CLARITHRO-NATRAPHARM Clarithromycin 125mg / 5mL Granule for Suspension 50mL

Clarithromycin 50 mg/mL granules for oral suspension is indicated in adults, adolescents and children, 6 months to 12 years, for the treatment of the following acute and chronic bacterial infections, when caused by clarithromycin susceptible organisms.
Infections of the upper respiratory tract such as tonsillitis/pharyngitis, as an alternative when beta lactam antibiotics are not appropriate.
Acute otitis media in children
Infections of the lower respiratory tract such as community acquired pneumonia.
Sinusitis and acute exacerbation of chronic bronchitis in adults and adolescents over 12 years of age.
Skin infections and soft tissue infections of mild to moderate severity.
In appropriate combination with antibacterial therapeutic regimens and an appropriate ulcer health medicinal product for the eradication of Helicobacter pylori in adult patients with H. pylori associated ulcers (see Dosage & Administration).
Consideration should be given to official guidance on the appropriate use of antibacterial agents.

The dose of clarithromycin depends on the clinical condition of the patient and has to be defined in any case by the physician.
Adults and adolescents: Standard dose: The usual dose is 250 mg twice daily.
High dose treatment (severe infections): The usual dose may be increased to 500 mg twice daily in severe infections.
Elimination of Helicobacter pylori in adults: In patients with gastro-duodenal ulcers due to H. pylori infection clarithromycin as part of the first line triple therapy is given in dose of 500 mg twice daily. The national recommendations for Helicobacter pylori eradication have to be considered.
Dose in renal function impairment: The maximum recommended doses should be reduced proportionately to renal impairment.
At creatinine clearance rate of less than 30 mL/min, the dose should be halved to 250 mg daily or in the most severe infections to 250 mg twice daily. The duration of treatment should not exceed 14 days in these patients.
Children 6 months to 12 years of age: The recommended dose is 7.5 mg/kg twice a day. (See Table 3.)



Children weighing less than 8 kg should be treated on their bodyweight.
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 (granules for oral suspension).
There is limited experience of treatment of children below 6 months of age.
For the indication community acquired pneumonia effect in children under 3 years of age is not documented.
In patients with renal impairment with creatinine clearance less than 30 mL/min, the dose of clarithromycin should be halved, i.e. 7.5 mg/kg once a day, and the duration of treatment should not exceed 14 days.
Duration of therapy: The duration of therapy with clarithromycin depends on the clinical condition of the patient. The duration of therapy has in any case to be determined by the physician.
The usual duration of treatment of children up to 12 years of age is 5 to 10 days.
The usual duration of treatment of adults and adolescents is 6 to 14 days.
Therapy should be continued at least for 2 days after symptoms have subsided.
In Streptococcus pyogenes (as a beta-haemolytic streptococcal) infections the duration of therapy should be at least 10 days.
Combination therapy for the eradication of H. pylori infection, e.g. clarithromycin 500 mg twice daily in combination with amoxicillin 1000 mg twice daily and omeprazole 20 mg twice daily should be continued for 7 days.
Method of administration: Before administration the granules must be reconstituted with water, see Direction for reconstitution as follows.
For administration after reconstitution an oral PE/PP- measuring syringe or a PP-measuring spoon are used.
Direction for reconstitution: 125 mg/5 mL: Fill the bottle with 29.5 mL of cold drinking water and shake well before every use.
Granules of the oral suspension can cause bitter aftertaste when remaining in the mouth. This can be avoided by eating or drinking something immediately after the intake of suspension.
Clarithromycin may be given irrespective of food intake. Food does not affect the extent of bioavailability. Food does only slightly delay the onset of absorption of clarithromycin.

May be taken with or without food.

Hypersensitivity to macrolide antibiotics or to any of its excipients.
Concomitant administration of clarithromycin and any of the following active substances in contraindicated: astemizole, cisapride, domperidone, pimozide, terfenadine as this may result in QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and Torsades de pointes (see Interactions).
Concomitant administration with ticagrelor or ranolazine is contraindicated.
Concomitant administration of clarithromycin and ergot alkaloids (e.g. ergotamine or dihydroergotamine) is contraindicated, as this may result in ergot toxicity (see Interactions).
Clarithromycin should not be given to patients with history of QT prolongation (congenital or documented acquired QT prolongation) or ventricular cardiac arrhythmia, including torsade de pointes (see Precautions and Interactions).
Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolised by CYP3A4, (lovastatin or simvastatin), due to increased risk of myopathy, including rhabdomyolysis (see Interactions).
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.
As with other strong CYP3A4 inhibitors, clarithromycin should not be used in patients taking colchicine (see Precautions and Interactions).
Concomitant administration of clarithromycin and oral midazolam is contraindicated (see Interactions).

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 Use in Pregnancy & Lactation).
Caution is advised in patients with severe renal insufficiency (see Dosage & Administration).
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 patients with moderate to severe renal impairment.
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 instance, 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.
Cases of fatal hepatic failure (see Adverse Reactions) 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 clarithromcyin, 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. Medicinal products 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 Interactions).
Concomitant administration of clarithromycin and colchicine is contraindicated (see Contraindications).
Caution is advised regarding concomitant administration of clarithromycin and triazolobenzodiazepines, such as triazolam, and intravenous or oromucosal midazolam (see Interactions).
Cardiovascular events: Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsade de pointes, have been seen in treatments with macrolides including clarithromycin (see Adverse Reactions). Therefore as the following situations may lead to an increased risk for ventricular arrhythmias (including torsade de pointes), clarithromycin should be used with caution in the following patients: Patients with coronary artery disease, severe cardiac insufficiency, conduction disturbances or clinically relevant bradycardia.
Patients with electrolyte disturbances such as hypomagnesaemia. Clarithromycin must not be given to patients with hypokalemia (see Contraindications).
Patients concomitantly taking other medicinal products associated with QT prolongation (see Interactions).
Concomitant administration of clarithromycin with astemizole, cisapride, pimozide and terfenadine is contraindicated (see Contraindications).
Clarithromycin must not be used in patients with congenital or documented acquired QT prolongation or history of ventricular arrhythmia (see Contraindications).
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. Considerations 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 pnuemonia, 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 medicinal product of first choice. Currently, macrolides are only considered to play a role in some skin and soft tissue infections, such as those caused by Corynebacterium minutissimum, acne vulgaris, and erysipelas and in situations where penicillin treatment cannot be used.
In the event of severe acute hypersensitivity reactions, such as anaphylaxis, severe cutaneous adverse reactions (SCAR) (e.g. acute generalised exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome, toxic epidermal necrolysis and drug rash with eosinophilia and systemic symptoms (DRESS), clarithromycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.
Clarithromycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme (see Interactions).
HMG-CoA Reductase Inhibitors (statins): Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see Contraindications).
Cautions 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 Interactions).
Oral hypoglycemic agents/Insulin: The concomitant use of clarithromycin and oral hypoglycemic agents (such as sulphonylureas) and/or insulin can result in significant hypoglycaemia.
Careful monitoring of glucose is recommended (see Interactions).
Oral anticoagulants: There is a risk of serious haemorrhage and significant elevations in International Normalised Ratio (INR) and prothrombin time when clarithromycin is co-administered with warfarin (see Interactions). INR and prothrombin times should be frequently monitored while patients are receiving clarithromycin and oral anticaogulants 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 macrolides, as well as lincomycin and clindamycin.
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.
Visual impairment and vision blurred may have an effect on a patient's ability to drive or oeprate machinery (see Adverse Reactions).

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 or 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.
Summary of adverse reactions: The following list displays adverse reactions reported in clinical trails 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 form 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. (See Table 4.)




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 Contraindications and Precautions).
There have been post-marketing reports of medicinal product 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 Interactions).
Special populations: Adverse Reactions in immunocompromised patients (see Other special populations as follows).
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.
Other special populations: Immunocompromised patients: In AIDS and other immunocompromised patients treated with the higher doses of clarithromycin over long periods of time of time for myocardial 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 dose of 1000 mg and 2000 mg of clarithromycin were: nausea, vomiting, taste perversion, abdominal pain, dairrhoea, 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 400 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 dose groups also had elevated blood urea nitrogen (BUN) levels. Slightly higher incidences of abnormal values were noted for patients who received 4000 mg daily for all parameters except white blood cell.

The use of the following medicinal products is strictly contraindicated due to the potential for severe medicinal product 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 torsade de pointes. Similar effects have been observed in patients taking clarithromycin and pimozide concomitantly (see Contraindications).
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 torsade de pointes (see Contraindications). In one study in 14 health volunteers, the concomitant administration of clarithromycin and terfenadine resulted in two to three fold increase in the serum level of the acid metabolite of terfenadine and in prolongation of the QT interval which did not lead to any clinically detectable effect. Similar effects have been observed with concomitant administration of astemizole and other macrolides.
Ergotamine/dihydroergotamine: Postmarketing reports indicate that co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterised by vasospasm, and ischaemia of the extremities and other tissues including the central nervous system. Concomitant administration of clarithromycin and these ergot alkaloids is contraindicated (see Contraindications).
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 Contraindications) as these statins are extensively metabolised by CYP3A4 and concomitant treatment with clarithromycin increases their plasma concentration, which increase 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 results 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 of rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis.
The following active substances are known or suspected to affect circulating concentrations of clarithromycin; clarithromycin dose 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 from 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 health volunteers led to increases in the main steady-state minimum clarithromycin concentration (C_min) 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 clarithromcyin C_max increased by 31 %, C_min 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 dose reduction should be necessary in patients with normal renal function. However, for patients with renal impairment, the following dose adjustments should be considered: For patients with CL_CR 30 to 60 mL/min the dose clarithromycin should be reduced by 50%. For patients with CL_CR <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 rionavir.
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 Bi-directional medicinal product interactions as follows).
Effects of clarithromycin on other medicinal products: CYP3A-based interactions: Co-administration of clarithromycin, known to inhibit CYP3A, and an active substance primarily metabolised by CYP3A may be associated with elevations in active substance concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant medicinal product.
The use of clarithromycin is contraindicated in patients receiving the CYP3A substrates astemizole, cisapride, domperidone, pimozide, and terfenadine due to the risk of QT prolongation and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see Contraindications and Precautions). The use of clarithromycin is also contraindicated with ergot alkaloids, oral midazolam, HMG CoA reductase inhibitors metabolised mainly by CYP3A4 (e.g. lovastatin and simvastatin), colchicine, ticagrelor and ranolazine (see Contraindications).
Clarithromycin should be used with caution in patients receiving treatment with other medicinal products 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.
Dose adjustment may be considered, and when possible, serum concentrations of active substances primarily metabolised by CYP3A should be monitored closely in patients concurrently receiving clarithromycin.
The following active substances or substance classes are known or suspected to be metabolised by the same CYP3A isozyme: alprazolam, astemizole, carbamazepine, cilostazole, cisapride, cyclosporine, disopyramide, ergot alkaloids, ibrutinib, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin, see Precautions), atypical antipsychotics (e.g. quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, sirolimus, 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.
Antiarrhythmics: There have been post-marketing reports of torsade de pointes occuring with the concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QT prolongation during co-administration of clarithromycin with these medicinal products. 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 medicinal product 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.
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 (C_max, AUC_0-24, and t_1/2 increased by 30%, 89%, and 34%, respectively), by the concomitant administration of clarithromycin. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when omeprazole was co-administered with clarithromycin.
Sildenafil, tadalafil, and vardenafil: Each of these phosphodiesterase inhibitors is metabolised, at least in part, by CYP3A, and CYP3A may be inhibited by concomitantly administered clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil or vardenafil would likely to result in increased phosphodiesterase inhibitor exposure. Reduction of sildenafil, tadalafil and vardenafil doses should be considered when these medicinal products are co-administered with clarithromycin.
Theophylline, carbamazepine: Results of clinical studies indicate that there was a modest but statistically significant (p≤0.05) increase of circulating theophylline or carbamazepine levels when either of these medicinal products were administered concomitantly with clarithromycin. Dose reduction may need to be considered.
Tolterodine: The primary route of metabolism for tolterodine is via the 2D6 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 dose may be necessary in the presence of CYP3A inhibitors, such as clarithromycin in the CYP2D6 poor metaboliser population.
Triazolobenzodiazepines (e.g. alprazolam, midazolam, triazolam): When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC was increased 2.7-fold after intravenous administration of midazolam. If intravenous midazolam is co-administered with clarithromycin, the patient must be closely monitored to allow dose adjustment. Active substance delivery of midazolam via oromucosal route, which could bypass pre-systemic elimination of the active substance, will likely result in a similar interaction to that observed after intravenous midazolam rather than oral administration.
The same precautions should also apply to other benzodiazepines that are metabolised by CYP3A, including triazolam and alprazolam. For benzodiazepines which are not dependent on CYP3A for their elimination (temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
There have been post-marking reports of medicinal product 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 (see Contraindications and Precautions).
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 by 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 arryhythmias. 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 medicinal products not thought to be metabolised by CYP3A (e.g. phenytoin and valproate). Serum level determinations are recommended for these medicinal products when administered concomitantly with clarithromycin. Increased serum levels have been reported.
Bi-directional medicinal product interactions: Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of bi-directional medicinal product 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 dose reduction should be necessary in patients with normal renal function. For patients with moderate renal function (creatinine clearance 30 to 60 mL/min), the dose of clarithromycin should be decreased by 50%. For patients with creatinine clearance <30 mL/min, the dose of clarithromycin should be decreased by 75% using an appropriate clarithromycin formulation. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Calcium channel blockers: Caution is advised regarding the concomitant administration of clarithromycin and calcium channel blockers metabolised 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 in taking clarithromycin and verapamil concomitantly.
Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, leading to a bi-directional medicinal product 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 bi-directional medicinal product 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 C_max values of the saquinavir which were 177% and 187% higher than those seen with saquinavir alone. Clarithromycin AUC and C_max values were approximately 40% higher than those seen with clarithromycin alone. No dose adjustment is required when the two medicinal products are co-administered for a limited time at the doses/formulations studied. Observations from medicinal product interaction studies using the soft gelatin capsule formulation may not be representative of the effects seen using the saquinavir hard gelatin capsule. Observations from medicinal product 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 Ritonavir as previously mentioned).

Macrolides