For the Use of a Registered Medical Practitioner Only

1. GENERIC NAME AND BRAND NAME
Clarithromycin Extended – Release Tablets USP
CELEX OD^®

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each extended-release film coated tablet contains:
Clarithromycin I.P. 500 mg
Excipients q.s.
Colours: Titanium Dioxide I.P. & Quinoline Yellow WS

3. DOSAGE FORM AND STRENGTH
Refer section 1 & 2

4. CLINICAL PARTICULARS
4.1 THERAPEUTIC INDICATION
Lower respiratory tract infection, upper respiratory tract infection & skin soft tissue infections.

4.2 POSOLOGY AND METHOD OF ADMINISTRATION
Adults
The recommended doses for clarithromycin ER in adults and children 12 years of age or older are presented in the following table.
Clarithromycin ER tablets should be taken once daily with food.
Tablets should be swallowed whole and not chewed, broken or crushed.
The doses presented in the following table were found to be efficacious in clinical studies with clarithromycin ER. Total daily doses for other indications would be equivalent to clarithromycin IR doses.

Elderly population
In the absence of severe renal impairment (creatinine clearance (CLCR) less than 30 ml/min), use the same doses as in Adults section.

Renal Impairment
The maximum daily dose for patients with severe renal impairment (< CLCR 30 ml/min) is 500 mg. No dose adjustment is required for patients with moderate renal impairment (CLCR 30 to 60 ml/min).

Hepatic Impairment
Based on studies done with clarithromycin IR, no adjustment of dosage is necessary for subjects with moderate or severe hepatic impairment but with normal renal function.

Pediatric population
The use of clarithromycin ER has not been studied in children less than 12 years old.

4.3 CONTRAINDICATIONS
Hypersensitivity to macrolide antibiotic drugs or any of the excipients. Concomitant administration of clarithromycin and any of the following drugs is contraindicated:

1. Astemizole, cisapride, pimozide, terfenadine as this may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, and torsades de pointes.
2. Concomitant administration of clarithromycin and ergot alkaloids (e.g., ergotamine or dihydroergotamine) is contraindicated, as this may result in ergot toxicity.
3. Concomitant administration of clarithromycin and oral midazolam is contraindicated.
4. Clarithromycin should not be given to patients with history of QT prolongation (congenital or documented acquired QT prolongation) or ventricular cardiac arrhythmia, including anti.
5. Clarithromycin should not be given to patients with hypokalemia (risk of prolongation of QT-time).
6. Clarithromycin should not be used in patients who suffer from severe hepatic failure in combination with renal impairment.
7. 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.
8. Clarithromycin (and other strong CYP3A4 inhibitors) should not be used concomitantly with colchicine.
9. Concomitant administration with ticagrelor or ranolazine is contraindicated.

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.
Long-term use may, as with other antibiotics, result in colonization with increased numbers of nonsusceptible bacteria and fungi. If superinfections occur, appropriate therapy should be instituted.
Caution is advised in patients with severe renal insufficiency. 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. In some instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Discontinue clarithromycin immediately if signs and symptoms of hepatitis occur, 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 diarrhea (CDAD) has been reported with use of nearly all antibacterial agents including clarithromycin and may range in severity from mild diarrhea 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 diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
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 clarithromycin to patients with moderate to severe renal impairment.

Colchicine
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. Concomitant administration of clarithromycin and colchicine is contraindicated.
Caution is advised regarding concomitant administration of clarithromycin and triazolo benzodiazepines, such as triazolam, and intravenous or oromucosal midazolam.

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. 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
• Clarithromycin is contraindicated in patients with electrolyte disturbances (hypokalemia or hypomagnesemia) due to the risk of QT interval prolongation and torsades de pointes.
• Patients concomitantly taking other medicinal products associated with QT prolongation.
• Concomitant administration of clarithromycin with astemizole, cisapride, pimozide and terfenadine is contraindicated.
• Clarithromycin must not be used in patients with congenital or documented acquired QT prolongation or history of ventricular arrhythmia.

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, Stevens-Johnson Syndrome, toxic epidermal necrolysis and 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. Attention should also be paid to the possibility of cross resistance between clarithromycin and other macrolide drugs, as well as lincomycin and clindamycin.

HMG-CoA Reductase Inhibitors (statins):
Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated. 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 myopathyIn 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.

Oral Hypoglycemic Agents/Insulin
The concomitant use of clarithromycin and oral hypoglycemic agents (such as sulphonylurias) and/or insulin can result in significant hypoglycemia. Careful monitoring of glucose is recommended.

Oral Anticoagulants
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. Thus, Caution should be exercised when clarithromycin is co-administered with direct acting oral anticoagulants, such as dabigatran, rivaroxaban, and apixaban, particularly to patients at high risk of bleeding.

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

4.5 DRUGS INTERACTIONS
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.
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. In one study in 14 healthy volunteers, the concomitant administration of clarithromycin and terfenadine resulted in a two to t 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
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 ergot alkaloids is contraindicated.

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.

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(R)-hydroxy-clarithromycin (14-OHclarithromycin), a metabolite that is also microbiologically active. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired duri ng 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 three fold increase in the serum level of the acid metabolite of terfenadine and in prolongation 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 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.

Effect of Clarithromycin on Other Medicinal Products
Antiarrhythmics
There have been postmarketed reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during co-administration of clarithromycin with these drugs. Serum levels of these medications 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.

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), atypical antipsychotics (e.g. quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam and vinblastine, but this list is not comprehensive. Drugs interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate.

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.

Theophylline, carbamazepine
Results of clinical studies indicate 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.

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 .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 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 colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine. Concomitant use of clarithromycin and colchicine is contraindicated.

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 pediatric 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 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 bid) and saquinavir (soft gelatin capsules, 1200 mg tid) 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 coadministered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin

4.6 USE IN SPECIAL POPULATIONS (SUCH AS PREGNANT WOMEN, LACTATING WOMEN, PAEDIATRIC PATIENTS, GERIATRIC PATIENTS ETC.)
Pregnancy
The safety of clarithromycin for use during pregnancy has not been established. Based on variable results obtained from animal studies and experience in humans, the possibility of adverse effects on embryofoetal development cannot be excluded. Some observational studies evaluating exposure to clarithromycin during the first and second trimester have reported an increased risk of miscarriage compared to no antibiotic use or other antibiotic use during the same period. The available epidemiological studies on the risk of major congenital malformations with use of macrolides including clarithromycin during pregnancy provide conflicting results. Therefore, use during pregnancy is not advised without carefully weighing the benefits against risks

Breastfeeding
The safety of clarithromycin for using during breast-feeding of infants has not been established. Clarithromycin is excreted into human breast milk in small amounts. It has been estimated that an exclusively breastfed infant would receive about 1.7% of the maternal weight-adjusted dose of clarithromycin.

Pediatric Patients
Safety and effectiveness of clarithromycin in pediatric patients under 6 months of age have not been established. The safety of clarithromycin has not been studied in MAC patients under the age of 20 months. Neonatal and juvenile animals tolerated clarithromycin in a manner similar to adult animals. Young animals were slightly more intolerant to acute overdosage and to subtle reductions in erythrocytes, platelets and leukocytes but were less sensitive to toxicity in the liver, kidney, thymus, and genitalia.

Geriatric Patients
In clinical trials, elderly patients did not have an increased incidence of adverse events when compared to younger patients. Dosage adjustment should be considered in elderly patients with severe renal impairment. Elderly patients may be more susceptible to development of torsades de pointes arrhythmias than younger patients.

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
The most frequent and common adverse reactions related to clarithromycin therapy for both adult and pediatric 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.
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
The following table displays adverse reactions reported in clinical trials and from post-marketing experience with clarithromycin ER.
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.

ADVERSE REACTIONS

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 HIV disease or intercurrent illness.

In adult patients, the most frequently reported adverse events by patients treated with total daily doses of 1000 mg of clarithromycin were: nausea, vomiting, taste perversion, abdominal pain, diarrhoea, rash, flatulence, headache, constipation, hearing disturbance, serum glutamic oxalo-acetic transaminase (SGOT) and serum glutamic pyruvate transaminase (SGPT) elevations. Additional low-frequency events included dyspnea, insomnia, and dry mouth.

In these immunocompromised patients evaluations of laboratory values were made by analyzing those values outside the seriously abnormal level (i.e., the extreme high or low limit) for the specified test. On the basis of this criteria, about 2 to 3% of these patients who received 1000 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 also had elevated BUN levels.

4.9 OVERDOSE
Symptoms
Reports indicate the ingestion of large amounts of clarithromycin can be expected to produce gastrointestinal symptoms. One patient who had a history of bipolar disorder ingested eight grams of clarithromycin and showed altered mental status, paranoid behaviour, hypokalemia, and hypoxemia.
Treatment
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 hemodialysis or peritoneal dialysis.

5. PHARMACOLOGICAL PROPERTIES
5.1 MECHANISM OF ACTION
Clarithromycin is an antibiotic belonging to the macrolide antibiotic group. It exerts its antibacterial action by selectively binding to the 50s ribosomal subunit of susceptible bacteria preventing translocation of 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 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.

5.2 PHARMACODYNAMICPROPERTIES
Pharmacotherapeutic group: Antibacterial for systemic use, macrolide ATC-Code: J01FA09

Clarithromycin is a semi-synthetic macrolide antibiotic obtained by substitution of a CH3O group for the hydroxyl (OH) group at position 6 of the erythromycin lactonic ring. Specifically clarithromycin is 6-O-methyl erythromycin A. The white to off-white antibiotic powder is bitter, practically odorless, essentially insoluble in water, and slightly soluble in ethanol, methanol, and acetonitrile. Its molecular weight is 747.96.

Microbiology
Clarithromycin exerts its antibacterial action by binding to the 5OS ribosomal subunits of susceptible bacteria and suppressing protein synthesis.
Clarithromycin has demonstrated excellent in vitro activity against both standard strains of bacteria and clinical isolates. It is highly potent against a wide variety of aerobic and anaerobic Gram-positive and Gram-negative organisms. The minimum inhibitory concentrations (MIC’s) of clarithromycin are generally one log2 dilution more potent than the MIC’s of erythromycin. In vitro data also indicate clarithromycin has excellent activity against Legionella pneumophila, and Mycoplasma pneumoniae. It is bactericidal to Helicobacter pylori; this activity of clarithromycin is greater at neutral pH than at acid pH. In vitro and in vivo data show this antibiotic has activity against clinically significant mycobacterial species. The in vitro data indicate Enterobacteriaceae, pseudomonas species and other non-lactose fermenting Gram-negative bacilli are not susceptible to clarithromycin.
Clarithromycin has been shown to be active against most strains of the following micro- organisms both in vitro and in clinical infections as described in section 4.1:

Aerobic Gram-Positive microorganisms
Staphylococcus aureus
Streptococcus pneumoniae
Streptococcus pyogenes
Listeria monocytogenes
Aerobic Gram-negative microorganisms
Haemophilus influenzae
Haemophilus parainfluenzae
Moraxella catarrhalis
Neisseria gonorrhoeae
Legionella pneumophila
Other microorganisms
Mycoplasma pneumoniae
Chlamydia pneumoniae (TWAR)
Mycobacteria
Mycobacterium leprae
Mycobacterium kansasii
Mycobacterium chelonae
Mycobacterium fortuitum
Mycobacterium avium complex (MAC) consisting of: Mycobacterium avium
Mycobacterium Intracellulare
Beta-lactamase production should have no effect on clarithromycin activity.
NOTE: Most strains of methicillin-resistant and oxacillin-resistant staphylococci are resistant to clarithromycin.

Helicobacter
Helicobacter pylori
In cultures performed prior to therapy, H. pylori was isolated and clarithromycin MIC’s were determined pre-treatment in 104 patients. Of these, four patients had resistant strains, two patients had strains with intermediate susceptibility, and 98 patients had susceptible strains.
The following in vitro data are available, but their clinical significance is unknown. Clarithromycin exhibits in vitro activity against most strains of the following microorganisms; however, the safety and effectiveness of clarithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic Gram-positive microorganisms
Streptococcus agalactiae
Streptococci (Group C,F,G)
Viridans group streptococci
Aerobic Gram-negative microorganisms
Bordetella pertussis
Pasteurella multocida
Anaerobic Gram-positive microorganisms
Clostridium perfringens
Peptococcus niger
Propionibacterium acnes
Anaerobic Gram-negative microorganisms
Bacteroides melaninogenicus
Spirochetes
Borrelia burgdorferi
Treponema pallidum
Campylobacter
Campylobacter jejuni
The principal metabolite of clarithromycin in man and other primates is a microbiologically- active metabolite, 14-OH-clarithromycin. This metabolite is as active or 1- to 2-fold less active than the parent compound for most organisms, except for H. influenzae against which it is twice as active. The parent compound and the 14-OH metabolite exert either an additive or synergistic effect on H. influenzae in vitro and in vivo, depending on bacterial strains.
Clarithromycin was found to be two to ten times more active than erythromycin in several experimental animal infection models. It was shown, for example, to be more effective than erythromycin in mouse systemic infection, mouse subcutaneous abscess, and mouse respiratory tract infections caused by S. pneumoniae, S. aureus, S. pyogenes, and H. influenzae. In guinea pigs with Legionella infection this effect was more pronounced; an intraperitoneal dose of 1.6 mg/kg/day of clarithromycin was more effective than 50 mg/kg/day of erythromycin.

Susceptibility Tests
Quantitative methods that require measurement of zone diameters give the most precise estimates of susceptibility of bacteria to antimicrobial agents. One recommended procedure uses discs impregnated with 15 μg of clarithromycin for testing susceptibility (Kirby-Bauer diffusion test); interpretations correlate inhibition zone diameters of this disc test with MIC values for clarithromycin. The MICs are determined by the broth or agar dilution method.
With these procedures, a report from the aboratory of “susceptible” indicates the infecting organism is likely to respond to therapy. A report of “resistant” indicates the infective organism is not likely to respond to therapy. A report of “Intermediate Susceptibility” suggests the therapeutic effect of the drug may be equivocal or the organism would be susceptible if higher doses were used. (Intermediate susceptibility is also referred to as moderately susceptible.) Please reference your country or region specific information regarding absolute breakpoints ranges for susceptible, resistant and intermediate susceptibility.

5.3 PHARMACOKINETIC PROPERTIES
Absorption
Clarithromycin ER tablets allow absorption of clarithromycin from the gastrointestinal tract over 12 to 14 hours after oral administration. Relative to an equal total dose of clarithromycin IR tablets, clarithromycin ER tablets provide lower and later steady-state peak plasma concentrations but equivalent 24-hour exposures for both clarithromycin and 14-OH-clarithromycin. The area under the plasma concentration-time curve (AUC) values from time zero (pre-dose) to three hours after dosing (AUC0-3) were higher for clarithromycin IR administered b.i.d than for an equal total daily dose of clarithromycin ER, indicating that there was no dose dumping with the clarithromycin ER ormulation.

The pharmacokinetics of orally administered clarithromycin IR have been studied extensively in a number of animal species and adult humans. These studies have shown clarithromycin is readily and rapidly absorbed with an absolute bioavailability of approximately 50%. Little or no unpredicted accumulation was found and the metabolic disposition did not change in any species following multiple dosing.
Bioequivalence studies comparing clarithromycin ER and IR formulations have shown relative bioavailability of approximately 0.96 for clarithromycin and 1.0 for 14-OH-clarithromycin. These findings support that administration of clarithromycin ER tablets to a patient population normally treated with clarithromycin IR tablets would result in similar efficacy. While the extent of formation of 14-OH-clarithromycin following administration of clarithromycin ER tablets (1000 mg once daily) is not affected by food, administration under fasting conditions is associated with approximately 30% lower clarithromycin AUC relative to administration with food. Therefore, clarithromycin ER tablets should be taken with food.

Distribution
Clarithromycin and the 14-OH-clarithromycin metabolite distribute readily into body tissues and fluids. A tissue penetration study with clarithromycin ER confirmed that therapeutic levels of clarithromycin and its active metabolite are present at tissue sites important for lower respiratory tract infections up to at least 24 hours after 1000 mg once daily dosing. Clarithromycin ER dosed at 1000 mg once daily achieved higher steady state clarithromycin concentrations in epithelial lining fluid (4 to 25X) and alveolar macrophages (150 to 250X) as compared to simultaneous plasma concentrations throughout the 24-hour period after drug administration. Additionally, 14-OH-clarithromycin achieved higher steady-state concentrations in alveolar macrophages (40 to 80X) compared to plasma concentrations.
Concentrations of clarithromycin for the ER formulation, dosed as 500 mg or 1000 mg daily, resulted in both plasma and lung tissue concentrations that exceeded the MIC values of most common respiratory and skin and soft tissue pathogens and these concentrations were similar to the values obtained with clarithromycin IR formulations.
In vitro studies with clarithromycin showed the protein binding of clarithromycin in human plasma averaged about 70% at concentrations of 0.45 to 4.5 μg/ml. A decrease in binding to 41% at 45.0 μg/ml suggested the binding sites might become saturated, but this only occurred at concentrations far in excess of the therapeutic drug levels.

Biotransformation
Data available to date indicate clarithromycin is metabolized primarily by the hepatic cytochrome P450 3A (CYP3A) isoform subfamily.

Elimination
Clarithromycin is eliminated by the liver and kidney. In human adults given single oral doses of 250 mg or 1200 mg clarithromycin IR, urinary excretion accounted for 37.9% of the lower dose and 46.0% of the higher dose. Fecal elimination accounted for 40.2% and 29.1% (this included a subject with only one stool sample containing 14.1%) of these respective doses.

Hepatic Impairment
In a study comparing one group of healthy human subjects with a group of subjects with liver impairment who were given 250 mg of clarithromycin IR b.i.d. for two days and a single 250 mg dose the third day, steady state plasma levels and systemic clearing of clarithromycin were not significantly different between the two groups. In contrast, steady state concentrations of the 14-OH metabolite were markedly lower in the group of hepatic-impaired subjects. This decreased metabolic clearance of the parent compound by 14-hydroxylation was partially offset by an increase in the renal clearance of parent drug, resulting in comparable steady state levels of parent drug in the hepatic impaired and healthy subjects. These results indicate no adjustment of dosage is necessary for subjects with moderate or severe hepatic impairment but with normal renal function

Renal Impairment
A study was conducted to evaluate and compare the pharmacokinetic profile of multiple 500 mg oral doses of clarithromycin IR in subjects with normal and decreased renal function. The plasma levels, half-life, Cmax and Cmin for both clarithromycin and its 14-OH metabolite were higher and AUC was larger in subjects with renal impairment. Kelim and urinary excretion were lower. The extent to which these parameters differed was correlated with the degree of renal impairment; the more severe the renal impairment, the more significant the difference.

Elderly population
A study was also conducted to evaluate and compare the safety and pharmacokinetic profiles of multiple 500 mg oral doses of clarithromycin IR in healthy elderly male and female subjects to those in healthy young adult male subjects. In the elderly group, circulating plasma levels were higher and elimination slower than in the younger group for both parent drug and 14-OH metabolite. However, there was no difference between the two groups when renal clearance was correlated with creatinine clearance. It is concluded from those results that any effect on the handling of clarithromycin is related to renal function and not to age.

6. NONCLINICAL PROPERTIES
6.1 ANIMAL TOXICOLOGY OR PHARMACOLOGY
Corneal opacity occurred in dogs at doses 12 times and in monkeys at doses 8 times greater than the maximum human daily dose (on a body surface area basis). Lymphoid depletion occurred in dogs at doses 3 times greater than and in monkeys at doses 2 times greater than the maximum human daily dose (on a body surface area basis).

7. DESCRIPTION
CELEX OD is supplied for oral administration, as an extended – release tablet of Clarithromycin. Each extended – release tablet of CELEX OD contains Clarithromycin 500 mg.

8. PHARMACEUTICAL PARTICULARS
8.1 INCOMPATIBILITIES
Not applicable

8.2 SHELF-LIFE
Refer pack

8.3 PACKAGING INFORMATION
Refer pack

8.4 STORAGE AND HANDING INSTRUCTIONS
Refer pack

9. PATIENT COUNSELLING INFORMATION

• Patient should be informed that antibacterial drugs including Clarithromycin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Clarithromycin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.
• Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Clarithromycin or other antibacterial drugs in the future.
• Patients should be advised that diarrhea is a common problem caused by antibacterials including Clarithromycin which usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial. If this occurs, instruct patients to contact their healthcare provider as soon as possible.
• Advise patients that Clarithromycin may interact with some drugs; therefore, advise patients to report to their healthcare provider the use of any other medications.
• Advise patients that Clarithromycin extended-release tablet should be taken with food. There are no data on the effect of Clarithromycin on the ability to drive or use machines. However, counsel patients regarding the potential for dizziness, vertigo, confusion and disorientation, which may occur with the medication. The potential for these adverse reactions should be taken into account before patients drive or use machines.
• Advise patients who have coronary artery disease to continue medications and lifestyle modifications for their coronary artery disease because Clarithromycin may be associated with increased risk for mortality years after the end of Clarithromycin treatment.
• Patient should be informed that Clarithromycin can lead to development of arrythmias in patients who have electrolyte imbalance.
• Patient should be advised to immediately inform the healthcare if they suffer from any skin reaction like a red, scaly rash with bumps under the skin and blisters after receiving Clarithromycin.

10. DETAILS OF MANUFACTURER
Refer Pack for manufacturer details.

Marketed by:

Abbott Healthcare Pvt. Ltd.
Angel Space, Bldg. D-4, Gala No. 1 to 6 &
11 to 16 Ground Floor, 101 to 106 &
111 to 116 First Floor, 201 to 206 & 211 to 216
2nd Floor, Pimplas, Dist. Thane, Bhiwandi – 421 302, India.

® – Celex OD is a Regd. Trademark of Abbott Laboratories.

11. DETAILS OF PERMISSION OR LICENCE NUMBER
Refer Pack for Permission/License details

12. DATE OF REVISION
Version: 5.0, dated: 5th September 2023

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