Saquinavir
Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Concomitant administration of clarithromycin (500 mg twice daily) and saquinavir (soft gelatin capsules, 1200 mg three times daily) to 12 healthy volunteers resulted in steady-state AUC and Cmax values of saquinavir which were 177% and 187% higher than those seen with saquinavir alone. Clarithromycin AUC and Cmax values were approximately 40% higher than those seen with clarithromycin alone. No dose adjustment is required when the two drugs are co-administered for a limited time at the doses/formulations studied. Observations from drug interaction studies using the soft gelatin capsule formulation may not be representative of the effects seen using the saquinavir hard gelatin capsule. Observations from drug interaction studies performed with saquinavir alone may not be representative of the effects seen with saquinavir/ritonavir therapy. When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (see section 4.5: Ritonavir).
Clarithromycin has been shown not to interact with oral contraceptives.
4.6 Fertility, Pregnancy and lactation
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.
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 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, . . 2 gastroenteritis , infection3, vaginal infection |
Pseudomembranous colitis, erysipelas, | ||
|
Blood and lymphatic system |
Leukopenia, neutropenia , 3 thrombocythaemia , eosinophilia4 |
Agranulocytosis, thrombocytopenia | ||
|
Immune system disorders |
Anaphylactoid reaction1, hypersensitivity |
Anaphylactic reaction. angioedema |
|
Metabolism and nutrition disorders |
Anorexia, decreased appetite | |||
|
Psychiatric disorders |
Insomnia |
Anxiety, nervousness3, screaming3 |
Psychotic disorder, confusional state5, depersonalisation, depression, disorientation, hallucination, abnormal dreams | |
|
Nervous system disorders |
Dysgeusia, headache, taste perversion |
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, el ectrocardi ogram QT prolonged, extrasystoles1, palpitations |
Torsades de pointes, ventricular tachycardia | ||
|
Vascular disorders |
Vasodilation1 |
Haemorrhage8 | ||
|
Respiratory, thoracic and mediastinal disorder |
Asthma1, epistaxis2, pulmonary embolism1 | |||
|
Gastrointesti nal disorders |
Diarrhoea, vomiting, dyspepsia, nausea, abdominal pain |
Oesophagitis1, gastrooesophageal reflux disease2, gastritis, proctalgia , stomatitis, glossitis, abdominal distension4, constipation, dry mouth, eructation, flatulence |
Pancreatitis acute, tongue discolouration, tooth discolouration | |
|
Hepatobiliar y disorders |
Liver function test abnormal |
Cholestasis4, hepatitis4, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased4 |
Hepatic failure, jaundice hepatocellular | |
|
Skin and |
Rash, |
Dermatitis bullous1, |
Stevens-Johnson |
|
subcutaneous tissue disorders |
hyperhidrosis |
pruritus, urticaria, rash maculo-papular3 |
syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), acne | |
|
Musculoskel etal and connective tissue disorders |
Muscle spasms3, musculoskeletal stiffness , myalgia |
Rhabdomyolysis2,6, myopathy | ||
|
Renal and urinary disorders |
Blood creatinine increased1, blood urea increased1 |
Renal failure, nephritis interstitial | ||
|
General disorders and administratio n site conditions |
Injection site phlebitis1 |
Injection site pain1, injection site inflammation 1 |
Malaise4, pyrexia3, asthenia, chest pain4, chills4, fatigue4 | |
|
Investigation s |
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 Solution for Injection formulation 2ADRs reported only for the Extended-Release Tablets formulation
3 ADRs reported only for the Granules for Oral Suspension formulation
4 ADRs reported only for the Immediate-Release Tablets formulation 5,6 See section c)
* Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Patient exposure is estimated to be greater than 1 billion patient treatment days for clarithromycin.
c. Description of selected adverse reactions
Injection site phlebitis, injection site pain, and injection site inflammation are specific to the clarithromycin intravenous formulation.
In some of the reports of rhabdomyolysis, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol (see section 4.3 and 4.4).
There have been post-marketing reports of drug interactions and central nervous system (CNS) effects (e.g. somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested (see section 4.5).
There have been rare reports of clarithromycin ER tablets in the stool, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In several reports, tablet residues have occurred in the context of diarrhoea. It is recommended that patients who experience tablet residue in the stool and no improvement in their condition should be switched to a different clarithromycin formulation (e.g. suspension) or another antibiotic.
Special population: Adverse Reactions in Immunocompromised Patients (see section e).
d. Paediatric populations
Clinical trials have been conducted using clarithromycin paediatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use clarithromycin paediatric suspension.
Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.
e. Other special populations
Immunocompromised patients
In AIDS and other immunocompromised patients treated with the higher doses of clarithromycin over long periods of time for mycobacterial infections, it was often difficult to distinguish adverse events possibly associated with clarithromycin administration from underlying signs of Human Immunodeficiency Virus (HIV) disease or intercurrent illness.
In adult patients, the most frequently reported adverse reactions by patients treated with total daily doses of 1000 mg and 2000mg of clarithromycin were: nausea, vomiting, taste perversion, abdominal pain, diarrhoea, rash, flatulence, headache, constipation, hearing disturbance, Serum Glutamic Oxaloacetic Transaminase (SGOT) and Serum Glutamic Pyruvate Transaminase (SGPT) elevations. Additional low-frequency events included dyspnoea, insomnia and dry mouth. The incidences were comparable for patients treated with 1000mg and 2000mg, but were generally about 3 to 4 times as frequent for those patients who received total daily doses of 4000mg of clarithromycin.
In these immunocompromised patients, evaluations of laboratory values were made by analysing those values outside the seriously abnormal level (i.e. the extreme high or low limit) for the specified test. On the basis of these criteria, about 2% to 3% of those patients who received 1000mg or 2000mg of clarithromycin daily had seriously abnormal elevated levels of SGOT and SGPT, and abnormally low white blood cell and platelet counts. A lower percentage of patients in these two dosage groups also had elevated Blood Urea Nitrogen levels. Slightly higher incidences of abnormal values were noted for patients who received 4000mg daily for all parameters except White Blood Cell.
4.9 Overdose
Reports indicate that the ingestion of large amounts of clarithromycin can be expected to produce gastro-intestinal symptoms. One patient who had a history of bipolar disorder ingested 8 grams of clarithromycin and showed altered mental status, paranoid behaviour, hypokalaemia and hypoxaemia.
Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed drug and supportive measures. As with other macrolides, clarithromycin serum levels are not expected to be appreciably affected by haemodialysis or peritoneal dialysis.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC Classification:
Pharmacotherapeutic group: Antibacterial for systemic use, macrolide ATC-Code: J01FA09
Mode of Action:
Clarithromycin is an antibiotic belonging to the macrolide antibiotic group.It exerts its antibacterial action by selectively binding to the 50s ribosomal sub-unit of susceptible bacteria preventing translocation of activitate amino acids. It inhibits the intracellular protein synthesis of susceptible bacteria.
The 14-(R)-hydroxy metabolite of clarithromycin, a product of parent drug metabolism also has antimicrobial activity. The metabolite is less active than the parent compound for most organisms, including mycobacterium spp. An exception is Haemophilus influenza where the 14-hydroxy metabolite is two-fold more active than the parent compound.
Clarithromycin is usually active against the following organisms in vitro:
Gram-positive Bacteria: Staphylococcus aureus (methicillin susceptible); Streptococcus pyogenes (Group A beta-hemolytic streptococci); alpha-hemolytic streptococci (viridans group); Streptococcus (Diplococcus) pneumoniae; Streptococcus agalactiae; Listeria monocytogenes.
Gram-negative Bacteria: Haemophilus influenza; Haemophilus parainfluenza; Moraxella (Branhamella) catarrhalis; Neisseria gonorrhoeae; Legionella pneumophila; Bordetella pertussis; Campylobacter jejuni.
Mycoplasma: Mycoplasma pneumoniae; Ureaplasma urealyticum.
Other Organisms: Chlamydia trachomatis; Mycobacterium avium; Mycobacterium leprae; Mycobacterium kansasii; Mycobacterium chelonae; Mycobacterium fortuitum; Mycobacterium intracellularis; Chlamydia pneumoniae.
Anaerobes: Clostridium perfringens; Peptococcus species; Peptostreptococcus species; Propionibacterium acnes.
Clarithromycin has bactericidal activity against several bacterial strains. The organisms include Haemophilus influenzae; Streptococcus pneumoniae; Streptococcus pyogenes; Streptococcus agalactiae; Moraxella (Branhamella) catarrhalis; Neisseria gonorrhoeae and Campylobacter spp.
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.
5.2 Pharmacokinetic properties
The kinetics of orally administered modified-release clarithromycin have been studied in adult humans and compared with clarithromycin 250mg and 500mg immediate release tablets. The extent of absorption was found to be equivalent when equal total daily doses were administered. The absolute bioavailability is approximately 50%. Little or no unpredicted accumulation was found and the metabolic disposition did not change in any species following multiple dosing. Based upon the finding of equivalent absorption the following in vitro and in vivo data are applicable to the modified-release formulation.
In vitro: Results of in vitro studies showed that the protein binding of clarithromycin in human plasma averaged about 70 % at concentrations of 0.45 - 4.5pg/mL. A decrease in binding to 41% at 45.0pg/mL suggested that the binding sites might become saturated, but this only occurred at concentrations far in excess of therapeutic drug levels.
In vivo: Clarithromycin levels in all tissues, except the central nervous system, were several times higher than the circulating drug levels. The highest concentrations were found in the liver and lung tissue, where the tissue to plasma ratios reached 10 to 20.
The pharmacokinetic behaviour of clarithromycin is non-linear. In fed patients given 500mg clarithromycin modified-release daily, the peak steady state plasma concentration of clarithromycin and 14 hydroxy clarithromycin were 1.3 and 0.48pg/mL, respectively. When the dosage was increased to 1000mg daily, these steady-state values were 2.4pg/mL and 0.67pg/mL respectively. Elimination halflives of the parent drug and metabolite were approximately 5.3 and 7.7 hours respectively. The apparent half-lives of both clarithromycin and its hydroxylated metabolite tended to be longer at higher doses.
Urinary excretion accounted for approximately 40% of the clarithromycin dose. Faecal elimination accounts for approximately 30%.
5.3 Preclinical safety data
In repeated dose studies, clarithromycin toxicity was related to dose and duration of treatment. The primary target organ was the liver in all species, with hepatic lesions seen after 14 days in dogs and monkeys. Systemic exposure levels associated with this toxicity are not known but toxic mg/kg doses were higher than the dose recommended for patient treatment.
No evidence of mutagenic potential of clarithromycin was seen during a range of in vitro and in vivo tests.
Fertility and reproduction studies in rats have shown no adverse effects. Teratogenicity studies in rats (Wistar (p.o.) and Sprague-Dawley (p.o. and i.v.)), New Zealand White rabbits and cynomolgous monkeys failed to demonstrate any teratogenicity from clarithromycin. However, a further similar study in Sprague-Dawley rats indicated a low (6%) incidence of cardiovascular abnormalities which appeared to be due to spontaneous expression of genetic changes. Two mouse studies revealed a variable incidence (3-30%) of cleft palate and in monkeys embryonic loss was seen but only at dose levels which were clearly toxic to the mothers.
No other toxicological findings considered to be of relevance to the dose level recommended for patient treatment have been reported.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Citric acid anhydrous, sodium alginate, sodium calcium alginate, lactose, povidone K30, talc, stearic acid, magnesium stearate, methyl hydroxypropylcellulose 6cps, polyethylene glycol 400, macrogol 8000, titanium dioxide (E171), sorbic acid, quinoline yellow (dye) aluminium lake (E104).
6.2 Incompatibilities
None known.
6.3 Shelf life
The shelf-life is 18 months when stored in HDPE or glass bottles and 36 months when stored in PVC/PVdC blisters.
6.4 Special precautions for storage
Do not store above 30°C Store in the original package.
6.5 Nature and contents of container
4,5,6,7 or 14 tablets in a blister original pack or in bottles. The blisters, of PVC/PVdC, are heat sealed with 20 micron hard tempered aluminium foil and packaged in a cardboard carton with a pack insert. The bottles, of HDPE or glass, are packaged in a cardboard carton with a pack insert.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
BGP Products Ltd.
Abbott House
Vanwall Business Park
Vanwall Road
Maidenhead
Berkshire
SL6 4XE
UK.
8 MARKETING AUTHORISATION NUMBER(S)
PL 43900/0060
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
December 1996
10
DATE OF REVISION OF THE TEXT
19/07/2016