TRADE NAME: Clarimycin F.C. tablets GENERIC NAME: COMPOSITION: Each tablet contains: Active ingredient: Clarithromycin 500 mg Excipients: Microcrystalline cellulose (Avicel PH 102), Crosscarmellose Sodium, Polyvinyl pyrrolidone ( PVP K30) , Pregelatinized Maize starch, Magnesium stearate. Composition of film coat: Hydroxypropyl methyl cellulose E15, Polyethylene glycol 6000, Titanium dioxide, Talc powder, Tween 80, purified water. PHARMACEUTICAL FORM: Film coated tablet. PHARMACOLOGICAL ACTION: PHARMACODYNAMICS: Pharmacotherapeutic group: Antibacterial for systemic use, macrolide. Mechanism of action: Clarithromycin is a semi-synthetic derivative of erythromycin A. It exerts its antibacterial action by binding to the 50s ribosomal sub-unit of susceptible bacteria and suppresses protein synthesis. It is highly potent against a wide variety of aerobic and anaerobic gram-positive and gram-negative organisms. The minimum inhibitory concentrations (MICs) of clarithromycin are generally two-fold lower than the MICs of erythromycin. The 14-hydroxy metabolite of clarithromycin also has antimicrobial activity. The MICs of this metabolite are equal or two-fold higher than the MICs of the parent compound, except for H. influenzae where the 14-hydroxy metabolite is two-fold more active than the parent compound. Commonly susceptible species Aerobic Gram-negative microorganisms Moraxella catarrhalis Anaerobic microorganisms Peptococcus species Peptostreptococcus species Propionibacterium acnes Clostridium perfringens Other Microorganisms Chlamydia pneumoniae Legionella pneumophila Mycoplasma pneumoniae Species for which acquired resistance may be a problem Aerobic Gram-positive microorganisms Staphylococcus aureus (methicillin-susceptible) Staphylococcus aureus (methicillin-resistant)+ Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes Aerobic Gram-negative microorganisms Haemophilus influenzae $ +Resistance to macrolides among MRSA is commonly more than 50% in the EU and affects nearly all strains in some areas. $ The species may be regarded as being of intermediate susceptibility to clarithromycin and may also acquire high-level resistance to macrolides. Resistance Resistance mechanisms against macrolide antibiotics include alteration of the target site of the antibiotic or are based on modification and/or the active efflux of the antibiotic. Resistance development can be mediated via chromosomes or plasmids, be induced or exists constitutively. Macrolide/resistant bacteria generates enzymes which lead to methylation of residual adenine at ribosomal RNA and consequently to inhibition of the antibiotic binding to the ribosome. Macrolide/resistant organisms are generally cross/resistant to lincosamides and streptogramin B based on methylation of the ribosomal binding site. Clarithromycin ranks among the strong inducers of this enzyme as well. Furthermore, macrolides have a bacteriostatic action by inhibiting the peptidyl transferase of ribosomes. A complete cross-resistance exists among clarithromycin, erythromycin and azithromycin. Methicillin/resistant staphylococci and penicillin-resistant Streptococcus pneumoniae are resistant to macrolides such as clarithromycin. PHARMACOKINETICS: Clarithromycin is rapidly and well absorbed from the gastro-intestinal tract after oral administration of Clarithromycin tablets. The microbiologically active metabolite 14- hydroxyclarithromycin is formed by first pass metabolism. Clarithromycin Tablets may be given without regard to meals as food does not affect the extent of bioavailability of Clarithromycin tablets. Food does slightly delay the onset of absorption of clarithromycin and formation of the 14-hydroxymetabolite. The pharmacokinetics of clarithromycin are nonlinear; however, steady-state is attained within 2 days of dosing. At 250 mg b.i.d. 15-20% of unchanged drug is excreted in the urine. With 500 mg b.i.d. daily dosing urinary excretion is greater (approximately 36%). The 14-hydroxyclarithromycin is the major urinary metabolite and accounts for 10-15% of the dose. Most of the remainder of the dose is eliminated in the faeces, primarily via the bile. 5-10% of the parent drug is recovered from the faeces. When clarithromycin 500 mg is given three times daily, the clarithromycin plasma concentrations are increased with respect to the 500 mg twice daily dosage. Clarithromycin provides tissue concentrations that are several times higher than the circulating drug levels. Increased levels have been found in both tonsillar and lung tissue. Clarithromycin is 80% bound to plasma proteins at therapeutic levels. Clarithromycin also penetrates the gastric mucus. Levels of clarithromycin in gastric mucus and gastric tissue are higher when clarithromycin is co-administered with omeprazole than when clarithromycin is administered alone. INDICATIONS: Consideration should be given to official guidance on the appropriate use of antibacterial agents. Clarimycin is indicated in adults and children aged 12 years and older. Clarimycin Tablets are indicated for treatment of infections caused by susceptible organisms. Indications include: * Lower respiratory tract infections for example, acute and chronic bronchitis, and pneumonia. * Upper respiratory tract infections for example, sinusitis and pharyngitis. * Clarimycin is indicated for initial therapy in community acquired respiratory infections and has been shown to be active in vitro against common and atypical respiratory pathogens as listed in the microbiology section. * Clarimycin is also indicated in skin and soft tissue infections of mild to moderate severity (e.g. folliculitis, cellulitis, erysipelas). * Clarimycin in the presence of acid suppression effected by omeprazole or lansoprazole is also indicated for the eradication of Helicobacter pylori in patients with duodenal ulcers. DOSAGE AND ADMINISTRATION: Posology For doses of 250 mg twice daily, the 250 mg tablet must be used, as the 500 mg tablet cannot be halved. Patients with respiratory tract/skin and soft tissue infections. Adults: The usual dose is 250 mg twice daily although this may be increased to 500 mg twice daily in severe infections. The usual duration of treatment is 6 to 14 days. Children aged 12 years and older: As for adults. Children younger than 12 years: Use of Clarimycin Tablets is not recommended for children younger than 12 years. Eradication of Helicobacter pylori in patients with duodenal ulcers (Adults) The usual duration of treatment is 6 to 14 days. Triple Therapy: Clarimycin 500 mg twice daily and lansoprazole 30 mg twice daily should be given with amoxicillin 1000 mg twice daily. Triple Therapy: Clarimycin 500 mg twice daily and lansoprazole 30 mg twice daily should be given with metronidazole 400 mg twice daily (susceptibility testing is recommended if the potential effectiveness of metronidazole therapy is uncertain). Triple Therapy: Clarimycin 500 mg twice daily and omeprazole 40 mg daily should be given with amoxicillin 1000 mg twice daily or metronidazole 400 mg twice daily (susceptibility testing is recommended if the potential effectiveness of metronidazole therapy is uncertain). Triple Therapy: Clarimycin 500 mg twice daily and omeprazole 20 mg daily should be given with amoxicillin 1000 mg twice daily. Elderly: As for adults. - Renal impairment: In patients with renal impairment with creatinine clearance < 30 ml/min, the dosage of Clarimycin should be reduced by 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. - Patients with hepatic dysfunction: Dosage adjustments are not usually required, but caution should be exercised when administering Clarimycin to patients with impaired hepatic function. Method of administration The tablets should be swallowed whole with some liquid. Clarimycin may be given without regard to meals as food does not affect the extent of bioavailability. CONTRAINDICATIONS: - Hypersensitivity to clarithromycin, to any other macrolide antibiotic drug, or to any of the listed excipients. - Concomitant administration of Clarimycin and ergot alkaloids (e.g. ergotamine or dihydroergotamine) is contraindicated, as this may result in ergot toxicity. - Concomitant administration of Clarimycin and oral midazolam is contraindicated. - Concomitant administration of Clarimycin and any of the following drugs is contraindicated: astemizole (an antihistamine), cisapride (a motility stimulant), domperidone (an antiemetic), pimozide (an antipsychotic) and terfenadine (an antihistamine) as this may result in QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and Torsade de pointes. - Clarimycin should not be given to patients with history of QT prolongation (congenital or documented acquired QT prolongation) or ventricular cardiac arrhythmia, including Torsades de pointes. - Concomitant administration with ticagrelor or ranolazine is contraindicated. Clarimycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolised by CYP3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis. - As with other strong CYP3A4 inhibitors, Clarimycin should not be used in patients taking colchicine. - Clarimycin should not be given to patients with hypokalaemia (risk of prolongation of QT-time). - Clarimycin should not be used in patients who suffer from severe hepatic failure in combination with renal impairment. - Clarimycin is contraindicated in patients with a history of cholestatic jaundice/ hepatic dysfunction associated with prior use of Clarimycin . UNDESIRABLE EFFECTS: a. Summary of the safety profile The most frequent and common adverse reactions related to Clarimycin 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. There was no significant difference in the incidence of these gastrointestinal adverse reactions during clinical trials between the patient population with or without pre-existing mycobacterial infections. b. Tabulated summary of adverse reactions The following table displays adverse reactions reported in clinical trials and from postmarketing experience with Clarithromycin immediate-release tablets, granules for oral suspension, powder for solution for injection, extended-release tablets and modified-release tablets. The reactions considered at least possibly related to clarithromycin are displayed by system organ class and frequency using the following convention: very common (≥1/10), common (≥ 1/100 to < 1/10), uncommon (≥1/1,000 to < 1/100), very rare (< 1/10000) and not known (adverse reactions from postmarketing 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 Common Uncommon Very rare Not known* Infections and infestations Candidiasis, vaginal infection Pseudomembranous colitis, erysipelas Blood and lymphatic system Leukopenia, neutropenia1, eosinophilia1 Agranulocytosis, thrombocytopenia Immune system disorders Hypersensitivity Anaphylactic reaction, angioedema Metabolism and nutrition disorders Anorexia, decreased appetite Psychiatric disorders Insomnia Anxiety Nightmares Psychotic disorder, confusional state, depersonalisation, depression, disorientation, hallucination, abnormal dreams, mania Nervous system disorders Dysgeusia, headache Dizziness, somnolence2, tremor Convulsion, ageusia, parosmia, anosmia, paraesthesia Ear and labyrinth disorders Vertigo, hearing impaired, tinnitus Deafness Cardiac disorders Electrocardiogram QT prolonged, palpitations Torsades de pointes, ventricular tachycardia, ventricular fibrillation Vascular disorders Haemorrhage Gastrointestinal disorders Diarrhoea3, vomiting, dyspepsia, nausea, abdominal Pain Gastritis, stomatitis, glossitis, abdominal distension1, constipation, dry mouth, eructation, flatulence Pancreatitis acute, tongue discolouration, tooth discolouration Hepatobiliary Disorders Liver function test abnormal Cholestasis1, hepatitis1, alanine aminotransferase increased, aspartate aminotransferase increased, gammaglutamyl transferase increased1 Hepatic failure, jaundice hepatocellular Skin and subcutaneous tissue disorders Rash, hyperhidrosis Pruritus, urticaria Severe cutaneous adverse reactions (SCAR) (e.g. acute generalised exanthematous pustulosis (AGE), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS)), acne Musculoskeletal and connective tissue disorders Rhabdomyolysis4, myopathy Renal and urinary disorders Renal failure,nephritis interstitial General disorders and administration site conditions Malaise1,asthenia, chest pain1, chills1,fatigue1 Investigations Elevated BUN (blood urea nitrogen) Blood creatinine increased, blood alkaline phosphatase increased1, blood lactate dehydrogenase increased1 International normalised ratio increased, prothrombin time prolonged urine colour abnormal 1 ADRs reported only for the Immediate-Release Tablets formulation 3 See section a) 2,4 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 In some of the reports of rhabdomyolysis, Clarimycin was administered concomitantly with statins, fibrates, colchicine or allopurinol. 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 Clarimycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. Special population: Adverse Reactions in Immunocompromised Patients (see section d). d. Other special populations Immunocompromised patients In AIDS and other immunocompromised patients treated with the higher doses of Clarimycin over long periods of time for mycobacterial infections, it was often difficult to distinguish adverse events possibly associated with Clarimycin administration from underlying signs of Human Immunodeficiency Virus (HIV) disease or intercurrent illness. In adult patients, the most frequently reported adverse reactions by patients treated with total daily doses of 1000 mg and 2000 mg of Clarithromycin were: nausea, vomiting, taste perversion, abdominal pain, 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 1000 mg and 2000 mg, but were generally about 3 to 4 times as frequent for those patients who received total daily doses of 4000 mg of clarithromycin. In these immunocompromised patients, evaluations of laboratory values were made by analysing those values outside the seriously abnormal level (i.e. the extreme high or low limit) for the specified test. On the basis of these criteria, about 2% to 3% of those patients who received 1000 mg or 2000 mg of clarithromycin daily had seriously abnormal elevated levels of SGOT and SGPT, and abnormally low white blood cell and platelet counts. A lower percentage of patients in these two dosage groups also had elevated Blood Urea Nitrogen levels. Slightly higher incidences of abnormal values were noted for patients who received 4000 mg daily for all parameters except White Blood Cell. "Postmarketing experience": Liver/Biliary: Adverse reactions related to hepatic dysfunction have been reported in postmarketing experience with clarimycin. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via sending e-mail to pv@memphis.com.eg or via website www.epvc.gov.eg 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: Astemizole, cisapride, domperidone, pimozide and terfenadine Elevated cisapride levels have been reported in patients receiving clarithromycin and cisapride concomitantly. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and Torsades de pointes. Similar effects have been observed in patients taking clarithromycin and pimozide concomitantly. 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. Ergot alkoloids Post-marketing reports indicate that co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterised 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. 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 as these statins are extensively metabolised by CYP3A4 and concomitant treatment with clarithromycin increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis. Reports of rhabdomyolysis have been received for patients taking clarithromycin concomitantly with these statins. If treatment with clarithromycin cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment. Caution should be exercised when prescribing clarithromycin with statins. In situations where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered. Patients should be monitored for signs and symptoms of myopathy. Effects of other medicinal products on clarithromycin Drugs that are inducers of CYP3A (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St John’s wort) may induce the metabolism of clarithromycin. This may result in subtherapeutic levels of clarithromycin leading to reduced efficacy. Furthermore, it might be necessary to monitor the plasma levels of the CYP3A inducer, which could be increased owing to the inhibition of CYP3A by clarithromycin. 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. A 39% reduction in AUC for clarithromycin and a 34% increase in AUC for the active 14-hydroxy metabolite have been seen when clarithromycin was used concomitantly with the CYP3A4 inducer efavirenz. In such circumstances, it may be necessary to increase the dose of clarithromycin and monitor the safety and efficacy. Monitoring the plasma levels of the CYP3A4 inducer may be necessary because the levels could be increased owing to the inhibition of CYP3A4 by clarithromycin. Etravirine Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC. Fluconazole Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers led to increases in the mean steady-state minimum clarithromycin concentration (Cmin) and area under the curve (AUC) of 33% and 18% respectively. Steady state concentrations of the active metabolite 14-OH-clarithromycin were not significantly affected by concomitant administration of fluconazole. No clarithromycin dose adjustment is necessary. Ritonavir A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200 mg every eight hours and clarithromycin 500 mg every 12 hours resulted in a marked inhibition of the metabolism of clarithromycin. The clarithromycin Cmax increased by 31%, Cmin increased 182% and AUC increased by 77% with concomitant administration of ritonavir. An essentially complete inhibition of the formation of 14-OH-clarithromycin was noted. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. However, for patients with renal impairment, the following dosage adjustments should be considered: For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CLCR <30 mL/min the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin greater than 1 g/day should not be coadministered with ritonavir. Similar dose adjustments should be considered in patients with reduced renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors including atazanavir and saquinavir (see section below, Bi-directional drug interactions) Effects 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. Alternatively, treatment with these medicinal products may be interrupted during clarithromycin treatment. The following drugs or drug classes are known or suspected to be metabolised by the same CYP3A isozyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, domperidone, ergot alkaloids, ibrutinib, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin), atypical antipsychotics (e.g. quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, tacrolimus, terfenadine, triazolam and vinblastine but this list is not exhaustive. Drugs interacting by similar mechanisms through other isozymes within the cytochrome P450 system include phenytoin, theophylline and valproate. Antiarrhythmics There have been post-marketing reports of Torsades de pointes occurring with the concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QT prolongation during co-administration of clarithromycin with these drugs. Serum levels of quinidine and disopyramide should be monitored during clarithromycin therapy. There have been post-marketing reports of hypoglycaemia with the concomitant administration of clarithromycin and disopyramide. Therefore blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. Oral hypoglycaemic agents/insulin With certain hypoglycaemic drugs such as nateglinide and repaglinide, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypoglycaemia when used concomitantly. Careful monitoring of glucose is recommended.
