KLARICID Clarithromycin 125mg / 5mL Granule for Suspension 50mL

Klaricid: Clarithromycin is indicated for treatment of infections due to susceptible organisms in adults and children 12 years and older. Such infections include: Lower respiratory tract infections (e.g., bronchitis, pneumonia) (see Precautions and Pharmacology: Pharmacodynamics under Actions regarding Sensitivity Testing).
Upper respiratory tract infections (e.g., pharyngitis, sinusitis).
Skin and soft tissue infections (e.g., folliculitis, cellulitis, erysipelas) (see Precautions and Pharmacology: Pharmacodynamics under Actions regarding Sensitivity Testing).
Disseminated or localized mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare. Localized infections due to Mycobacterium chelonae, Mycobacterium fortuitum, or Mycobacterium kansasii.
Clarithromycin is indicated for the prevention of disseminated Mycobacterium avium complex infection in HIV-infected patients with CD4 lymphocyte counts less than or equal to 100/mm³.
Clarithromycin in the presence of acid suppression is also indicated for the eradication of H. pylori resulting in decreased recurrence of duodenal ulcer (see Pharmacology: Pharmacodynamics under Actions).
Treatment of odontogenic infections.
Consideration should be given to national official guidance on the appropriate use of antibacterial agents.
Klaricid OD: Clarithromycin is indicated for treatment of infections due to susceptible organisms in adults and children 12 years and older. Such infections include: Lower respiratory tract infections (e.g., bronchitis, pneumonia) (see Precautions and Pharmacology: Pharmacodynamics under Actions regarding Sensitivity Testing).
Upper respiratory tract infections (e.g., pharyngitis, sinusitis).
Skin and soft tissue infections (e.g., folliculitis, cellulitis, erysipelas) (see Precautions and Pharmacology: Pharmacodynamics under Actions regarding Sensitivity Testing).
Treatment of odontogenic infections.
Consideration should be given to national official guidance on the appropriate use of antibacterial agents.
Klaricid Pediatric: Clarithromycin is indicated for treatment of infections due to susceptible organisms in children 6 months to 12 years. Such infections include: Lower respiratory tract infections (e.g., bronchitis, pneumonia) (see Precautions and Pharmacology: Pharmacodynamics under Actions regarding Sensitivity Testing).
Upper respiratory tract infections (e.g., pharyngitis, sinusitis).
Skin and soft tissue infections (e.g., folliculitis, cellulitis, erysipelas) (see Precautions and Pharmacology: Pharmacodynamics under Actions regarding Sensitivity Testing).
Disseminated or localized mycobacterial infections due to Mycobacterium avium or Mycobacterium intracellulare. Localized infections due to Mycobacterium chelonae, Mycobacterium fortuitum, or Mycobacterium kansasii.
Acute otitis media.
Consideration should be given to national official guidance on the appropriate use of antibacterial agents.

 

Klaricid: Adults: The usual recommended dosage of clarithromycin in adults and children 12 years of age or older, is one 250 mg tablet twice daily. In more severe infections, the dosage can be increased to 500 mg twice daily. The usual duration of therapy is 5 to 14 days, excluding treatment of community acquired pneumonia and sinusitis which require 6 to 14 days of therapy.
Dosage in patients with mycobacterial infections: The recommended dose for adults with mycobacterial infections is 500 mg b.i.d.
Treatment of disseminated MAC infections in AIDS patients should be continued, as long as clinical and microbiological benefit is demonstrated. Clarithromycin should be used in conjunction with other antimycobacterial agents.
Treatment of other nontuberculous mycobacterial infections should continue at the discretion of the physician.
Dosage for MAC prophylaxis: The recommended dosage of clarithromycin in adults is 500 mg twice daily.
In the treatment of odontogenic infections, the dosage of clarithromycin is one 250 mg tablet twice daily for five days.
In patients with peptic ulcer due to H. pylori infection, clarithromycin can be administered in a dose of 500mg twice daily in combination with other appropriate anti-microbial treatments and a proton pump inhibitor for 7-14 days in consultation with national or international guideline recommendations for H. pylori eradication.
Renal Impairment: In patients with renal impairment with creatinine clearance less than 30 ml/min, the dosage of clarithromycin should be reduced by one-half, i.e., 250 mg once daily, or 250 mg twice daily in more severe infections. Treatment should not be continued beyond 14 days in these patients.
Pediatric Population: The use of clarithromycin (Klaricid) has not been studied in children less than 12 years of age.
Klaricid OD: Adults: The usual recommended dosage of clarithromycin (Klaricid OD) modified release tablets in adults and children 12 years of age or older is 500 mg once-daily with food. In more severe infections, the dosage may be increased to 1000 mg once-daily (2 x 500 mg). The usual duration of therapy is 5 to 14 days, excluding treatment of community acquired pneumonia and sinusitis which require 6 to 14 days therapy.
Odontogenic Infections: In the treatment of odontogenic infections, the usual dosage of clarithromycin (Klaricid OD) is one 500 mg modified release tablet once daily for 5 days.
Do not crush or chew clarithromycin modified release tablets.
Renal Impairment: In patients with severe renal impairment (creatinine clearance less than 30 mL/min), the usual recommended dose is 250 mg once daily. Because the modified-release tablet cannot be split, instead immediate-release tablets should be used. In more severe infections, the recommended dose is one 500 mg modified-release tablet once daily. No dose adjustment is required for patients with moderate renal impairment (creatinine clearance 30 to 60 ml/min).
Pediatric population: The use of clarithromycin (Klaricid OD) has not been studied in children less than 12 years of age.
Klaricid Pediatric: Pediatric Patients under 12 years of age: Clinical trials have been conducted using clarithromycin pediatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use clarithromycin pediatric suspension (granules for oral suspension).
The recommended daily dosage of Clarithromycin Pediatric Suspension (125 mg/5 ml or 250 mg/5 ml) in children is 7.5 mg/kg b.i.d. up to a maximum dose of 500 mg b.i.d. for non-mycobacterial infections. The usual duration of treatment is for 5 to 10 days depending on the pathogen involved and the severity of the condition. The prepared suspension can be taken with or without meals, and can be taken with milk.
The following table is a suggested guide for determining dosage, based on the weight of the child and the concentration of the suspension (125 mg/5 ml or 250 mg/5 ml). (See Table 3.)

Dosage in Patients with Mycobacterial Infections: In children with disseminated or localized mycobacterial infections (M. avium, M. intracellulare, M. chelonae, M. fortuitum, M. kansasii), the recommended dose is 7.5 to 15 mg/kg clarithromycin b.i.d., not exceeding a maximum dose of 500 mg b.i.d.
Treatment with clarithromycin should continue as long as clinical benefit is demonstrated. The addition of other antimycobacterial agents may be of benefit. (See Table 4.)

Renal Impairment: In children with creatinine clearance less than 30 ml/min/1.73 m², the dosage of clarithromycin should be reduced by one-half, i.e., up to 250 mg once daily, or 250 mg twice daily in more severe infections. Dosage should not be continued beyond 14 days in these patients.
Preparation for Use: See Special precautions for disposal and other handling under Cautions for Usage.

 

Overdosage

Klaricid tab May be taken with or without food. Klaricid OD MR tab Should be taken with food. Swallow whole, do not chew/crush. Klaricid oral susp May be taken with or without food. May be taken w/ milk.

Hypersensitivity to macrolide antibiotic drugs or any of the excipients.
Concomitant administration of clarithromycin and any of the following drugs is contraindicated: astemizole, cisapride, pimozide, terfenadine as this may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, and torsades de pointes (see Interactions).
Concomitant administration of clarithromycin and ergot alkaloids (e.g., ergotamine or dihydroergotamine) is contraindicated, as this may result in ergot toxicity (see Interactions).
Concomitant administration of clarithromycin and oral midazolam is contraindicated (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 torsades de pointes (see Precautions and Interactions).
Clarithromycin should not be given to patients with electrolyte disturbances (hypokalemia or hypomagnesemia, due to the risk of prolongation of the QT interval).
Clarithromycin should not be used in patients who suffer from severe hepatic failure in combination with renal impairment.
Clarithromycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis (see Precautions).
Clarithromycin (and other strong CYP3A4 inhibitors) should not be used concomitantly with colchicine (see Precautions and Interactions).
Concomitant administration with ticagrelor or ranolazine is contraindicated.
Concomitant administration of clarithromycin and lomitapide 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.
Long-term use may, as with other antibiotics, result in colonization with increased numbers of non-susceptible bacteria and fungi. If superinfections occur, appropriate therapy should be instituted.
Clarithromycin is principally metabolized 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.
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.
Klaricid: Use of any antimicrobial therapy, such as clarithromycin, to treat H. pylori infection may select for drug-resistant organisms.
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 (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 torsades de pointes, have been seen in treatment with macrolides including clarithromycin (see Adverse Reactions). 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 must not be given to patients with hypokalemia or hypomagnesemia (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. 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, severe cutaneous adverse reactions (SCAR) (e.g. Acute generalized exanthematous pustulosis (AGEP), 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 (see Interactions).
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 (see Contraindications). Caution should be exercised when prescribing clarithromycin with other statins. Rhabdomyolysis has been reported in patients taking clarithromycin and statins. Patients should be monitored for signs and symptoms of myopathy. In situations where the concomitant use of clarithromycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of the statin. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered (see Interactions).
Oral Hypoglycemic Agents/Insulin: The concomitant use of clarithromycin and oral hypoglycemic agents (such as sulphonylureas) 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.
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 (see Interactions).
Excipients: Klaricid OD: Clarithromycin Modified Release tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Clarithromycin Modified Release tablets contain 15.3 mg sodium per modified release 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.
Klaricid Pediatric: Clarithromycin Granules for Oral Suspension (Adult Sachet, Pediatric Suspension) contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
When prescribing to diabetic patients, the sucrose content should be taken into account.
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.

 

Use In Pregnancy & Lactation

The most frequent and common adverse reactions related to clarithromycin therapy for both adult and pediatric populations are abdominal pain, diarrhea, 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 IR, granules for oral suspension, IV, MR and 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. (See Table 5.)

There have been rare reports of clarithromycin ER tablets in the stool, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In several reports, tablet residues have occurred in the context of diarrhea. It is recommended that patients who experience tablet residue in the stool and no improvement in their condition should be switched to a different clarithromycin formulation (e.g. suspension) or another antibiotic.
Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.
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, diarrhea, rash, flatulence, headache, constipation, hearing disturbance, serum glutamic oxaloacetic 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.

 

The use of the following drugs is strictly contraindicated due to the potential for severe drug interaction effects: Cisapride, pimozide, astemizole and terfenadine: Elevated cisapride levels have been reported in patients receiving clarithromycin and cisapride concomitantly. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes. Similar effects have been observed in patients taking clarithromycin and pimozide concomitantly (see 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 torsades de pointes (see Contraindications). In one study in 14 healthy volunteers, the concomitant administration of clarithromycin and terfenadine resulted in a two to three fold increase in the serum level of the acid metabolite of terfenadine and in prolongation of the QT interval which did not lead to any clinically detectable effect. Similar effects have been observed with concomitant administration of astemizole and other macrolides.
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 (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 (see Contraindications).
HMG-CoA Reductase Inhibitors (statins): Concomitant use of clarithromycin with lovastatin or simvastatin is contraindicated (see Contraindications) 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.
Lomitapide: Concomitant administration of clarithromycin with lomitapide is contraindicated due the potential for markedly increased transaminases (see Contraindications).
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 inducer 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-OH-clarithromycin), a metabolite that is also microbiologically active. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers.
Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore, alternatives to clarithromycin should be considered for the treatment of MAC.
Fluconazole: Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers led to increases in the mean steady-state minimum clarithromycin concentration (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 clarithromycin 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 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 CL_CR 30 to 60 ml/min the dose of 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 gm/day should not be coadministered with ritonavir.
Similar dose adjustments should be considered in patients with reduced renal function when ritonavir is used as a pharmacokinetic enhancer with other HIV protease inhibitors including atazanavir and saquinavir (see Bi-directional Drug Interactions as follows).
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 hypoglycemia 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, rivaroxaban, apixaban), 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.
Direct acting oral anticoagulant (DOACs): The DOAC dabigatran is a substrate for the efflux transporter P-gp. Rivaroxaban and apixaban are metabolized via CYP3A4 and are also substrates for P-gp. Caution should be exercised when clarithromycin is co-administered with these agents particularly to patients at high risk of bleeding (see Precautions).
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_½ 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 (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 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/modified release 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 co-administered 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 C_max values of 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 drugs are co-administered for a limited time at the doses/formulations studied. Observations from drug interaction studies using the soft gelatin capsule formulation may not be representative of the effects seen using the saquinavir hard gelatin capsule. Observations from drug interaction studies performed with saquinavir alone may not be representative of the effects seen with saquinavir/ritonavir therapy. When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (see Interactions).

 

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