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clarithromycin 500 mg tablet generic biaxin

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Uses

Clarithromycin is used orally for the treatment of pharyngitis and tonsillitis, mild to moderate respiratory tract infections (acute bacterial exacerbation of chronic bronchitis, acute maxillary sinusitis, community-acquired pneumonia), uncomplicated skin and skin structure infections, and acute otitis media caused by susceptible organisms. Clarithromycin also is used orally in the treatment of disseminated infections caused by Mycobacterium avium complex (MAC) in patients with advanced human immunodeficiency virus (HIV) infection and for prevention of disseminated MAC infection (both primary and secondary prophylaxis) in HIV-infected individuals.

Oral clarithromycin is used in combination with amoxicillin and lansoprazole or omeprazole (triple therapy) for the treatment of Helicobacter pylori infection and duodenal ulcer disease. Clarithromycin also is used orally in combination with omeprazole (dual therapy) or ranitidine bismuth citrate for the treatment of H. pylori infection in patients with an active duodenal ulcer. Clarithromycin also has been used orally in other multiple-drug regimens (with or without amoxicillin, lansoprazole, omeprazole, or ranitidine bismuth citrate) for the treatment of H. pylori infection associated with peptic ulcer disease.

Safety and efficacy of clarithromycin extended-release tablets have been established only for the treatment of certain respiratory tract infections in adults (acute bacterial exacerbations of chronic bronchitis, acute maxillary sinusitis, community-acquired pneumonia); safety and efficacy of the extended-release formulation of the drug have not been established for the treatment of other infections that are treated with clarithromycin conventional tablets or oral suspension.

Acute Otitis Media

Clarithromycin (conventional tablets, oral suspension) is used for the treatment of acute otitis media (AOM) caused by Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae in children. Various anti-infectives, including oral amoxicillin, oral amoxicillin and clavulanate potassium, various oral cephalosporins (cefaclor, cefdinir, cefixime, cefpodoxime proxetil, cefprozil, ceftibuten, cefuroxime axetil, cephalexin), IM ceftriaxone, oral co-trimoxazole, oral erythromycin-sulfisoxazole, oral azithromycin, oral clarithromycin, and oral loracarbef, have been used in the treatment of AOM. The American Academy of Pediatrics (AAP), US Centers for Disease Control and Prevention (CDC), and other clinicians state that, despite the increasing prevalence of multidrug-resistant S. pneumoniae and presence of β-lactamase-producing H. influenzae or M. catarrhalis in many communities, amoxicillin remains the anti-infective of first choice when treatment of uncomplicated AOM is indicated since amoxicillin is highly effective, has a narrow spectrum of activity, is well distributed into middle ear fluid, and is well tolerated and inexpensive.

Clarithromycin is not considered a first-line agent for treatment of AOM, but is recommended as an alternative for individuals with type I penicillin hypersensitivity. Because S. pneumoniae resistant to amoxicillin also frequently are resistant to co-trimoxazole, clarithromycin, and azithromycin, these drugs may not be effective in patients with AOM who fail to respond to amoxicillin. For additional information regarding treatment of AOM and information regarding prophylaxis of recurrent AOM, treatment of persistent or recurrent AOM, and treatment of otitis media with effusion (OME), .

In controlled clinical trials of therapy for children with otitis media in areas of the US where the rate of β-lactamase-producing bacteria is high, clarithromycin therapy was compared with cephalosporin therapy alone or other antibiotic therapy with a concomitant β-lactamase inhibitor. In these studies, the combined clinical success rate (i.e., cure plus improvement) for clarithromycin therapy ranged from 88-91%, while that for the comparison therapies was 91%. The overall clinical success rate (i.e., presumed bacterial eradication/clinical cure outcomes) for clarithromycin ranged from 81-83%, while that for the comparison agents ranged from 73-97%. In all studies, the adverse effects associated with any therapy were principally GI related (e.g., diarrhea, vomiting), with a similar or lower incidence of effects occurring in the clarithromycin-treated group as compared with group treated with the comparison agent.

Pharyngitis and Tonsillitis

Clarithromycin (conventional tablets, oral suspension) is used for the treatment of pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A β-hemolytic streptococci) in adults and children. Although clarithromycin generally is effective in the eradicating S. pyogenes from the nasopharynx, efficacy of the drug in the subsequent prevention of rheumatic fever has not been established. Strains of S. pyogenes resistant to macrolides are common in some areas of the world (e.g., Italy, Japan, Korea, Finland, Spain, Taiwan) and clarithromycin-resistant strains have been reported in the US.(See Resistance: Resistance in Gram-positive Bacteria.)

Because penicillin has a narrow spectrum of activity, is inexpensive, and generally effective, the CDC, AAP, American Academy of Family Physicians (AAFP), Infectious Diseases Society of America (IDSA), American Heart Association (AHA), American College of Physicians (ACP), and others consider natural penicillins (i.e., 10 days of oral penicillin V or a single IM dose of penicillin G benzathine) the treatment of choice for streptococcal pharyngitis and tonsillitis and prevention of initial attacks (primary prevention) of rheumatic fever, although oral amoxicillin often is used instead of penicillin V in small children because of a more acceptable taste. Other anti-infectives (e.g., oral cephalosporins, oral macrolides) generally are considered alternatives.

In a limited number of controlled, comparative studies, microbiologic and clinical response rates of approximately 90% or greater were achieved in patients 12 years of age or older who received oral therapy with either clarithromycin 250 mg every 12 hours, penicillin V 250 mg every 6 hours, or erythromycin 500 mg every 12 hours; most patients were treated for approximately 7-10 days. Comparable clinical and microbiologic response rates have been reported in children as young as 6 months of age who received clarithromycin 7.5 mg/kg (maximum dose: 250 mg) twice daily or penicillin V 13.3 mg/kg (maximum dose: 500 mg) 3 times daily as oral suspensions.

Respiratory Tract Infections

Acute Exacerbations of Chronic Bronchitis

Clarithromycin (conventional tablets, oral suspension, extended-release tablets) is used for the treatment of acute bacterial exacerbations of chronic bronchitis caused by H. influenzae, H. parainfluenzae, M. catarrhalis, or S. pneumoniae in adults. Data from a limited number of studies from which patients with β-lactamase-positive infections generally were excluded suggest similar clinical and microbiologic efficacy for oral clarithromycin and oral ampicillin in these infections.

Acute Sinusitis

Clarithromycin (conventional tablets, oral suspension) is used for the treatment of acute maxillary sinusitis caused by H. influenzae, M. catarrhalis, or S. pneumoniae in adults or children; clarithromycin (extended-release tablets) is used for the treatment of these infections in adults.

In one study in patients with acute maxillary sinusitis caused principally by S. pneumoniae or Haemophilus spp., oral therapy with clarithromycin 500 mg every 12 hours or amoxicillin 500 mg every 8 hours for 9-11 days resulted in clinical response in 91% of patients in each group, with similar microbiologic responses. All microbiologic treatment failures in patients receiving clarithromycin involved Haemophilus spp. However, patients with β-lactamase-producing organisms were excluded from this study, and bacteriologic response rates may not be representative of those generally encountered in clinical practice. Limited data from another study in patients with acute maxillary sinusitis suggest that oral clarithromycin 500 mg every 12 hours or amoxicillin and clavulanate potassium 500 mg every 8 hours produce comparable clinical and bacteriologic responses.

Community-acquired Pneumonia

Clarithromycin (conventional tablets, oral suspension) is used for the treatment of mild to moderate community-acquired pneumonia (CAP) caused by Mycoplasma pneumoniae, Chlamydophila pneumoniae (Chlamydia pneumoniae), or S. pneumoniae in adults and children; clarithromycin (conventional tablets, oral suspension) also is used in adults for the treatment of CAP caused by H. influenzae. In addition, clarithromycin (extended-release tablets) is used in adults for the treatment of CAP caused by H. influenzae, H. parainfluenzae, M. catarrhalis, M. pneumoniae, C. pneumoniae, or S. pneumoniae.

Limited data in patients with CAP caused by these pathogens suggest that oral therapy with clarithromycin given twice daily generally is as effective as erythromycin given 2-4 times daily.

Initial treatment of CAP generally involves use of an empiric anti-infective regimen based on the most likely pathogens; therapy may then be changed (if possible) to a pathogen-specific regimen based on results of in vitro culture and susceptibility testing, especially in hospitalized patients. The most appropriate empiric regimen varies depending on the severity of illness at the time of presentation and whether outpatient treatment or hospitalization in or out of an intensive care unit (ICU) is indicated and the presence or absence of cardiopulmonary disease and other modifying factors that increase the risk of certain pathogens (e.g., penicillin- or multidrug-resistant S. pneumoniae, enteric gram- negative bacilli, Ps. aeruginosa). For both outpatients and inpatients, most experts recommend that an empiric regimen for the treatment of CAP include an anti-infective active against S. pneumoniae since this organism is the most commonly identified cause of bacterial pneumonia and causes more severe disease than many other common CAP pathogens.

For information on recommendations of the IDSA and American Thoracic Society (ATS) regarding use of clarithromycin and other macrolides in empiric regimens for the inpatient or outpatient treatment of CAP, see Community-acquired Pneumonia under Uses: Respiratory Tract Infections, in the Erythromycins General Statement 8:12.12.04.

Skin and Skin Structure Infections

Clarithromycin (conventional tablets, oral suspension) is used in adults and children for the treatment of uncomplicated skin and skin structure infections caused by Staphylococcus aureus or S. pyogenes. Some data in adults and children suggest that oral clarithromycin has efficacy comparable to that of oral erythromycin or an oral cephalosporin (e.g., cefadroxil) in treating various bacterial skin and skin structure infections (e.g., impetigo, cellulitis). Further comparative studies are needed to determine the relative efficacy of clarithromycin versus other anti-infective agents in treating various skin and skin structure infections, and other drugs (e.g., an oral penicillinase-resistant penicillin or cephalosporin) generally are preferred for the treatment of these infections.

Helicobacter pylori Infection and Duodenal Ulcer Disease

Clarithromycin (conventional tablets) is used in conjunction with amoxicillin and lansoprazole or omeprazole (triple therapy) for the treatment of Helicobacter pylori (formerly Campylobacter pylori or C. pyloridis) infection in patients with duodenal ulcer disease (active or up to 1-year history of duodenal ulcer). Clarithromycin also is used in conjunction with omeprazole (dual therapy) or ranitidine bismuth citrate for the treatment of H. pylori infection in patients with an active duodenal ulcer. Clarithromycin also has been used orally in other multiple-drug regimens (with or without amoxicillin, omeprazole, lansoprazole, or ranitidine bismuth citrate) for the treatment of H. pylori infection associated with peptic ulcer disease. While some evidence indicates that combined therapy with 2 drugs (e.g., clarithromycin-omeprazole, ranitidine bismuth citrate-omeprazole, amoxicillin-omeprazole) can successfully eradicate H. pylori infection and prevent recurrence of duodenal ulcer at least in the short term (e.g., at 6 months following completion of anti-H. pylori therapy), the American College of Gastroenterology (ACG) and some clinicians currently recommend anti-H. pylori regimens consisting of at least 3 drugs (e.g., 2 anti-infective agents plus a proton-pump inhibitor) because of enhanced H. pylori eradication rates, decreased treatment failures due to resistance, and shorter treatment periods compared with those apparently required with 2-drug regimens.

Pathogenesis

Current epidemiologic and clinical evidence supports a strong association between gastric infection with H. pylori and the pathogenesis of duodenal and gastric ulcers; with the exception of ulcers associated with gastrinoma (Zollinger-Ellison syndrome) or use of NSAIAs, almost all cases of duodenal ulcer and most cases of gastric ulcer are associated with H. pylori infection.

Although H. pylori eradication (generally defined as the absence of H. pylori organisms in the stomach documented at least 1 month after completion of anti-H. pylori therapy) reduces ulcer relapse rates, other factors appear to be essential for the development of peptic ulcer because most individuals with H. pylori infection do not develop peptic ulcers, and such ulcers are healed by various other therapies despite the presence of the organism in the stomach. Once acquired, H. pylori infection may persist for decades or even for life, causing chronic inflammation, although most infected individuals reportedly are asymptomatic. Since type B active chronic gastritis is caused by H. pylori infection and may eventually progress to chronic atrophic gastritis, a well- recognized risk factor for gastric carcinoma, long-term H. pylori infection also has been implicated as a risk factor for gastric cancer. However, whether eradication of H. pylori ultimately will reduce the incidence of gastric carcinoma remains to be established, and most clinicians currently do not advocate the use of anti-H. pylori therapy solely as a potential means of lowering the risk of gastric cancer given the prevalence of H. pylori infection in the general population and the potential costs and complications of current treatment regimens.

Although H. pylori eradication (generally defined as the absence of H. pylori organisms in the stomach documented at least 1 month after completion of anti-H. pylori therapy) reduces ulcer relapse rates, other factors appear to be essential for the development of peptic ulcer because most individuals with H. pylori infection do not develop peptic ulcers, and such ulcers are healed by various other therapies despite the presence of the organism in the stomach. Once acquired, H. pylori infection may persist for decades or even for life, causing chronic inflammation, although most infected individuals reportedly are asymptomatic. Since type B active chronic gastritis is caused by H. pylori infection and may eventually progress to chronic atrophic gastritis, a well- recognized risk factor for gastric carcinoma, long-term H. pylori infection also has been implicated as a risk factor for gastric cancer. However, whether eradication of H. pylori ultimately will reduce the incidence of gastric carcinoma remains to be established, and most clinicians currently do not advocate the use of anti-H. pylori therapy solely as a potential means of lowering the risk of gastric cancer given the prevalence of H. pylori infection in the general population and the potential costs and complications of current treatment regimens.

Therapeutic Regimens

Conventional antiulcer therapy with H2-receptor antagonists, proton-pump inhibitors, sucralfate, and/or antacids heals ulcers but generally is ineffective in eradicating H. pylori, and such therapy is associated with a high rate of ulcer recurrence (e.g., 60-100% per year). Several useful therapeutic regimens for H. pylori-associated peptic ulcer disease have been identified, and the ACG, the National Institutes of Health (NIH), and most clinicians currently recommend that all patients with initial or recurrent duodenal or gastric ulcer and documented H. pylori infection receive anti-infective therapy for treatment of the infection.

The optimum regimen for treatment of H. pylori infection has not been established; however, combined therapy with 3 drugs that have activity against H. pylori (e.g., a bismuth salt, metronidazole, and tetracycline or amoxicillin) has been effective in eradicating the infection, resolving associated gastritis, healing peptic ulcer, and preventing ulcer recurrence in many patients with H. pylori-associated peptic ulcer disease. Although such 3-drug regimens typically have been administered for 10-14 days, current evidence principally from studies in Europe suggests that 1 week of such therapy provides H. pylori eradication rates comparable to those of longer treatment periods. Other regimens that combine one or more anti-infective agents (e.g., clarithromycin, amoxicillin) with a bismuth salt and/or an antisecretory agent (e.g., omeprazole, lansoprazole, H2-receptor antagonist) also have been used successfully for H. pylori eradication, and the choice of a particular regimen should be based on the rapidly evolving data on optimal therapy, including consideration of the patient's prior exposure to anti-infective agents, the local prevalence of resistance, patient compliance, and costs of therapy.Current data suggest that eradication of H. pylori infection using regimens consisting of 1 or 2 anti-infective agents with a bismuth salt and/or an H2-receptor antagonist or proton-pump inhibitor (e.g., omeprazole, lansoprazole) is cost effective compared with intermittent or continuous maintenance therapy with an H2-receptor antagonist (considering the costs associated with ulcer recurrence, including endoscopic or other diagnostic procedures, physician visits, and/or hospitalization).

The ACG and some clinicians currently state that an H. pylori eradication rate of approximately 90% with a 1-week treatment period represents a realistic goal of therapy for H. pylori infection. However, some clinicians state that results of 1-week anti-H. pylori regimens in Europe generally have been superior to those conducted in the US to date and that additional US studies with these regimens are needed to confirm the efficacy of 1-week regimens in the US. Although high eradication rates have been achieved with standard 3-drug, bismuth-based regimens (e.g., bismuth-metronidazole-tetracycline or bismuth- metronidazole-amoxicillin), such regimens typically involve administration of many tablets/capsules and have been associated with a relatively high (although variable) incidence of adverse effects. In addition, the efficacy of these regimens generally is unacceptable in patients with H. pylori strains resistant to the imidazole anti-infective (e.g., metronidazole) component.

Current evidence suggests that inclusion of a proton-pump inhibitor (e.g., omeprazole, lansoprazole) in anti-H. pylori regimens containing 2 anti-infectives enhances effectiveness, and limited data suggest that such regimens retain good efficacy despite imidazole (e.g., metronidazole) resistance. Therefore, the ACG and many clinicians currently recommend 1 week of therapy with a proton-pump inhibitor and 2 anti-infective agents (usually clarithromycin and amoxicillin or metronidazole), or a 3-drug, bismuth-based regimen (e.g., bismuth-metronidazole-tetracycline) concomitantly with a proton-pump inhibitor, for treatment of H. pylori infection. Although few comparative studies have been performed, such regimens appear to provide high (e.g., 85-90%) H. pylori eradication rates, are well tolerated, and may be associated with better patient compliance than more prolonged therapy. The ACG states that in a cost-sensitive environment, an alternative regimen consisting of a bismuth salt, metronidazole, and tetracycline for 14 days is a reasonable choice in patients who are compliant and in whom there is a low expectation of metronidazole resistance (no prior exposure to the drug and a low regional prevalence of resistance).

Current data suggest that modification of bismuth-metronidazole-tetracycline regimens by substituting clarithromycin for metronidazole or amoxicillin (but not ampicillin) for tetracycline also results in effective therapy, but the substitution of either amoxicillin or another tetracycline derivative (i.e., doxycycline) for tetracycline hydrochloride in such regimens reduces efficacy. While azithromycin has been used in a limited number of multiple-drug regimens (e.g., with tetracycline, metronidazole, bismuth salts, and/or omeprazole) for the treatment of Helicobacter pylori infection and peptic ulcer disease, such combination regimens generally have been associated with a high incidence of adverse effects (principally GI effects) or low H. pylori eradication rates (e.g., 50-70%). Additional controlled, comparative studies and long-term follow-up are needed to determine optimal drug regimens for H. pylori-associated peptic ulcer and to elucidate the effects of H. pylori eradication on potential long- term complications of peptic ulcer disease such as GI bleeding and gastric carcinoma.

Current evidence suggests that eradication of H. pylori by anti-infective agents may be facilitated by increased gastric pH, and many clinicians recommend concomitant treatment with antisecretory agents (e.g., omeprazole, lansoprazole, H2-receptor antagonists) to enhance ulcer healing and symptom relief while allowing relatively short (e.g., 1-week) treatment periods in patients with active peptic ulcer disease. Eradication rates of almost 100% have been reported with addition of omeprazole to a 3-drug anti-H. pylori regimen. Therapy with an antisecretory drug and a single anti-infective agent (i.e., ''dual therapy'') also has been used successfully for treatment of H. pylori infection. However, rates of H. pylori eradication have varied considerably in some studies using combined therapy with 2 drugs (e.g., amoxicillin and omeprazole) depending on dosage, timing of administration, and possibly the age of the patient. An analysis of pooled data from a number of studies in which combined therapy with omeprazole and either amoxicillin or clarithromycin was used indicate H. pylori eradication rates averaging approximately 55-62% with amoxicillin-omeprazole and 67-75% with clarithromycin-omeprazole therapy.

In 4 randomized, controlled trials in patients with active duodenal ulcer, combined therapy with clarithromycin (500 mg 3 times daily for 14 days) and omeprazole (40 mg daily for 14 days followed by either 20 or 40 mg daily for an additional 14 days) was successful in eradicating H. pylori (defined as 2 negative tests for H. pylori 4 weeks after the end of treatment) in 64-83% of patients compared with 0-1% of patients receiving omeprazole alone or (in 2 trials) 31-39% of patients receiving clarithromycin alone. Ulcer healing rates at 4 weeks averaged 94-100% with clarithromycin-omeprazole treatment, 88- 99% with omeprazole alone, and (in 2 trials) 64-71% with clarithromycin alone. In addition, follow-up evaluations at 6 months in patients whose ulcers were healed demonstrated a reduction in ulcer recurrence in patients in whom H. pylori was eradicated. In 2 other randomized, controlled trials in patients with active duodenal ulcer, eradication of H. pylori (defined as 2 negative tests for H. pylori 4 weeks after the end of anti-H. pylori treatment) was achieved in 72 or 71% of patients receiving 2 weeks of combined therapy with clarithromycin (500 mg 2 or 3 times daily, respectively) and ranitidine bismuth citrate (400 mg twice daily) followed by 2 weeks of monotherapy with ranitidine bismuth citrate (400 mg 2 times daily). Follow-up evaluations demonstrated a twofold reduction in the risk of ulcer recurrence within 6 months of completing treatment in patients in whom H. pylori was eradicated compared with those in whom the infection was not eradicated. The contribution, if any, of bismuth citrate to the healing effects of ranitidine alone was not evaluated in these studies.

While some studies demonstrate that certain 2-drug anti-H. pylori regimens (e.g., clarithromycin-omeprazole, ranitidine bismuth citrate-omeprazole, amoxicillin-omeprazole) can successfully eradicate H. pylori infection and prevent recurrence of duodenal ulcer at least in the short term (e.g., at 6 months following completion of anti-H. pylori therapy), 3-drug regimens appear to be associated with higher H. pylori overall eradication rates than dual-therapy combinations. In 2 randomized, controlled trials in patients with H. pylori infection and duodenal ulcer disease (i.e., active ulcer or history of an ulcer within 1 year) who received triple therapy for 14 days with clarithromycin (500 mg twice daily), amoxicillin (1 g twice daily), and lansoprazole (30 mg twice daily), H. pylori was eradicated (defined as 2 negative tests for H. pylori by culture or histology 4-6 weeks after the end of anti-H. pylori treatment) in 92 or 86% of evaluable patients (86 or 83% of patients, respectively, by intent- to-treat analysis); while dual therapy with lansoprazole (30 mg 3 times daily) and amoxicillin (1 g 3 times daily) for 14 days produced H. pylori eradication in 77 or 66% of evaluable patients (70 or 61% of patients, respectively, by intent-to-treat analysis). Therapy with the 3-drug combination was more effective than all possible dual-therapy combination regimens with these drugs (i.e., lansoprazole-amoxicillin, lansoprazole-clarithromycin, and amoxicillin-clarithromycin).

In 3 randomized, double-blind trials in patients with H. pylori infection and duodenal ulcer disease (active ulcer or a history of duodenal ulcer in the previous 5 years) who were treated for 10 days, triple therapy with clarithromycin (500 mg twice daily), amoxicillin (1 g twice daily), and omeprazole (20 mg twice daily) eradicated H. pylori (defined as 2 negative and no positive tests for H. pylori as assessed by CLOtest, histology, and/or culture) in 77, 78, or 90% of evaluable patients (69, 73, or 83% of patients, respectively, by intent- to-treat analysis); dual therapy with clarithromycin and amoxicillin eradicated H. pylori infection in 43, 41, or 33% of evaluable patients (37, 36, or 32% of patients, respectively, by intent-to-treat analysis). In 2 of these studies, patients receiving the triple-therapy regimen for eradication of H. pylori continued omeprazole 20 mg daily for an additional 18 days.

The ACG and some clinicians currently state that anti-H. pylori regimens consisting of at least 3 drugs (e.g., 2 anti-infective agents plus a proton-pump inhibitor) are recommended because of enhanced H. pylori eradication rates, decreased failures secondary to resistance, and shorter treatment periods (e.g., 1 week) compared with those apparently required with 2-drug regimens (e.g., 10-14 days). Additional randomized, controlled studies comparing various anti-H. pylori regimens are needed to clarify optimum drug combinations, dosages, and duration of treatment for H. pylori infection.

Duration of Therapy

The minimum duration of therapy required to eradicate H. pylori infection in peptic ulcer disease has not been fully established. In a randomized trial in patients with H. pylori infection and duodenal ulcer disease, 10 days of therapy with clarithromycin (500 mg twice daily), amoxicillin (1 g twice daily), and lansoprazole (30 mg twice daily) was as effective in eradicating H. pylori as 14 days of therapy with this drug regimen; H. pylori eradication was achieved in 85% of evaluable patients with the 14-day regimen compared with 84% of those receiving the 10-day regimen (82 versus 81% of patients, respectively, by intent-to-treat analysis). In patients with uncomplicated ulcers who receive a proton-pump inhibitor (e.g., omeprazole) plus 2 anti-infective agents or a proton-pump inhibitor and bismuth-tetracycline-metronidazole, the ACG and many clinicians state that treatment for longer than 1 week probably is not necessary. However, more prolonged anti-infective and/or antisecretory therapy is recommended for patients with complicated, large, or refractory ulcers; therapy in such patients should be continued at least until successful eradication of H. pylori has been confirmed.

Resistant and Recurrent Infection

The optimum method of treating patients who fail to respond to currently recommended anti-H. pylori regimens is unknown. However, clarithromycin or metronidazole should not be used subsequently in patients with H. pylori infection who fail therapy that includes these drugs since resistance commonly emerges during such unsuccessful therapy.

Rapid development of resistance by H. pylori to certain drugs (e.g., metronidazole, clarithromycin and other macrolides, quinolones) has occurred when these drugs were used as monotherapy or as the only anti-infective agent in anti-H. pylori regimens. Resistance commonly emerges during therapy with clarithromycin or metronidazole when eradication of H. pylori is not achieved; therefore, prior exposure to these anti-infectives predicts resistance in individual patients and should be considered when selecting anti-H. pylori treatment regimens. Clarithromycin-containing regimens should not be used for eradication of H. pylori in patients with known or suspected clarithromycin-resistant isolates because of reduced efficacy in such patients.(See Cautions: Precautions and Contraindications.) Some clinicians state that the same anti-infective regimen should not be used for retreatment of H. pylori infection even if antibiotic resistance has not developed. In clinical trials in patients who received clarithromycin as the sole anti-infective agent in combination regimens for H. pylori infection, some H. pylori isolates demonstrated an increase in clarithromycin MICs over time, indicating decreased susceptibility and increasing resistance to the drug. Agents that do not induce resistance in H. pylori include amoxicillin, tetracycline, and bismuth; 1 or 2 of these drugs generally are included in regimens that contain metronidazole or clarithromycin. The ACG states that possible regimens for treatment of metronidazole-resistant H. pylori infections include bismuth-clarithromycin-tetracycline or omeprazole-amoxicillin-clarithromycin. In patients who develop clarithromycin resistance, the ACG suggests potential alternative therapy consisting of omeprazole, a bismuth salt, metronidazole, and tetracycline; or omeprazole, amoxicillin, and metronidazole. A regimen consisting of amoxicillin (1 g twice daily), rifabutin (300 mg daily), and a proton-pump inhibitor (pantoprazole 40 mg twice daily) for one week reportedly was effective in eradicating H. pylori (according to the results of a C urea breath test) in about 79% of patients who had failed at least 2 prior courses of anti-H. pylori therapy. Some clinicians also suggest that a 3-drug, furazolidone-containing regimen could be used in patients with metronidazole- or clarithromycin-resistant H. pylori infection.

The most common cause of ulcer recurrence after anti-infective therapy for H. pylori infection is failure to eradicate the organism since reinfection with H. pylori in developed countries appears to occur very infrequently. The ACG and some clinicians state that diagnostic confirmation of H. pylori eradication is important in patients with complicated, giant, or refractory ulcers but is controversial or generally not needed in those with uncomplicated ulcers who remain asymptomatic after anti-infective therapy. If diagnostic tests for H. pylori are used, such tests should be performed at least 1 month or, preferably, longer after discontinuance of anti-H. pylori therapy to minimize the potential for false-negative test results attributable to suppression rather than eradication of the organism.

Therapy in Children

Combined therapy with 1 or 2 anti-infective agents (e.g., generally amoxicillin with or without metronidazole) and bismuth subsalicylate in children with H. pylori infection and associated peptic ulcer disease appears to promote healing and reduces ulcer recurrence. Although the prevalence of H. pylori infection is lower in children than in adults, the organism reportedly has been identified in approximately 50% of children with gastritis or gastric ulcers and in 60% of those with duodenitis or duodenal ulcers. Limited data suggest that therapy with H2-receptor antagonists or a single antibiotic is associated with a high risk of disease recurrence; in addition, reinfection with H. pylori has been reported to be more common in children than in adults. Because the prevalence of H. pylori infection and the incidence of H. pylori-associated gastroduodenal inflammation are much lower in children than in adults, H. pylori is more likely to be associated with peptic ulcer disease when found in a child. Therefore, some clinicians have recommended that children with symptoms suggesting gastroduodenal inflammation that do not respond to antacid therapy should be evaluated for the presence of H. pylori and, if the organism is found, given therapy aimed at eradicating the infection. In a study in a limited number of children (mean age: 12.2 years) with H. pylori-associated duodenal ulcer, treatment with a 6-week regimen of bismuth subsalicylate and amoxicillin, or these 2 drugs plus metronidazole in cases of initial treatment failure, resulted in endoscopically proved eradication of the organism in 100% of patients at long- term (mean: 6.5 months) follow-up.

Nonulcer Dyspepsia

Although it has been suggested that patients with nonulcer dyspepsia and concomitant H. pylori infection also may benefit from eradicative therapy for H. pylori, evidence from several well-designed clinical trials has been conflicting regarding an association between this organism and nonulcer dyspepsia. Nevertheless, while therapy for H. pylori eradication in such patients generally is not routinely recommended, some evidence suggests that initial anti-H. pylori therapy may be a cost-effective management strategy compared with initial endoscopy for patients with simple dyspepsia who are H. pylori-positive on noninvasive (e.g., serologic) testing.

Bartonella Infections

Clarithromycin has been used in a few patients, including HIV-infected patients, for the treatment of infections caused by Bartonella henselae (formerly Rochalimaea henselae) (e.g., cat scratch disease, bacillary angiomatosis, peliosis hepatitis). Cat scratch disease generally is a self-limited illness in immunocompetent individuals and may resolve spontaneously in 2-4 months; however, some clinicians suggest that anti-infective therapy be considered for acutely or severely ill patients with systemic symptoms, particularly those with hepatosplenomegaly or painful lymphadenopathy, and such therapy probably is indicated in immunocompromised patients. Anti-infectives also are indicated in patients with B. henselae infections who develop bacillary angiomatosis, neuroretinitis, or Parinaud's oculoglandular syndrome. While the optimum anti-infective regimen for the treatment of cat scratch disease or other B. henselae infections has not been identified, some clinicians recommend use of erythromycin, doxycycline, ciprofloxacin, rifampin, co-trimoxazole, gentamicin, azithromycin, clarithromycin, or third generation cephalosporins.

Cryptosporidiosis

It has been reported that use of clarithromycin or rifabutin in HIV-infected adults for prevention of MAC infection may also decrease the incidence of cryptosporidiosis is these patients. No anti-infective agent has been found to reliably eradicate Cryptosporidium, although several drugs (e.g., paromomycin, azithromycin, nitazoxanide) may improve symptoms or suppress the infection.

HIV-infected individuals at greatest risk for cryptosporidiosis are those with advanced immunosuppression (i.e., CD4 T-cell counts less than 100/mm) and fulminant infections usually have occurred in those with CD4 T-cell counts less than 50/ mm. The CDC, National Institutes of Health (NIH), IDSA, and other clinicians state that the most appropriate treatment for cryptosporidiosis in HIV-infected individuals is the use of potent antiretroviral agents and symptomatic treatment of diarrhea. A highly potent antiretroviral regimen can result in immune restoration (CD4 T-cell counts exceeding 100/ mm) which usually results in resolution of the infection. Symptomatic treatment of diarrhea in HIV-infected or immunocompetent individuals with cryptosporidiosis should include oral or IV fluids and electrolyte replacement to correct dehydration and nutritional supplementation when necessary; severe diarrhea may require intensive support. Adjunctive use of antimotility agents may be indicated, but these agents are not consistently effective and should be used with caution in young children.

Legionella Infections

Clarithromycin has been used for the treatment of Legionnaires' disease caused by Legionella pneumophila. Macrolides (usually azithromycin) or fluoroquinolones are considered the drugs of choice for the treatment of pneumonia caused by L. pneumophila and doxycycline and co-trimoxazole are alternatives. An oral regimen (e.g., azithromycin, erythromycin, doxycycline, clarithromycin, a fluoroquinolone) may be effective for patients with mild to moderate Legionnaires' disease. However, a parenteral regimen (e.g., azithromycin or a fluoroquinolone) usually is necessary for the initial treatment of severe Legionnaires' disease and the addition of oral rifampin is recommended during the first 3-5 days of therapy in severely ill and/or immunocompromised patients; after a response is obtained, rifampin can be discontinued and therapy changed to an oral regimen.

Lyme Disease

Clarithromycin (500 mg twice daily for 21 days) has been used with apparent success (based on a 6-month follow-up period) in a limited number of patients with early Lyme disease. However, some evidence in patients with early Lyme disease suggests that other macrolides (e.g., azithromycin, erythromycin) may be less effective than penicillins or tetracyclines, and the IDSA, AAP, and other clinicians recommend that macrolide antibiotics not be used as first-line therapy for early Lyme disease.

Oral doxycycline or oral amoxicillin is recommended as first-line therapy for the treatment of early localized or early disseminated Lyme disease associated with erythema migrans, in the absence of neurologic involvement or third-degree atrioventricular (AV) heart block; alternatively, oral cefuroxime axetil has been used. The IDSA and other clinicians state that macrolide antibiotics should be reserved for patients who are intolerant of doxycycline, amoxicillin, and cefuroxime axetil and that patients treated with macrolides should be monitored closely. For more detailed information on the manifestations of Lyme disease and the efficacy of various anti-infective regimens in early or late Lyme disease,

Mycobacterial Infections

Mycobacterium avium Complex (MAC) Infections

Primary Prevention of Disseminated MAC Infection

Clarithromycin (conventional tablets, oral suspension) is used to prevent Mycobacterium avium complex (MAC) bacteremia and disseminated infections (primary prophylaxis) in patients with advanced HIV infection. The Prevention of Opportunistic Infections Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA) state that either clarithromycin or azithromycin is the preferred drug for primary prevention of disseminated MAC infection in adults and pediatric patients.

Results of a limited number of controlled studies in patients with HIV infection and absolute helper/inducer (CD4, T4) T-cell counts less than 100/ mm indicate that clarithromycin used alone is more effective than placebo in preventing disseminated MAC disease; clarithromycin prophylaxis also has been shown to reduce mortality in at least one placebo-controlled study. In a randomized, double-blind study in patients with acquired immunodeficiency syndrome (AIDS) and baseline median CD4 counts of 25-30 cells/ mm, the risk of MAC infection (defined as at least one positive culture for MAC bacteria from blood or another normally sterile site) was reduced by 69% in patients receiving clarithromycin 500 mg twice daily compared with that in patients receiving placebo (6 versus 16% incidence of MAC infection with clarithromycin or placebo prophylaxis, respectively). On an intent-to-treat basis, the 1- year cumulative incidence of MAC bacteremia was 5% for patients receiving clarithromycin and 19.4% for patients receiving placebo. Clarithromycin-resistant MAC isolates developed in 11 of 19 clarithromycin recipients who developed MAC infection compared with none of the 53 placebo recipients in whom MAC bacteremia developed. Despite this higher incidence of clarithromycin resistance, clarithromycin prophylaxis was associated with reduced mortality compared with placebo, particularly during the first 12 months of the study.

During a follow-up period of about 10 months, the incidence of mortality with clarithromycin prophylaxis was 32% versus 41% with placebo, a 26% reduction. The incidences of hospitalization and of certain complications of HIV infection (e.g., pneumonia, giardiasis) also were reduced in patients receiving clarithromycin prophylaxis. Patients receiving clarithromycin also showed reductions in the manifestations of disseminated MAC disease, including fever, night sweats, weight loss, and anemia. Although the incidence of adverse effects attributed to the study drug was higher in patients receiving clarithromycin (42%) than in those receiving placebo (26%), taste perversion (11 versus 2% with clarithromycin or placebo, respectively) and rectal disorders (8 versus 3%, respectively) were the only adverse effects that occurred more frequently with clarithromycin than with placebo. The incidence of severe adverse effects was similar with clarithromycin (7%) and placebo (6%), and discontinuance of clarithromycin prophylaxis because of adverse events (principally headache, nausea, vomiting, depression and taste perversion) was required in 18% of patients receiving the drug compared with 17% of those receiving placebo.

The USPHS/IDSA recommends primary prophylaxis against MAC disease for HIV-infected adults and adolescents (13 years or older) who have CD4 T-cell counts less than 50/ mm. Severely immunocompromised HIV-infected children younger than 13 years of age also should receive primary prophylaxis against MAC disease according to the following age-specific CD4 T-cell counts: children 6-13 years of age, less than 50 cells/ mm; children 2- 6 years of age, less than 75 cells/ mm; children 1-2 years of age, less than 500 cells/ mm; and infants younger than 1 year of age, less than 750 cells/ mm.

Although either azithromycin or clarithromycin is the preferred drug for primary prophylaxis against MAC, the USPHS/IDSA states that rifabutin may be used if the macrolides cannot be tolerated. There is evidence from placebo-controlled studies that concomitant use of clarithromycin and rifabutin for primary prophylaxis is no more effective than clarithromycin used alone and the combination regimen appears to be associated with an increased incidence of adverse effects. Therefore, the USPHS/IDSA does not recommend concomitant use of clarithromycin and rifabutin for primary MAC prophylaxis. Although the combination of azithromycin and rifabutin is more effective than azithromycin alone for primary MAC prophylaxis, the USPHS/IDSA does not recommend this combination regimen because of additional cost, increased incidence of adverse effects, and absence of a difference in survival in patients receiving the combination compared with azithromycin prophylaxis alone.

Current evidence indicates that primary MAC prophylaxis can be discontinued with minimal risk of developing disseminated MAC disease in HIV- infected adults and adolescents who have responded to highly active antiretroviral therapy (HAART) with an increase in CD4 T-cell counts to greater than 100/ mm that has been sustained for at least 3 months. The USPHS/IDSA states that discontinuance of primary prophylaxis against MAC is recommended in adults and adolescents meeting these criteria because prophylaxis in these individuals appears to add little benefit in terms of disease prevention for MAC or bacterial infections, and discontinuance reduces the medication burden, the potential for toxicity, drug interactions, selection of drug-resistant pathogens, and cost. However, the USPHS/IDSA states that primary MAC prophylaxis should be restarted in adults and adolescents if CD4 T-cell counts decrease to less than 50-100/ mm. The safety of discontinuing MAC prophylaxis in children whose CD4 T-cell counts have increased as a result of highly active antiretroviral therapy has not been studied to date.

HIV-infected pregnant women are at risk for MAC disease, and primary prophylaxis against the infection should be given to such women who have T- cell counts less than 50/ mm. However, some clinicians may choose to withhold prophylaxis during the first trimester of pregnancy because of general concerns regarding drug administration during this period. Of the available agents, the USPHS/IDSA considers azithromycin the drug of choice for MAC prophylaxis in HIV-infected pregnant women because of the drug's safety profile in animal studies and anecdotal information on safety in humans. Clarithromycin has demonstrated adverse effects on pregnancy outcome and/or embryo-fetal development in animals and should be used during pregnancy only in clinical circumstances where no alternative therapy is appropriate.(See Cautions: Pregnancy, Fertility, and Lactation.).

HIV-infected patients who develop MAC disease while receiving prophylaxis for the infection require treatment with multiple drugs since monotherapy results in drug resistance and clinical failure.

Treatment and Prevention of Recurrence of Disseminated MAC Infection

Clarithromycin (conventional tablets, oral suspension) is used as part of a multiple-drug regimen for the treatment of disseminated MAC infections and for prevention of recurrence (secondary prophylaxis) of MAC infections. Although clarithromycin has been effective when used alone for the treatment of MAC, most authorities recommend the use of multiple-drug regimens for the treatment or secondary prevention of these infections.

For the treatment of disseminated MAC infections in HIV-infected adults, adolescents, and children, the ATS, CDC, NIH, IDSA, and other clinicians recommend a regimen of clarithromycin (or azithromycin) and ethambutol and state that consideration can be given to adding a third drug (preferably rifabutin). Some clinicians state that clarithromycin is the preferred macrolide for the initial treatment regimen because of more extensive experience and because it appears to be associated with more rapid clearance of MAC from blood; however, azithromycin can be substituted if clarithromycin cannot be used because of drug interactions or intolerance and is preferred in pregnant women. Rifabutin should be included in the treatment regimen if the patient has advanced immunosuppression (CD4 T-cell count less than 50/mm) or high mycobacterial load (exceeding 2 log10 colony forming units/mL of blood) or is not receiving effective antiretroviral therapy since there is an increased risk of mortality and emergence of drug resistance. If a third drug is indicated in the treatment regimen and rifabutin cannot be used (e.g., because of drug interactions or intolerance), use of a fluoroquinolone (ciprofloxacin or levofloxacin) or amikacin can be considered.

Limited data from comparative trials suggest that concomitant use of ethambutol and clarithromycin may decrease emergence of clarithromycin-resistant MAC; however, inclusion of clofazimine in multiple-drug regimens containing clarithromycin (e.g., with or without ethambutol) does not add to the efficacy (e.g., in terms of prevention of clarithromycin resistance) of such regimens and may even be associated with reduced survival. Therefore, clofazimine should not be used for the treatment of disseminated MAC disease.

Clarithromycin appears to be one of the most active single agents against MAC; however, monotherapy with clarithromycin has been associated with clinical and bacteriologic relapse and the development of clarithromycin-resistant MAC isolates. Randomized studies in adults and children infected with HIV and MAC who had peripheral blood absolute helper/inducer (CD4, T4) T-cell counts less than 100/ mm (with most patients having such T-cell counts less than 50/ mm), demonstrated that oral monotherapy with clarithromycin (0.5-2 g twice daily in adults, 3.75-15 mg/kg twice daily in children) resulted in clinical and laboratory improvement of the MAC infection. In 52-61% of treated patients in these studies, colony counts of MAC in sequential blood cultures decreased or became absent within 29-54 days; patients also experienced decreases in the incidence of fever, night sweats, weight loss, diarrhea, splenomegaly, and hepatomegaly. However, effects of clarithromycin monotherapy were not sustained; only 8-25% of treated patients maintained negative blood cultures for 12 weeks or longer and median duration of clinical improvement was 2-6 weeks. In addition, development of drug resistance has been reported after 2-7 months of clarithromycin monotherapy.

High clarithromycin dosages (e.g., 1 or 2 g twice daily) for the treatment of disseminated MAC infection have been associated with reduced survival in some studies compared with that in patients receiving clarithromycin 500 mg twice daily; while these findings are not fully understood, dosages exceeding 500 mg twice daily currently are not recommended in HIV-infected patients with disseminated MAC infection. In randomized studies in HIV-infected patients who had peripheral blood absolute helper/inducer (CD4, T4) T-cell counts less than 100/ mm (with most patients having such T-cell counts less than 50/ mm), median survival was 199-249 or 179-215 days in adults receiving clarithromycin dosages of 0.5 or 1 g twice daily, respectively. Higher dosages (e.g., 1-2 g twice daily) of clarithromycin were associated with better bacteriologic improvement during the first 4 weeks of therapy; median time to achieve negative blood culture was 54, 41, or 29 days in patients receiving 0.5, 1, or 2 g of the drug twice daily, respectively. However, no substantial differences in the time required to achieve negative blood cultures were observed later in therapy.

To prevent recurrence of MAC disease in HIV-infected adults, adolescents, or children who have previously been treated for an acute episode of MAC infection and in whom macrolide resistance has not been documented, the USPHS/IDSA, CDC, NIH, and IDSA recommend a regimen consisting of a macrolide (clarithromycin or azithromycin) given with ethambutol (with or without rifabutin). Azithromycin usually is the preferred macrolide for use in conjunction with ethambutol for secondary prophylaxis of disseminated MAC infection in pregnant women. Secondary MAC prophylaxis generally is administered for life in adults and adolescents unless immune recovery has occurred as a result of potent antiretroviral therapy. Limited data indicate that secondary MAC prophylaxis can be discontinued in adults and adolescents who have immune recovery in response to potent antiretroviral therapy. Based on these data and more extensive cumulative data on safety of discontinuing secondary prophylaxis for other opportunistic infections, the USPHS/IDSA, CDC, NIH, and IDSA state that it may be reasonable to consider discontinuance of secondary MAC prophylaxis in adults and adolescents who have successfully completed at least 12 months of MAC therapy, have remained asymptomatic with respect to MAC, and have CD4 T-cell counts exceeding 100/ mm as the result of potent antiretroviral therapy and this increase has been sustained (e.g., for 6 months or longer). Some experts would obtain a blood culture for MAC (even in asymptomatic patients) prior to discontinuing secondary MAC prophylaxis to substantiate that the disease is no longer active. Secondary MAC prophylaxis should be restarted in adults or adolescents if CD4 T-cell counts decrease to less than 100/ mm. The safety of discontinuing secondary MAC prophylaxis in HIV-infected children receiving potent antiretroviral therapy has not been studied and children with a history of disseminated MAC should receive lifelong secondary prophylaxis.

Treatment of Pulmonary MAC Infections in HIV-negative Adults

Clarithromycin has been used in multiple-drug regimens for the treatment of pulmonary MAC infections in patients not infected with HIV.

The ATS recommends that pulmonary MAC infections in HIV-negative adults be treated with a regimen that includes at least 3 drugs, including clarithromycin (500 mg twice daily) or azithromycin (250 mg daily or 500 mg 3 times weekly), rifabutin (300 mg daily) or rifampin (600 mg daily), and ethambutol (25 mg/kg daily for 2 months, then 15 mg/kg daily). For patients with a small body mass and/or who are older than 70 years of age, clarithromycin 250 mg twice daily or azithromycin 250 mg 3 times weekly may be better tolerated. The ATS states that the addition of streptomycin given intermittently (2 or 3 times weekly) for the first 2-3 months may be considered for patients with extensive disease.

Other Mycobacterial Infections

Clarithromycin has been used with some success in the treatment of various other mycobacterial infections; however, further experience and study are needed to establish the role of clarithromycin in the treatment of these infections.

The ATS and other clinicians suggest that clarithromycin can be used as an alternative agent for the treatment of infections caused by M. kansasii. Although a regimen of isoniazid, rifampin, and ethambutol usually is recommended for the treatment of pulmonary or extrapulmonary infections caused by M. kansasii, the ATS states that clarithromycin is a reasonable alternative in patients who are unable to tolerate one of these drugs or when retreatment is necessary. It also has been suggested that clarithromycin may be substituted for rifampin for the treatment of M. kansasii infections in HIV-infected individuals who are receiving indinavir and therefore cannot receive concomitant rifampin. Although M. kansasii generally are susceptible to clarithromycin in vitro, clinical experience is limited and efficacy of the drug for the treatment of infections caused by this organism has not been established.

The ATS suggests that use of clarithromycin can be considered for the treatment of cutaneous infections caused by M. abscessus or M. chelonae and states that treatment of these infections should be based on results of in vitro susceptibility testing. Although there is some evidence that clarithromycin monotherapy may be effective for the treatment of cutaneous M. chelonae infections in adults, preliminary studies indicate that monotherapy with macrolides is insufficient to produce microbiologic cure for pulmonary M. abscessus infection. In an open, noncomparative trial evaluating clarithromycin in cutaneous (disseminated) infection caused by M. chelonae in a limited number of patients with immunosuppression secondary to disease (e.g., organ transplant, autoimmune disease) or drug therapy (e.g., corticosteroids, cyclophosphamide), clarithromycin (0.5-1 g twice daily for 6 months) resolved the infection in all patients completing therapy; 82% of patient who completed therapy had complete remission of the infection. Oral clarithromycin has been used in the treatment of an outbreak of cutaneous M. abscessus infections involving the hands and feet that occurred in children and one adult as the result of exposure at a public wading pool; however, the benefits of the drug in this infection are unclear since lesions eventually resolved in all patients, including those who did not receive clarithromycin treatment (with or without incision and drainage of lesions).

The ATS and others suggest that clarithromycin monotherapy is one of several acceptable regimens for the treatment of cutaneous infections caused by M. marinum.

Limited in vitro and in vivo studies suggest that clarithromycin has bactericidal activity against M. leprae, and the drug has been used with some success in multiple-drug regimens for short periods in a few patients with leprosy.

Pertussis

Clarithromycin has been effective when used for the treatment of pertussis caused by Bordetella pertussis. In a randomized study in children 1 month to 16 years of age with culture-proven B. pertussis infection or a cough illness suspected of being pertussis, a 7-day regimen of oral clarithromycin (7.5 mg/kg twice daily) was as effective and better tolerated than a 14-day regimen of oral erythromycin (13.3 mg/kg 3 times daily).

A 14-day regimen of oral erythromycin usually is considered the drug of choice for the treatment of pertussis and for prevention in contacts of patients with pertussis. However, other macrolides (azithromycin, clarithromycin) appear to be as effective and may be associated with better compliance since they are better tolerated.

Toxoplasmosis

Clarithromycin has been used in conjunction with pyrimethamine for the treatment of encephalitis caused by Toxoplasma gondii in a few patients with AIDS. The USPHS/IDSA states that use of clarithromycin for primary or secondary prophylaxis of toxoplasmosis in HIV-infected individuals cannot be recommended based on current data. The CDC, NIH, IDSA, and other clinicians usually recommend a regimen of pyrimethamine in conjunction with sulfadiazine and leucovorin for the treatment of toxoplasmosis in adults and children, especially immunocompromised patients (e.g., HIV-infected individuals).

For information on recommendations regarding treatment and prophylaxis of toxoplasmosis,

Prevention of Bacterial Endocarditis

Clarithromycin has been recommended for prevention of α-hemolytic (viridans group) streptococcal endocarditis in penicillin-allergic adults and children with congenital heart disease, rheumatic or other acquired valvular heart dysfunction (even after valvular surgery), prosthetic heart valves (including bioprosthetic or allograft valves), surgically constructed systemic pulmonary shunts or conduits, hypertrophic cardiomyopathy, mitral valve prolapse with valvular regurgitation and/or thickened leaflets, or previous bacterial endocarditis (even in the absence of heart disease) who undergo dental procedures that are likely to result in gingival or mucosal bleeding (e.g., dental extractions; periodontal procedures such as scaling, root planing, probing, and maintenance; dental implant placement or reimplantation of avulsed teeth; root-filling procedures; subgingival placement of antibiotic fibers or strips; initial placement of orthodontic bands; intraligamentary local anesthetic injections; routine professional cleaning) or minor upper respiratory tract surgery or instrumentation (e.g., tonsillectomy, adenoidectomy, bronchoscopy with a rigid bronchoscope). The AHA recognizes that its current recommendations for prevention of bacterial endocarditis are empiric, since no controlled efficacy studies have been published, and that prophylaxis of endocarditis is not always effective. However, the AHA, the ADA, and most clinicians generally recommend routine use of prophylactic anti-infectives in patients at risk for bacterial endocarditis. When selecting anti-infectives for prophylaxis of recurrent rheumatic fever or prophylaxis of bacterial endocarditis, the current recommendations published by the AHA should be consulted.

Dosage and Administration

Reconstitution and Administration

Clarithromycin conventional tablets and oral suspension are administered orally and may be given without regard to meals. Clarithromycin oral suspension may be administered with milk. Clarithromycin extended-release tablets should be taken with food.

Clarithromycin granules for oral suspension should be reconstituted at the time of dispensing by adding the amount of water specified on the bottle to provide a suspension containing 125 or 250 mg of clarithromycin per 5 mL of suspension. The water should be added in two portions and the suspension agitated well after each addition. The suspension should be agitated well just prior to each use.

Dosage

Safety and efficacy of clarithromycin extended-release tablets have been established for the treatment of acute bacterial exacerbations of chronic bronchitis, acute maxillary sinusitis, and community-acquired pneumonia (CAP) in adults; safety and efficacy of the extended-release formulation of the drug have not been established for the treatment of other infections that are treated with clarithromycin conventional tablets or oral suspension.

Adult Dosage

Pharyngitis and Tonsillitis

The usual oral dosage of clarithromycin conventional tablets or oral suspension for the treatment of pharyngitis and tonsillitis in adults is 250 mg every 12 hours for 10 days.

Acute Exacerbations of Chronic Bronchitis

For the treatment of acute exacerbations of chronic bronchitis caused by Haemophilus influenzae or H. parainfluenzae, the usual adult dosage of clarithromycin conventional tablets or oral suspension is 500 mg every 12 hours for 7-14 days or 7 days, respectively. The usual adult dosage of clarithromycin conventional tablets or oral suspension for the treatment of acute bacterial exacerbations of chronic bronchitis caused by Moraxella catarrhalis or Streptococcus pneumoniae is 250 mg every 12 hours for 7-14 days. Lower dosage should not be used (e.g., 250 mg twice daily) since such regimens have failed to eradicate H. influenzae in clinical studies.

If clarithromycin extended-release tablets are used for the treatment of acute exacerbations of chronic bronchitis caused by H. influenzae, H. parainfluenzae, M. catarrhalis, or S. pneumoniae, the usual adult dosage is 1 g (two 500-mg extended-release tablets) once daily for 7 days.

Acute Sinusitis

The usual oral dosage of clarithromycin conventional tablets or oral suspension for the treatment of acute maxillary sinusitis in adults is 500 mg every 12 hours for 14 days.

If clarithromycin extended-release tablets are used for the treatment of acute maxillary sinusitis, the usual adult dosage is 1 g (two 500- mg extended-release tablets) once daily for 14 days.

Community-acquired Pneumonia

For the treatment of community-acquired pneumonia (CAP) in adults, the usual dosage of clarithromycin conventional tablets or oral suspension is 250 mg every 12 hours. The usual duration of treatment is 7-14 days for infections caused by Chlamydophila pneumoniae (Chlamydia pneumoniae), Mycoplasma pneumoniae, or S. pneumoniae or 7 days for infections caused by H. influenzae. The fact that this dosage has failed to eradicate H. influenzae in some clinical studies should be considered.

If clarithromycin extended-release tablets are used for the treatment of CAP caused by H. influenzae, H. parainfluenzae, M. catarrhalis, S. pneumoniae, C. pneumoniae, or M. pneumoniae, the usual adult dosage is 1 g (two 500 mg extended-release tablets) once daily for 7 days.

Skin and Skin Structure Infections

The usual adult dosage of clarithromycin conventional tablets or oral suspension for the treatment of uncomplicated skin and skin structure infections is 250 mg every 12 hours for 7-14 days.

Helicobacter pylori Infection and Duodenal Ulcer Disease

When used in combination with omeprazole (40 mg daily in the morning for 14 days) for the treatment of H. pylori infection in adults with duodenal ulcer disease (active or up to 1-year history), the recommended dosage of clarithromycin (conventional tablets or oral suspension) is 500 mg 3 times daily for 14 days; an additional 14 days of omeprazole monotherapy (20 mg daily in the morning) is recommended for ulcer healing and symptom relief in patients with an active duodenal ulcer at the time treatment is initiated to complete 28 days of therapy.

When used in combination with ranitidine bismuth citrate (400 mg twice daily for 14 days) the recommended dosage of clarithromycin (conventional tablets or oral suspension) for the treatment of H. pylori infection and duodenal ulcer is 500 mg 2 or 3 times daily for 14 days; an additional 14 days of ranitidine bismuth citrate monotherapy (400 mg twice daily) is then administered to complete 28 days of therapy.

When used in combination with amoxicillin (1 g twice daily for 10 or 14 days) and lansoprazole (30 mg twice daily for 10 or 14 days), the recommended dosage of clarithromycin (conventional tablets or oral suspension) for the treatment of H. pylori infection and duodenal ulcer in adults is 500 mg twice daily for 10 or 14 days.

When used in combination with amoxicillin (1 g twice daily for 10 days) and omeprazole (20 mg twice daily for 10 days), the recommended dosage of clarithromycin (conventional tablets or oral suspension) for the treatment of H. pylori infection and duodenal ulcer disease (active or up to 1-year history of duodenal ulcer) in adults is 500 mg twice daily for 10 days. An additional 18 days of omeprazole monotherapy (20 mg daily) is recommended for ulcer healing and symptom relief in patients with an active duodenal ulcer at the time therapy is initiated.

Multiple-drug regimens recommended by the American College of Gastroenterology (ACG) and many clinicians for the treatment of H. pylori infection consist of a proton-pump inhibitor (e.g., omeprazole, lansoprazole) and 2 anti-infective agents (e.g., clarithromycin and amoxicillin or metronidazole) or a 3-drug, bismuth-based regimen (e.g., bismuth-metronidazole-tetracycline) concomitantly with a proton-pump inhibitor; when clarithromycin has been used in these regimens, dosages of 250 mg twice daily to 500 mg 3 times daily (generally 500 mg 2 or 3 times daily) have been used.

While the minimum duration of therapy required to eradicate H. pylori infection with these 3- or 4-drug regimens has not been fully elucidated, the ACG and many clinicians state that treatment for longer than 1 week probably is not necessary. However, more prolonged therapy is recommended for patients with complicated, large, or refractory ulcers; therapy in such patients should be continued at least until successful eradication of H. pylori has been confirmed.(See Helicobacter pylori Infection, in Uses.)

Bartonella Infections

For the treatment of cat scratch disease caused by Bartonella henselae, clarithromycin has been given in a dosage of 500 mg daily for 4 weeks.

If clarithromycin is used for the treatment of infections caused by Bartonella in HIV-infected adults or adolescents, the CDC, NIH, and IDSA recommend a dosage of 500 mg twice daily for at least 3 months. If relapse occurs, lifelong secondary prophylaxis (chronic maintenance therapy) with erythromycin or doxycycline should be considered.

Legionella Infections

For the treatment of Legionnaires' disease, some clinicians recommend that clarithromycin be given in a dosage of 500 mg twice daily. The usual duration of clarithromycin therapy is 10 days for the treatment of mild to moderate infections in immunocompetent patients; however, 3 weeks of treatment may be necessary to prevent relapse, especially in those with more severe infections or with underlying comorbidity or immunodeficiency.

Lyme Disease

For the treatment of early localized or early disseminated Lyme disease associated with erythema migrans (but without neurologic involvement or third-degree AV heart block) in patients who are allergic to or intolerant of amoxicillin, doxycycline, and cefuroxime axetil, the Infectious Diseases Society of America (IDSA) suggests that adults receive oral clarithromycin in a dosage of 500 mg (conventional tablets or oral suspension) twice daily for 14-21 days.

Mycobacterium Avium Complex (MAC) Infections (Primary Prophylaxis)

For primary prevention of disseminated Mycobacterium avium complex (MAC) infection (primary prophylaxis) in adults and adolescents with human immunodeficiency virus (HIV) infection, the usual dosage of clarithromycin (conventional tablets or oral suspension) is 500 mg every 12 hours.

The Prevention of Opportunistic Infections Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/ IDSA) recommends primary prophylaxis against disseminated MAC infection in HIV-infected adults and adolescents with CD4 T-cell counts less than 50/mm. Although consideration can be given to discontinuing such prophylaxis in adults and adolescents when there is immune recovery in response to potent antiretroviral therapy and an increase in CD4 T-cell count to greater than 100/mm has been sustained for at least 3 months (see Primary Prevention of Disseminated MAC Infection under Mycobacterial Infections: Mycobacterium avium Complex [MAC] Infections under Uses), the USPHS/IDSA states that primary MAC prophylaxis should be restarted if the CD4 T-cell count decreases to less than 50-100/ mm.

Mycobacterium avium Complex (MAC) Infections (Treatment and Prevention of Recurrence)

For the treatment of disseminated MAC infection, adults and adolescents should receive 500 mg of clarithromycin (conventional tablets or oral suspension) every 12 hours in conjunction with ethambutol (15 mg/kg daily) with or without a third drug (e.g., rifabutin 300 mg once daily). Clarithromycin dosages higher than 500 mg twice daily are not recommended since such dosages have been associated with reduced survival in clinical studies in patients with disseminated MAC disease.

For prevention of recurrence (secondary prophylaxis or chronic maintenance therapy) of disseminated MAC in HIV-infected adults or adolescents who responded to treatment, the USPHS/IDSA, CDC, NIH, and IDSA recommend that adults and adolescents receive clarithromycin in a dosage of 500 mg twice daily in conjunction with ethambutol (15 mg/kg once daily) with or without rifabutin (300 mg once daily). Secondary MAC prophylaxis in HIV-infected individuals usually is continued for life therapy. However, consideration can be given to discontinuing secondary MAC prophylaxis in adults and adolescents when there is immune recovery in response to potent antiretroviral therapy (see Treatment and Prevention of Recurrence of Disseminated MAC Infection under Mycobacterial Infections: Mycobacterium avium Complex [MAC] Infections in Uses) but such prophylaxis should be restarted if CD4 T-cell counts decrease to less than 100/ mm.

Mycobacterium avium Complex (MAC) Infections (Treatment of Pulmonary Infections in HIV-negative Adults)

For the treatment of mild to moderately advanced MAC pulmonary infections in HIV-negative adults, the ATS recommends therapy with clarithromycin 500 mg twice daily in conjunction with rifabutin (300 mg daily) or rifampin (600 mg daily) and ethambutol (25 mg/kg daily for 2 months, then 15 mg/kg daily). A lower dosage of clarithromycin (250 mg twice daily) in this regimen may be better tolerated in patients with a small body mass and/or those who are older than 70 years of age. The ATS states that the addition of streptomycin therapy given intermittently (2 or 3 times weekly) for the first 2-3 months may be considered in patients with extensive disease. The optimal duration of therapy for pulmonary MAC disease has not been established, but patients probably should be treated until they are culture-negative on therapy for 1 year.

Mycobacterium chelonae and M. abscessus Infections

For the treatment of cutaneous infections caused by Mycobacterium chelonae or M. abscessus, adults have received oral clarithromycin in a dosage of 0.5-1 g twice daily for 6 months.

Mycobacterium marinum Infections

For the treatment of cutaneous infections caused by M. marinum, adults have received oral clarithromycin in a dosage of 500 mg twice daily for at least 3 months.

Prevention of Bacterial Endocarditis

For prevention of bacterial endocarditis in adults undergoing certain dental, oral, respiratory tract, or esophageal procedures, the usual dosage of clarithromycin is 500 mg given as a single dose 1 hour prior to the procedure.

Pediatric Dosage

Acute Otitis Media

The usual oral dosage of clarithromycin for the treatment of acute otitis media (AOM) in children is 7.5 mg/kg every 12 hours for 10 days.

Pharyngitis and Tonsillitis

The usual oral dosage of clarithromycin conventional tablets or oral suspension for the treatment of pharyngitis and tonsillitis in children is 7.5 mg/kg every 12 hours for 10 days.

Acute Sinusitis

Children receiving clarithromycin conventional tablets or oral suspension for the treatment of acute maxillary sinusitis should receive 7.5 mg/kg every 12 hours for 10 days.

Community-acquired Pneumonia

Children receiving clarithromycin conventional tablets or oral suspension for the treatment of CAP should receive 7.5 mg/kg every 12 hours for 10 days.

Skin and Skin Structure Infections

The usual dosage of clarithromycin conventional tablets or oral suspension for the treatment of uncomplicated skin and skin structure infections in children is 7.5 mg/kg every 12 hours for 10 days.

Lyme Disease

For the treatment of early localized or early disseminated Lyme disease associated with erythema migrans (but without neurologic involvement or third-degree AV heart block) in patients who are allergic to or intolerant of amoxicillin, doxycycline, and cefuroxime axetil, the IDSA suggests that children receive oral clarithromycin in a dosage 7.5 mg/kg (up to 500 mg) twice daily for 14-21 days.

Mycobacterium avium Complex (MAC) Infections (Primary Prophylaxis)

For primary prevention of MAC infection (primary prophylaxis) in HIV-infected children, the usual dosage of clarithromycin (conventional tablets or oral suspension) is 7.5 mg/ kg (maximum 500 mg) every 12 hours. The manufacturer states that no studies evaluating clarithromycin prophylaxis of MAC infection have been conducted in pediatric patients and that clarithromycin dosage recommended for primary prophylaxis in children is derived from studies involving treatment of MAC infections in pediatric patients.

The safety of discontinuing primary MAC prophylaxis in children whose CD4 T-cell counts have increased as a result of highly active antiretroviral therapy has not been studied to date.

Mycobacterium avium Complex (MAC) Infections (Treatment and Prevention of Recurrence)

For the treatment of disseminated MAC infection, the manufacturer recommends that children receive clarithromycin in a dosage of 7.5 mg/kg (maximum 500 mg) every 12 hours in conjunction with other antimycobacterial drugs that have in vitro activity against MAC. The CDC, NIH, and IDSA state that HIV-infected children may receive clarithromycin in a dosage of 7.5-15 mg/kg (maximum 500 mg) twice daily in conjunction with ethambutol (15-25 mg/kg once daily [up to 1 g daily]) with or without rifabutin (10-20 mg/kg once daily [up to 300 mg daily]) for the treatment of MAC infections.

For long-term suppressive or chronic maintenance therapy (secondary prophylaxis) to prevent recurrence of disseminated MAC in HIV-infected infants or children who responded to treatment, the USPHS/IDSA recommends clarithromycin in a dosage of 7.5 mg/kg (maximum 500 mg) twice daily in conjunction with ethambutol (15 mg/kg [maximum 900 mg] once daily) with or without rifabutin (5 mg/kg [maximum 300 mg] once daily).

The safety of discontinuing secondary MAC prophylaxis in children receiving potent antiretroviral therapy has not been studied to date and HIV-infected children with a history of disseminated MAC should receive lifelong secondary prophylaxis.

Mycobacterium abscessus Infections

For the treatment of cutaneous infections caused by M. abscessus, children 1-15 years of age have received oral clarithromycin in a dosage of 15 mg/kg daily (with or without incision and drainage of lesions).

Pertussis

For the treatment of pertussis in children, oral clarithromycin has been given in a dosage of 15-20 mg/kg in 2 divided doses (up to 1 g daily) for 7 days. In one study in children 1 month to 16 years of age, clarithromycin was effective for the treatment of pertussis when given in a dosage of 7.5 mg/kg twice daily for 7 days.

Prevention of Bacterial Endocarditis

For prevention of bacterial endocarditis in children undergoing certain dental, oral, respiratory tract, or esophageal procedures, the usual dosage of clarithromycin is 15 mg/kg given as a single dose 1 hour prior to the procedure.

Dosage in Renal and Hepatic Impairment

Clarithromycin generally may be used without dosage adjustment in patients with hepatic impairment and normal renal function. However, in patients with creatinine clearances less than 30 mL/minute with or without hepatic impairment, the dosage should be halved or the dosing interval for clarithromycin doubled. An initial clarithromycin dose of 500 mg (conventional tablets or oral suspension) followed by 250 mg twice daily has been suggested for adults with creatinine clearances less than 30 mL/minute when a usual dosage of 500 mg twice daily would have been used in adults with normal renal function; a dosage of 250 mg (conventional tablets or oral suspension) daily has been suggested for such patients when a usual dosage of 250 mg twice daily would have been used in individuals with normal renal function.

Cautions

Clarithromycin generally is well tolerated. In clinical studies, most adverse effects were mild and transient; only about 1% of reported effects were described as severe. Limited data from comparative studies suggest that the overall incidence of adverse effects with oral clarithromycin therapy is similar to or lower than that with oral erythromycin. As with oral erythromycin, the most common adverse effects of oral clarithromycin involve the GI tract. The manufacturer states that fewer than 3% of patients receiving oral clarithromycin in clinical studies discontinued therapy because of adverse effects. In clinical trials in patients who received combined therapy with clarithromycin and omeprazole for the treatment of H. pylori infection and associated duodenal ulcer, most adverse effects reported with such combined therapy were mild to moderate in severity. However, discontinuance of therapy because of adverse effects was required in 3.5% of these patients.

In clinical trials in which dual therapy with clarithromycin and omeprazole or ranitidine bismuth citrate or triple therapy with clarithromycin, amoxicillin, and lansoprazole or omeprazole was used for the treatment of H. pylori infection and associated duodenal ulcer, no adverse effects peculiar to these drug combinations were observed. The most frequently reported adverse effects in patients receiving clarithromycin, amoxicillin, and lansoprazole were diarrhea (7% of patients), headache (6% of patients), and taste perversion (5% of patients). The incidence of adverse effects reported with the clarithromycin- amoxicillin-lansoprazole regimen given for 14 days was similar to that reported with the same regimen given for 10 days. The most frequently reported adverse effects in patients receiving triple therapy with clarithromycin, amoxicillin, and omeprazole were diarrhea (14%), taste perversion (10%), and headache (9%). Triple therapy with these drugs was not associated with a higher incidence of adverse effects than dual therapy. The most frequently reported adverse effects in patients receiving clarithromycin and ranitidine bismuth citrate were taste disturbance (8-11%), diarrhea (4-5%), and nausea and vomiting (3-5%).

GI Effects

Diarrhea, nausea, and abnormal taste were reported in 3-6% of patients receiving oral clarithromycin in clinical studies, while dyspepsia and abdominal discomfort occurred in 2% of patients receiving the drug. Oral candidiasis, glossitis, stomatitis, vomiting, flatulence, diaper dermatitis, constipation, tongue discoloration, anorexia, pancreatitis, and laryngismus also have been reported. Tooth discoloration, usually reversible with professional dental cleaning, has been reported in patients receiving clarithromycin.

Results of studies in animals indicate that clarithromycin causes less stimulation of GI smooth muscle motility than erythromycin, and some clinical studies suggest that clarithromycin may cause adverse GI effects less frequently than oral erythromycin. In patients with community-acquired pneumonia, adverse GI effects were reported less frequently in patients receiving clarithromycin (13%) than in those receiving oral erythromycin as the base or stearate salt (32%). In these studies, discontinuance of therapy because of adverse effects (e.g., vomiting, nausea diarrhea, abdominal pain) reportedly was required in 4% of patients receiving clarithromycin versus 17% of those receiving erythromycin as the base or stearate salt. Similar differences in the development of adverse GI effects were seen in comparative studies of clarithromycin versus amoxicillin and clavulanate potassium; 21% of patients receiving clarithromycin and 40% of patients receiving amoxicillin and clavulanate potassium therapy experienced adverse GI effects.

In studies in patients with acute exacerbation of chronic bronchitis or acute maxillary sinusitis, the incidence of GI overall adverse effects in patients receiving clarithromycin extended-release tablets was similar to the incidence in patients receiving clarithromycin conventional tablets; however, those receiving the extended-release tablets reported substantially less severe GI symptoms than those receiving the conventional tablets. In these studies, discontinuance of therapy because of adverse GI effects or abnormal taste was required more frequently in those receiving the conventional tablets than in those receiving the extended-release tablets.

In clinical trials in patients who received combined therapy with clarithromycin and omeprazole for the treatment of H. pylori infection and associated duodenal ulcer, taste perversion was reported in 15% of patients (versus 16 or 1% of those receiving clarithromycin or omeprazole alone, respectively). Nausea was reported in 5% of patients receiving clarithromycin-omeprazole therapy (versus 3 or 1% of those receiving clarithromycin or omeprazole alone, respectively), vomiting in 4% (versus 1% or less than 1% of those receiving clarithromycin or omeprazole alone, respectively), diarrhea in 4% (versus 7 or 3% of those receiving clarithromycin or omeprazole alone, respectively), and abdominal pain in 3% of patients (versus 1 or 2% of those receiving clarithromycin or omeprazole alone, respectively). Tongue discoloration was reported in 2% of patients receiving combined clarithromycin-omeprazole therapy in controlled clinical trials.

In clinical trials in patients who received combined therapy with clarithromycin and ranitidine bismuth citrate for the treatment of H. pylori infection and associated duodenal ulcer, taste disturbance occurred in 10% (versus 11 or less than 1% of those receiving clarithromycin or ranitidine bismuth citrate alone, respectively). Diarrhea was reported in 8% (versus 5 or 2% of those receiving clarithromycin or ranitidine bismuth citrate alone, respectively), nausea and vomiting in 3% (versus 2 or less than 1% of those receiving clarithromycin or ranitidine bismuth citrate alone, respectively), and constipation in 0% (versus 0 or 1% of those receiving clarithromycin or ranitidine bismuth citrate alone, respectively).

In clinical trials in which combined therapy with clarithromycin, amoxicillin, and lansoprazole was used for the treatment of H. pylori infection and associated duodenal ulcer, adverse GI effects reported in less than 3% of patients included abdominal pain, dark stools, dry mouth/thirst, glossitis, rectal itching, nausea, oral candidiasis, stomatitis, tongue discoloration, tongue disorder, and vomiting.

Hepatic Effects

Elevation in serum ALT (SGPT), AST (SGOT), γ-glutamyltransferase (γ- glutamyl transpeptidase, GGT, GGTP), alkaline phosphatase, LDH, and/or total bilirubin concentration has been reported infrequently (e.g., less than 1% of patients) in patients receiving clarithromycin alone or combined with omeprazole therapy. Hepatomegaly and hepatic dysfunction (including cholestasis, with or without jaundice) also have been reported in patients receiving the drug. This hepatic dysfunction may be severe but usually is reversible. However, hepatic failure leading to death has been reported rarely, generally in patients with serious underlying diseases and/or receiving concomitant drug therapy.

In animals, hepatotoxicity occurred in all species tested at clarithromycin dosages comparable to or twice the maximum recommended human dosage (on a mg/m basis).

Hematologic Effects

Increased prothrombin time has been reported in 1% of adult patients receiving clarithromycin. Decreased white blood cell (WBC) counts have been reported in less than 1% of patients receiving the drug. Thrombocytopenia has been reported in at least one patient receiving clarithromycin therapy.

Lymphoid depletion has occurred in animals at dosages 2-3 times the maximum recommended human dosage (on a mg/m basis).

Renal Effects

Elevated BUN has been reported in 4% of patients receiving clarithromycin. Elevated serum creatinine concentration has been reported in less than 1% of patients receiving clarithromycin alone or combined with omeprazole therapy. Acute renal failure reportedly has occurred with clarithromycin therapy.

In animals, renal tubular degeneration occurred at dosages 2-12 times (on a mg/m basis) the maximum recommended human dosage.

CNS Effects

Headache was reported in 2% of patients receiving clarithromycin in clinical studies. Transient adverse CNS effects, including acute psychosis, anxiety, behavioral changes, confusional states, depersonalization, disorientation, hallucinations, insomnia, nightmares, tinnitus, tremor, and vertigo, have been reported during postmarketing experience. These adverse effects usually resolve following discontinuance of clarithromycin therapy.

In clinical trials in patients who received combined therapy with clarithromycin and omeprazole for the treatment of H. pylori infection and associated duodenal ulcer, headache was reported in 5% of patients (versus 9 or 6% of those receiving clarithromycin or omeprazole alone, respectively), while infection was reported in 3% of patients receiving combined therapy (versus 2 or 4% of those receiving clarithromycin or omeprazole alone, respectively).

In clinical trials in patients who received combined therapy with clarithromycin and ranitidine bismuth citrate for the treatment of H. pylori infection and associated duodenal ulcer, headache occurred in 5% (versus less than 1 or 1% of those receiving clarithromycin or ranitidine bismuth citrate alone, respectively), dizziness in 0% (versus 2 or less than 1% of those receiving clarithromycin or ranitidine bismuth citrate alone, respectively), and sleep disorder in 2% (versus less than 1% each of those receiving clarithromycin or ranitidine bismuth citrate alone, respectively).

In clinical trials in which combined therapy with clarithromycin, amoxicillin, and lansoprazole was used for the treatment of H. pylori infection and associated duodenal ulcer, confusion or dizziness was reported in less than 3% of patients.

Dermatologic and Sensitivity Reactions

Allergic reactions ranging from mild urticaria and mild skin eruptions to rare cases of anaphylaxis, leukocytoclastic vasculitis, toxic epidermal necrolysis, and Stevens-Johnson syndrome have been reported in patients receiving clarithromycin. Pruritus and rash (e.g., fixed drug eruption) also have been reported.

Increased Mortality

An increased risk of all-cause mortality and cardiovascular mortality was reported during long-term follow-up of patients enrolled in a randomized, placebo-controlled study designed to evaluate the possible benefits of a 2-week regimen of clarithromycin (500 mg once daily) in patients with stable coronary heart disease (CLARICOR). At a mean follow-up period of 2.6 years, all-cause mortality was 27% higher (as the result of higher cardiovascular mortality) in study participants who had received the 2-week regimen of clarithromycin compared with those who had received placebo. At 10-year follow-up, data indicate that clarithromycin tended to increase all-cause mortality in all study participants and the increased risk was significant in the subset of study participants who were not receiving an HMG-CoA reductase inhibitor (statin) at study entry. Other limited observational studies have shown variable results regarding the effect of clarithromycin on the risk of death or other heart-related adverse effects. A possible mechanism by which clarithromycin may increase the risk of death in patients with heart disease is unknown. It also is unclear whether the follow-up data from patients in the CLARICOR study can be applied to patients without heart disease.

Other Adverse Effects

As with other macrolides, clarithromycin has been associated with QT prolongation and ventricular arrhythmias, including ventricular tachycardia and atypical ventricular tachycardia (torsades de pointes).

Although a causal relationship to the drug has not been demonstrated, reversible hypoacusis (hearing loss) has been reported in a few patients receiving high (e.g., 2 g daily) dosages of clarithromycin for the treatment of M. avium complex infections.

Hypoglycemia has been reported rarely with clarithromycin therapy; in some of these cases, patients were receiving concomitant therapy with insulin or oral antidiabetic agents.

In clinical trials in patients who received combined therapy with clarithromycin and ranitidine bismuth citrate for the treatment of H. pylori infection and associated duodenal ulcer, gynecologic problems occurred in 3% (versus 6 or less than 1% of those receiving clarithromycin or ranitidine bismuth citrate alone, respectively). Chest symptoms were reported in 2% (versus 0% of those receiving clarithromycin or ranitidine bismuth citrate alone, respectively) and pruritus in 3% (versus 0 or less than 1% of those receiving clarithromycin or ranitidine bismuth citrate alone, respectively).

In clinical trials in which combined therapy with clarithromycin, amoxicillin, and lansoprazole was used for the treatment of H. pylori infection and associated duodenal ulcer, other adverse effects reported in less than 3% of patients include myalgia, respiratory disorders, skin reactions, vaginitis, and vaginal candidiasis.

Other adverse effects reported with combined clarithromycin-omeprazole therapy that differed from those reported with omeprazole alone included rhinitis (2% of patients), pharyngitis (1% of patients), and flu syndrome (1% of patients).

Corneal opacities have occurred in animals at clarithromycin dosages 8- 12 times the maximum recommended human dosage (on a mg/m basis).

Precautions and Contraindications

Clarithromycin is contraindicated in patients with known hypersensitivity to clarithromycin, erythromycin, or any other macrolide antibiotic.

Concomitant use of clarithromycin with certain drugs, including terfenadine (no longer commercially available in the US), astemizole (no longer commercially available in the US), cisapride, and pimozide, is contraindicated because such use is likely to produce substantially increased plasma concentrations of the drugs and possibly cause serious and/or life-threatening cardiotoxicity. Concomitant use with ergot alkaloids (ergotamine, dihydroergotamine) also is contraindicated because of potentially serious toxicity. Concomitant use of clarithromycin and ranitidine bismuth citrate is not recommended in patients with creatinine clearance less than 25 mL/minute, and should not be used in patients with a history of acute porphyria.(See Drug Interactions.)

Other Precautions and Contraindications

The potential for increased risk of all-cause mortality and cardiovascular mortality in patients with cardiovascular disease (see Cautions: Increased Mortality) should be considered when weighing the risks and potential benefits of clarithromycin in all patients, particularly those with suspected or confirmed cardiovascular disease. Even if only a short course of clarithromycin is indicated, other available anti-infectives should be considered in those with heart disease. Patients should be advised of the importance of informing their clinicians if they have heart disease, especially when an anti-infective is being prescribed, and the importance of seeking immediate medical attention if they experience symptoms of a heart attack or stroke (e.g., chest pain, shortness of breath, pain or weakness in one part or side of the body, slurred speech). Clarithromycin is not indicated for the treatment of coronary artery disease.

To reduce development of drug-resistant bacteria and maintain effectiveness of clarithromycin and other antibacterials, the drug should be used only for the treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria. When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing. In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy. Patients should be advised that antibacterials (including clarithromycin) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold). Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with clarithromycin or other antibacterials in the future.

As with other anti-infective agents, use of clarithromycin may result in overgrowth of nonsusceptible bacteria or fungi. If superinfection occurs, appropriate therapy should be instituted.

Because Clostridium difficile-associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis) caused by overgrowth of toxin-producing clostridia has been reported with the use of many anti-infective agents, including macrolides, it should be considered in the differential diagnosis of patients who develop diarrhea during or following anti-infective therapy. Mild cases of colitis may respond to discontinuance of the drug alone, but diagnosis and management of moderate to severe cases should include sigmoidoscopy, appropriate bacteriologic studies, and treatment with fluid, electrolyte, and protein supplementation as indicated. If colitis is severe or is not relieved by discontinuance of the drug, appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) should be administered. Isolation of the patient may be advisable. Other causes of colitis also should be considered.

If clarithromycin is used as the sole anti-infective agent in regimens used for the treatment of H. pylori and duodenal ulcer disease, H. pylori with decreased susceptibility or resistance to clarithromycin may emerge. Patients in whom H. pylori was not eradicated following therapy with omeprazole/clarithromycin, ranitidine bismuth citrate/clarithromycin, omeprazole/clarithromycin/amoxicillin, or lansoprazole/clarithromycin/amoxicillin are likely to have clarithromycin-resistant H. pylori isolates. In vitro susceptibility testing should be performed if possible in patients with H. pylori infection who fail therapy (i.e., as determined in clinical trials by a positive result for H. pylori on culture or histologic testing 4 weeks following completion of therapy). If clarithromycin resistance is demonstrated or susceptibility testing is not possible, alternative anti-infective therapy (i.e., with a non-clarithromycin-containing regimen) should be instituted. The American College of Gastroenterology (ACG) states that clarithromycin or metronidazole should not be used subsequently in patients with H. pylori infection who fail therapy that includes these drugs since resistance commonly emerges during such unsuccessful therapy.

Clarithromycin generally may be used without dosage adjustment in patients with hepatic impairment who have normal renal function. However, in patients who have severe renal impairment with or without hepatic impairment, dosage reduction or prolongation of dosing intervals for clarithromycin may be necessary.(See Dosage and Administration: Dosage.)

Pediatric Precautions

The manufacturer states that safety and efficacy of clarithromycin in children younger than 6 months of age have not been established, and safety of the drug in children younger than 20 months of age with M. avium complex infection has not been established. However, children as young as 6 months of age have received the drug for the treatment of streptococcal pharyngitis or tonsillitis and for skin and skin structure infections without apparent unusual adverse effect.

Safety and efficacy, including associated dosage recommendations, for extended-release tablets of clarithromycin in pediatric patients have not been established.

Geriatric Precautions

Limited data indicate that peak serum concentrations of clarithromycin and 14-hydroxyclarithromycin and values for area under the concentration-time curve may be increased in healthy geriatric individuals 65-84 years of age relative to those in healthy younger adults; this increase appears to result from age-related decreases in renal function.(See Pharmacokinetics: Absorption.) An increased incidence of adverse effects in geriatric patients has not been reported to date in clinical studies. If clarithromycin is used in geriatric patients with severe renal impairment, use of a reduced dosage of the drug should be considered.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Mutagenicity and Carcinogenicity

Clarithromycin failed to exhibit mutagenic potential in several in vitro tests, including the Salmonella mammalian microsome test, bacterial induced mutation frequency test, rat hepatocyte DNA synthesis assay, mouse lymphoma assay, mouse dominant lethal test, and mouse micronucleus test. In the in vitro chromosome aberration test, clarithromycin produced weakly positive results in one test and negative results in another. Results of a bacterial reverse-mutation test (Ames test) performed on several clarithromycin metabolites also were negative.

Long-term studies have not been performed to date to evaluate the carcinogenic potential of clarithromycin.

Pregnancy, Fertility, and Lactation

Pregnancy

Although there are no adequate and controlled studies to date in humans, clarithromycin has been associated with adverse effects on pregnancy outcome and/or embryofetal development in animals at dosages that produced plasma drug concentrations 2-17 times those achieved with the maximum recommended human dosage. While the potential risk to the fetus has not been clearly elucidated to date, the manufacturer states that clarithromycin should be used during pregnancy only when safer drugs cannot be used or are ineffective. If clarithromycin is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.

Teratogenicity studies in rats with oral or IV clarithromycin dosages up to 160 mg/kg daily administered during the period of major organogenesis and in rabbits at oral dosages up to 125 mg/kg daily (approximately twice the maximum recommended human dosage on a mg/m basis) or IV dosages of 30 mg/ kg daily administered during days 6-18 of gestation did not demonstrate evidence of teratogenicity. However, other studies in a different rat strain demonstrated a low incidence of cardiovascular anomalies at a clarithromycin dosage of 150 mg/kg daily (resulting in plasma concentrations 2 times those in humans) administered during gestation days 6-15. Studies in mice revealed a variable incidence of cleft palate with oral dosages of 1000 mg/kg daily (resulting in plasma concentrations 17 times those in humans) during gestation days 6-15; cleft palate also was observed at a dosage of 500 mg/kg daily. In monkeys, an oral dosage of 70 mg/kg daily (approximately equivalent to the maximum recommended human dosage on a mg/m basis) produced fetal growth retardation at plasma concentrations twice those attained in humans.

Fertility

Fertility and reproduction studies in male and female rats using clarithromycin dosages up to 160 mg/kg daily (1.3 times the maximum recommended human dosage on a mg/m basis) have demonstrated no adverse effects of the drug on the estrous cycle, fertility, parturition, or number and viability of offspring. Plasma concentrations in rats following clarithromycin dosages of 150 mg/kg daily were twice those observed in humans. Embryonic loss in monkeys has occurred at an oral clarithromycin dosage of 150 mg/kg daily (2.4 times the maximum recommended dosage in humans on a mg/m basis); this effect has been attributed to marked maternal toxicity at this high dosage. In addition, in utero fetal loss in rabbits has occurred at an IV dosage of 33 mg/m, which is 17 times less than the proposed maximum human oral daily dosage of 618 mg/m.

Lactation

Clarithromycin should be used with caution in nursing women. The drug is distributed into milk. In 12 women who received oral clarithromycin in a dosage of 250 mg twice daily for 6 days, mean peak concentrations of clarithromycin and 14-hydroxyclarithromycin in milk were 25 and 75%, respectively, of corresponding serum concentrations. Pre-weaned rats, exposed indirectly via consumption of milk from dams treated with 150 mg/kg daily of clarithromycin for 3 weeks, did not demonstrate adverse effects despite evidence indicating higher drug concentrations in milk than in plasma.

Drug Interactions

Drugs Metabolized by Hepatic Microsomal Enzymes

Concomitant use of clarithromycin and drugs metabolized by hepatic microsomal enzymes (cytochrome P-450 (CYP) system) may be associated with increased serum concentrations of the latter drugs, and serum concentrations of such concomitantly administered drugs should be monitored closely.

Carbamazepine

Clarithromycin should be used with caution in patients receiving carbamazepine; if such concomitant therapy is used, a reduction in carbamazepine dosage and/or monitoring of plasma carbamazepine concentrations is advised.

Limited data in healthy men indicate that clarithromycin may increase area under the serum concentration-time curve (AUC) for carbamazepine and decrease peak serum concentration and AUC for carbamazepine 10,11-epoxide (CBZ-E). In addition, increased plasma concentrations of carbamazepine (but not CBZ-E) and, in some patients, manifestations of carbamazepine toxicity (i.e., drowsiness, dizziness, ataxia) occurred within 3-5 days after initiation of clarithromycin therapy (200 mg twice daily) in several patients receiving carbamazepine (600 mg/day) with or without other drugs; plasma carbamazepine concentrations decreased and toxic manifestations subsided within several days following carbamazepine discontinuation.

Cisapride

Concomitant administration of clarithromycin and cisapride is contraindicated.

Coadministration of clarithromycin and/or erythromycin with cisapride has been associated with QT prolongation and serious cardiac arrhythmias (ventricular tachycardia, ventricular fibrillation, torsades de pointes); fatalities have been reported. In 2 patients with chronic renal failure who were receiving cisapride (10 mg 3-4 times daily), QT prolongation and/or torsades de pointes occurred within several days after initiating therapy with clarithromycin (500 mg twice daily). Elevated serum cisapride concentrations observed in one patient decreased following discontinuance of clarithromycin.

Darifenacin

The manufacturer of darifenacin states that darifenacin dosage should not exceed 7.5 mg daily in patients receiving the drug concomitantly with potent CYP3A4 inhibitors, including clarithromycin.

Disopyramide

If clarithromycin and disopyramide are used concomitantly, ECGs and serum disopyramide concentrations should be monitored. Ventricular fibrillation, prolongation of the QT interval, and a marked increase in disopyramide elimination half-life (40 hours) were reported in a patient maintained on disopyramide (200 mg twice daily) who received clarithromycin (250 mg twice daily), omeprazole (20 mg twice daily), and metronidazole (400 mg twice daily) for the treatment of H. pylori-associated chronic duodenal ulceration. QT prolongation, which had not been documented previously during a 7-year period of disopyramide therapy, resolved with a decline in disopyramide plasma concentrations. There have been postmarketing reports of torsades de pointes occurring with concomitant use of clarithromycin and disopyramide.

Erlotinib

The manufacturer of erlotinib states that caution is advised if the drug is used concomitantly with potent CYP3A4 inhibitors, including clarithromycin, and a reduction in erlotinib dosage should be considered if severe adverse effects occur.

Eszopiclone

The manufacturer of eszopiclone states that eszopiclone dosage should be reduced if the drug is used concomitantly with a potent CYP3A4 inhibitor, including clarithromycin. In such situations, the initial eszopiclone dosage should not exceed 1 mg but may be increased to 2 mg if clinically indicated.

Hydroxymethylglutaryl-CoA (HMG-CoA) Reductase Inhibitors

As with other macrolides, clarithromycin has been reported to increase serum concentrations of concomitantly administered HMG-CoA reductase inhibitor (statin) antilipemic agents (e.g., lovastatin, simvastatin) via inhibition of metabolism by cytochrome P-450 isoenzymes. Rhabdomyolysis, sometimes accompanied by acute renal failure secondary to myoglobinuria, has been reported rarely with HMG-CoA reductase inhibitor therapy given alone or concomitantly with macrolide antibiotics (e.g., erythromycin, clarithromycin), immunosuppressive agents (including cyclosporine) in transplant patients, gemfibrozil, niacin (in dosages of at least 1 g daily), or nefazodone.

Pimozide

Concomitant administration of pimozide and macrolide antibiotics, including clarithromycin, is contraindicated. Macrolide antibiotics, including azithromycin, clarithromycin, and erythromycin, inhibit the metabolism of pimozide, resulting in increased plasma pimozide concentrations. Since pimozide prolongs the QT interval, such increased plasma concentrations of the drug may increase the risk of serious cardiovascular effects, including fatal ventricular arrhythmias; at least 2 deaths have been reported in patients following addition of clarithromycin to pimozide therapy.

Rifabutin and Rifampin

Concomitant administration of clarithromycin and rifabutin or rifampin has been reported to increase the metabolism of clarithromycin. In addition, in a randomized study in patients with advanced HIV infection (CD4 T-cell counts less than 200/mm), a drug interaction consistent with inhibition of rifabutin metabolism by clarithromycin and induction of clarithromycin metabolism by rifabutin was demonstrated. Four weeks after initiation of therapy with rifabutin (300 mg daily) in HIV-infected patients who had been receiving clarithromycin (500 mg every 12 hours) alone for 2 weeks, clarithromycin AUC had decreased by an average of 44%, AUC for 14-hydroxyclarithromycin had increased by 57%, and peak plasma clarithromycin concentration had decreased by 41%. In the same study, patients who received clarithromycin for 4 weeks after 2 weeks of rifabutin monotherapy had average increases of 99 and 375% in the AUCs of rifabutin and 25-desacetyl rifabutin, respectively, and an increase of 69% in peak plasma rifabutin concentration. It has been suggested that the increased plasma concentrations of rifabutin and/or its 25-desacetyl metabolite associated with concomitant administration of clarithromycin may explain the increased frequency of uveitis observed with such concomitant therapy.

Terfenadine and Astemizole

Current evidence indicates that certain macrolide antibiotics (e.g., erythromycin, clarithromycin) alter the metabolism of astemizole and terfenadine; however, these antihistamines are no longer commercially available in the US. and and Prolongation of the QT interval, ST-U abnormalities, and ventricular tachycardia, including torsades de pointes, have been reported in some patients receiving terfenadine concomitantly with erythromycin. Therefore, terfenadine was contraindicated in patients receiving clarithromycin or erythromycin, especially patients who had preexisting cardiac abnormalities (e.g., arrhythmia, bradycardia, QT interval prolongation, ischemic heart disease, congestive heart failure) or electrolyte disturbances. In addition, QT prolongation and torsades de pointes have been reported in patients receiving concomitant erythromycin and astemizole, and coadministration of these drugs was contraindicated. Because clarithromycin also is metabolized by the cytochrome P-450 system, coadministration of clarithromycin and astemizole also was contraindicated.

Other Drugs Affecting Hepatic Microsomal Enzymes

In postmarketing studies, interactions with erythromycin and/or clarithromycin have been reported with a number of other drugs metabolized by the cytochrome P-450 system, including cyclosporine, tacrolimus, hexobarbital, phenytoin, alfentanil, lovastatin, bromocriptine, and valproate. Serum concentrations of drugs metabolized by the cytochrome P-450 system should be monitored closely in patients receiving concomitant therapy with erythromycin or clarithromycin.

Anticoagulants

Postmarketing data suggest that the concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulant. The manufacturer recommends that the prothrombin time be monitored carefully in patients receiving concomitant clarithromycin and oral anticoagulant therapy.

Antiretroviral Agents

Amprenavir

Concomitant use of clarithromycin (500 mg twice daily) and amprenavir (1.2 g twice daily) results in slightly increased amprenavir concentrations and AUC and possible decreased clarithromycin concentrations. Dosage adjustments are not recommended.

Atazanavir

Concomitant use of clarithromycin (500 mg twice daily) and atazanavir (400 mg once daily) increased the peak plasma concentration and AUC of clarithromycin, decreased the peak plasma concentration and AUC of 14-hydroclarithromycin, and increased the peak plasma concentration and AUC of atazanavir. Increased concentrations of clarithromycin may result in prolongation of the QTc interval.

Clarithromycin dosage should be reduced by 50% in patients receiving atazanavir. In addition, alternative anti-infective therapy should be considered for indications other than Mycobacterium avium complex (MAC) infections since the decreased plasma concentrations of 14-hydroclarithromycin could adversely affect clarithromycin's efficacy in the treatment of certain infections.

Delavirdine

Concomitant use of clarithromycin (500 mg twice daily for 15 days) and delavirdine (300 mg 3 times daily for 30 days) resulted in a 100% increase in the AUC of clarithromycin but had no appreciable effect on the pharmacokinetics of delavirdine.

When clarithromycin is used in patients receiving delavirdine, modification of the usual clarithromycin dosage generally is not necessary in those with normal renal function; however, the clarithromycin dose should be reduced by 50% in patients with creatinine clearances of 30-60 mL/minute and reduced by 75% in patients with creatinine clearances less than 30 mL/minute.

Didanosine

Simultaneous administration of clarithromycin tablets and didanosine in a limited number of HIV-infected adults did not alter the pharmacokinetics of didanosine.

Efavirenz

Administration of clarithromycin (500 mg every 12 hours) and efavirenz (400 mg daily) for 7 days decreased the peak plasma concentration and AUC of clarithromycin by 26 and 39%, respectively, and increased the peak plasma concentration and AUC of 14-hydroxyclarithromycin by 49 and 34%, respectively. The AUC of efavirenz was not affected. The clinical importance of this pharmacokinetic interaction is not known. Rash developed in 46% of individuals receiving clarithromycin and efavirenz in drug interaction studies. Because of the reported pharmacokinetic interaction between clarithromycin and efavirenz and the high incidence of rash in individuals receiving the drugs concurrently, alternatives to clarithromycin (e.g., azithromycin) should be considered in patients receiving efavirenz. If the drugs are used concomitantly, monitor for macrolide efficacy.

Fosamprenavir

Studies using amprenavir indicate that concomitant use of clarithromycin and fosamprenavir may result in increased amprenavir concentrations and AUC. This pharmacokinetic interaction is not considered clinically important and dosage adjustments are not recommended.

Indinavir

Concomitant use of clarithromycin (500 mg every 12 hours) and indinavir (800 mg 3 times daily) results in increased indinavir concentrations and increased clarithromycin concentrations. Although some clinicians state that dosage adjustments are not needed if clarithromycin and indinavir are used concomitantly, the manufacturer of indinavir states that appropriate dosages for concomitant use with respect to safety and efficacy have not been established.

Lopinavir

Concomitant use of clarithromycin and the fixed combination of lopinavir and ritonavir may result in increased clarithromycin concentrations. The manufacturer of the fixed combination of lopinavir and ritonavir states that when clarithromycin is used in patients receiving lopinavir and ritonavir, modification of the usual dosage of clarithromycin is not necessary in those with normal renal function; however, the clarithromycin dosage should be reduced by 50% in patients with creatinine clearances of 30-60 mL/minute and reduced by 75% in patients with a creatinine clearances less than 30 mL/minute.

Nevirapine

Concomitant use of clarithromycin and nevirapine has resulted in decreased plasma concentrations and AUC of clarithromycin, increased plasma concentrations and AUC of its major metabolite (14-hydroxyclarithromycin), and increased nevirapine concentrations. Because the clarithromycin metabolite has reduced activity against Mycobacterium avium complex (MAC), overall activity of the drug against this organism may be altered. Therefore, an alternative to clarithromycin (e.g., azithromycin) should be used in patients receiving nevirapine. If the drugs are used concomitantly, monitor for macrolide efficacy.

Ritonavir

In a study in healthy individuals, concomitant administration of ritonavir (200 mg every 8 hours) with clarithromycin (500 mg every 12 hours) for 4 days increased the peak plasma concentration and area under the AUC of clarithromycin by 31 and 77%, respectively, and decreased the peak plasma concentration and AUC of 14-hydroxyclarithromycin by 99 and 100%, respectively. The peak plasma concentration and AUC of ritonavir also were increased by 12-15%. Because 14-hydroxyclarithromycin appears to enhance the antimicrobial activity of the parent drug against some pathogens (e.g., Haemophilus influenzae), it has been suggested that the decreased plasma concentrations of the metabolite reported with concomitant ritonavir theoretically could adversely affect clarithromycin's efficacy in the treatment of certain infections.

The manufacturer of clarithromycin and ritonavir states that when clarithromycin is used in patients receiving ritonavir, modification of the usual clarithromycin dosage generally is not necessary in those with normal renal function; however, the clarithromycin dosage should be reduced by 50% in patients with creatinine clearances of 30-60 mL/minute and reduced by 75% in patients with creatinine clearances less than 30 mL/minute.

Saquinavir

Concomitant use of clarithromycin and saquinavir may result in increased plasma concentrations of both drugs. In healthy individuals receiving clarithromycin (500 mg twice daily) and saquinavir (1.2 g 3 times daily as liquid-filled capsules) for 7 days, AUC or peak plasma concentrations of saquinavir increased 177 or 187%, respectively; AUC or plasma concentrations of clarithromycin increased 45 or 39%, respectively; and AUC and peak plasma concentrations of 14-hydroxyclarithromycin decreased 24 or 34%, respectively. Dosage adjustments may not be needed if clarithromycin and saquinavir are used concomitantly for a limited time at the dosages studied.

For those receiving ritonavir-boosted saquinavir, the manufacturer of saquinavir states that modification of dosage is not necessary in those with normal renal function but clarithromycin dosage should be reduced by 50% in those with creatinine clearances of 30-60 mL/minute and reduced by 75% in those with creatinine clearances less than 30 mL/minute.

Zidovudine

In one study, simultaneous administration of clarithromycin and zidovudine in HIV-infected adults decreased peak plasma concentrations of zidovudine by about 41% but had no appreciable effect on the pharmacokinetics of clarithromycin. In a limited number of HIV-infected adults, clarithromycin (500 mg twice daily) decreased the steady-state AUC of zidovudine by a mean of 12% (range: from a decrease of 34% to an increase of 14%). When clarithromycin tablets were administered 2-4 hours prior to zidovudine doses, steady-state peak zidovudine serum concentrations were increased twofold but the AUC was unaffected.

Benzodiazepines

Erythromycin has been reported to decrease the clearance of midazolam and triazolam and may increase the pharmacologic effects of these benzodiazepines. CNS effects (e.g., somnolence, confusion) have been reported in postmarketing experience when clarithromycin was used concomitantly with triazolam.

Colchicine

Some clinicians state that colchicine and clarithromycin should not be used concomitantly. There have been postmarketing reports of colchicine toxicity when clarithromycin was used concomitantly with colchicine, especially in elderly patients and/or in patients with renal impairment. In addition, a retrospective analysis of data from hospitalized patients who received colchicine and clarithromycin either concomitantly or sequentially suggests that concomitant use of the drugs increases the risk of fatal colchicine toxicity, especially in patients with renal impairment.

Digoxin

The manufacturer recommends that serum digoxin levels be monitored carefully in patients receiving concomitant clarithromycin and digoxin therapy. Elevated serum concentrations of digoxin have been reported during postmarketing surveillance in patients receiving concomitant digoxin and clarithromycin therapy. Some of these patients exhibited clinical manifestations consistent with digoxin toxicity, including arrhythmias.

Ergot Alkaloids

Concomitant use of clarithromycin and ergot alkaloids (ergotamine, dihydroergotamine) is contraindicated. Concurrent use of clarithromycin and ergotamine or dihydroergotamine has been associated with acute ergot toxicity, characterized by vasospasm and ischemia of the extremities and other tissues, including the CNS.

Fluconazole

In healthy individuals receiving clarithromycin 500 mg twice daily concomitantly with fluconazole 200 mg daily, steady-state trough serum concentrations and area under the serum concentration-time curve (AUC) for clarithromycin reportedly increased by an average of 33 and 18%, respectively; steady-state concentrations of 14-hydroxyclarithromycin were not substantially affected.

Omeprazole

Concomitant administration of clarithromycin and omeprazole alters the pharmacokinetics (e.g., increased concentrations in gastric tissue and/or serum) of clarithromycin, 14-hydroxyclarithromycin, and omeprazole.(See Pharmacokinetics: Absorption.)

Quinidine

Torsades de pointes has been reported rarely in patients receiving clarithromycin and quinidine concomitantly. If clarithromycin and quinidine are used concomitantly, ECGs and serum quinidine concentrations should be monitored.

Ranitidine

Concomitant use of ranitidine bismuth citrate and clarithromycin has resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14-hydroxy-clarithromycin plasma concentrations (31%). This pharmacokinetic interaction is not considered clinically important. However, clarithromycin should not be used concomitantly with ranitidine bismuth citrate in patients with creatinine clearances less than 25 mL/minute and should not be used in patients with a history of acute porphyria.

Sildenafil

Concomitant erythromycin has been reported to increase the AUC of sildenafil. Because a similar interaction could occur with clarithromycin, a reduction in sildenafil dosage should be considered.

Theophylline

Concomitant use of clarithromycin in patients who are receiving theophylline may be associated with an increase in serum theophylline concentrations, probably as a result of reduced hepatic metabolism and/or clearance of theophylline. Clarithromycin reportedly causes less alteration in serum theophylline concentration than erythromycin, but changes in theophylline dosage have been required in some patients treated concurrently with clarithromycin and theophylline. In 2 studies in healthy individuals who were given an extended-release theophylline preparation (6.5 or 12 mg/kg per dose) concomitantly with clarithromycin (250-500 mg every 12 hours), the peak and trough serum concentrations at steady state and the area under the serum concentration-time curve (AUC) for theophylline reportedly were increased by approximately 20%. However, in at least one of these studies in healthy men, serum theophylline concentrations remained within the therapeutic range, and no clinical toxicity was observed.

The manufacturer states that monitoring of serum theophylline concentrations should be considered for patients receiving clarithromycin concomitantly with high doses of theophylline or in those who have baseline serum theophylline concentrations in the upper therapeutic range. Theophylline dosage should be adjusted if necessary when clarithromycin is added or withdrawn in a patient receiving theophylline.

Pharmacokinetics

Absorption

Clarithromycin is absorbed rapidly from the GI tract after oral administration; GI absorption of the drug exceeds that of erythromycin. The absolute bioavailability of clarithromycin following oral administration of the drug as 250-mg conventional tablets has been reported to be approximately 50-55%, which probably is an underestimate of systemic activity because of the drug's rapid first-pass metabolism to its active metabolite 14-hydroxyclarithromycin. In a study in adults, the bioavailability of 10 mL of 125 mg/5 mL or 250 mg/ 5 mL clarithromycin suspension was similar to that of the 250- or 500-mg conventional tablet, respectively. While the 24-hour area under the plasma concentration-time curves (AUCs) for clarithromycin and 14-hydroxyclarithromycin following administration of clarithromycin extended-release tablets are equivalent to the 24-hour AUCs following administration of the same total daily dose as conventional tablets, the extended-release tablets result in lower and later steady-state plasma concentrations of clarithromycin and 14-hydroxyclarithromycin compared with conventional tablets.

Food causes a slight delay in the onset of clarithromycin absorption and increases the peak plasma concentration of clarithromycin by 24% when the drug is administered as conventional oral tablets; however, the extent of clarithromycin absorption is unaffected by concomitant ingestion of food. Food does not affect the onset of formation or the peak plasma concentration of 14- hydroxyclarithromycin when the drug is administered as conventional oral tablets; however, the AUC of the metabolite is decreased by about 11% when the conventional tablets are administered with food.

Administration of clarithromycin extended-release tablets under fasting conditions results in a 30% decrease in the AUC of clarithromycin compared with administration with food; the extent of formation of 14-hydroxyclarithromycin is not affected by food when the drug is administered as extended- release tablets .

In a limited number of adults, administration of 250 mg of clarithromycin as the oral suspension with food appeared to decrease the mean peak serum concentration by about 17% and the mean AUC by about 10%, while in a limited number of children, administration of a single 7.5-mg/kg dose of clarithromycin oral suspension with food appeared to increase the mean peak serum concentration of the drug by about 27% and the mean AUC by about 42%.

In fasting healthy adults receiving clarithromycin conventional tablets or oral suspension, peak serum clarithromycin concentrations averaged 0.6 mcg/ mL and were attained within 1-4 hours after administration of a single 250- mg dose. Following oral administration of the drug as conventional oral tablets, steady-state peak clarithromycin concentrations were achieved within 3 days and averaged approximately 1-2 or 3-4 mcg/mL following a 250-mg dose of the drug every 12 hours or a 500-mg dose every 8-12 hours, respectively. Following oral administration of clarithromycin as conventional oral tablets, steady-state peak 14-hydroxyclarithromycin concentrations were achieved after 3-4 days and were about 0.6 or up to 1 mcg/mL following a 250-mg dose of the drug every 12 hours or a 500-mg dose every 8-12 hours, respectively. Following oral administration of clarithromycin as extended-release tablets, steady-state peak clarithromycin concentrations of 2-3 mcg/mL were obtained 5-8 hours following a 1-g dose of the drug (two 500-mg extended-release tablets); steady-state peak concentrations were 1-2 mcg/mL and were obtained 5-6 hours following a 500-mg dose. Steady-state peak plasma concentrations of 14-hydroxyclarithromycin of 0.8 or 0.6 mcg/mL were achieved 6-9 hours following a 1- or 500-mg daily dose of clarithromycin extended-release tablets, respectively. Following oral administration of clarithromycin oral suspension in fasting healthy adults, steady-state peak clarithromycin concentrations were achieved after 2-3 days and averaged approximately 2 mcg/mL following a 250- mg dose of the drug every 12 hours. Peak serum concentrations of the principal metabolite, 14-hydroxyclarithromycin, reportedly average about 0.7 mcg/mL and are achieved approximately 2 hours after a 250-mg dose of clarithromycin. Preliminary data from a study in healthy men suggest that the ratio of the AUCs of clarithromycin to 14-hydroxyclarithromycin at steady state is approximately 3:1.

In children receiving therapy with clarithromycin as the oral suspension, administration of 7.5 mg/kg of the drug every 12 hours generally resulted in peak steady-state serum clarithromycin concentrations of 3-7 mcg/mL and peak steady-state serum 14-hydroxyclarithromycin concentrations of 1-2 mcg/mL.

In pharmacokinetic studies of HIV-infected adults receiving 500 mg of clarithromycin orally every 12 hours, steady-state concentrations of the drug and its 14-hydroxy metabolite were similar to those observed in healthy individuals receiving the same dose. Peak plasma concentrations of clarithromycin in HIV-infected adults receiving 0.5- or 1-g doses of the drug orally every 12 hours ranged from 2-4 or 5-10 mcg/mL, respectively. Following oral administration of the drug as the suspension every 12 hours in HIV-infected children, peak steady-state concentrations generally ranged from 6-15 mcg/mL following a dose of 15 mg/kg.

Following IV administration of a 250-mg dose of clarithromycin, peak serum concentrations of the parent drug and 14-hydroxyclarithromycin were 2.8 and 0.5 mcg/mL, respectively.

Plasma concentrations and areas under the concentration-time curve (AUCs) of clarithromycin and 14-hydroxyclarithromycin are increased by concomitant administration of omeprazole. In healthy men receiving clarithromycin 500 mg every 8 hours and omeprazole 40 mg daily, peak and trough plasma concentrations of clarithromycin averaged approximately 10 and 27% higher, respectively, than those following administration of clarithromycin alone, while AUC averaged 15% greater than that with administration of clarithromycin alone. Peak and trough plasma concentrations of 14-hydroxyclarithromycin averaged approximately 45 and 57% higher, respectively, and AUC averaged 45% greater, than those values with clarithromycin alone. In a limited number of healthy men, clarithromycin concentrations 2 hours after administration of clarithromycin alone or with omeprazole averaged 10.5 or 20 mcg/g, respectively, in the gastric antrum; 20.8 or 24.3 mcg/g, respectively, in the gastric fundus; and 4.2 or 39.3 mcg/g, respectively, in gastric mucus.

Concomitant administration of clarithromycin and omeprazole also results in increased steady-state peak plasma concentrations, area under the concentration-time curve (AUC), and elimination half-life of omeprazole compared with omeprazole administration alone. Coadministration of clarithromycin and ranitidine bismuth citrate results in increased plasma ranitidine concentrations, increased plasma bismuth trough concentrations, and increased plasma concentrations of 14- hydroxyclarithromycin.

Clarithromycin undergoes extensive first-pass metabolism and exhibits nonlinear, dose-dependent pharmacokinetics, apparently as a result of capacity- limited saturation of metabolic pathways; however, such nonlinearity is slight at the usual dosages of 250-500 mg every 8-12 hours.(See Pharmacokinetics: Elimination.) Disproportionate increases in peak serum concentrations and areas under the concentration-time curve (AUC) of clarithromycin and 14-hydroxyclarithromycin have been reported in patients receiving single high (e.g., 1.2 g) or multiple doses of clarithromycin, although some data indicate that peak serum concentrations of clarithromycin and 14-hydroxyclarithromycin are proportional to dose. In a single-dose study in healthy men, a fivefold increase in clarithromycin dosage (250 mg to 1.2g) resulted in a 13-fold increase in AUC of the parent drug. The AUC of 14-hydroxyclarithromycin following 250- mg oral or IV doses of clarithromycin was higher after oral administration, suggesting that the parent drug undergoes substantial first-pass metabolism in the liver to the 14-hydroxy metabolite.

In healthy geriatric individuals 65-84 years of age who received 500 mg of clarithromycin every 12 hours, peak and trough serum concentrations of clarithromycin and 14-hydroxyclarithromycin at steady state and area under the concentration-time curve (AUC) were increased relative to those in healthy younger adults (18-30 years of age); these increases were attributed to age- related reductions in renal function.(See Pharmacokinetics: Elimination.) Limited data indicate that serum concentrations of clarithromycin at steady state in patients with impaired hepatic function do not differ from those in healthy individuals; however, 14-hydroxyclarithromycin concentrations are lower in patients with hepatic dysfunction.(See Pharmacokinetics: Elimination.)

Distribution

Limited data are available on the distribution of clarithromycin in humans. Clarithromycin and 14-hydroxyclarithromycin appear to be distributed into most body tissues and fluids. Because of high intracellular concentrations of the drug, tissue concentrations are higher than serum concentrations. High concentrations of clarithromycin were present in tissue samples obtained from patients undergoing surgery. In patients who received 250-500 mg of clarithromycin orally every 12 hours for 3 days prior to surgery, peak clarithromycin concentrations in lung, tonsils, and nasal mucosa reportedly were attained 4 hours after administration and averaged 13.5-17.5, 5.3-6.5, and 5.9-8.3 mg/ kg, respectively; however, it has been suggested that these data may represent an overestimate of clarithromycin tissue concentrations because of the microbiologic assay's inability to distinguish between parent drug and its active metabolite. In children receiving clarithromycin suspension for otitis media at a dosage of 7.5 mg/kg every 12 hours for 5 doses, peak clarithromycin and 14- hydroxyclarithromycin concentrations in middle ear fluid were 2.5 and 1.3 mcg/ mL, respectively; concomitant serum concentrations were 1.7 and 0.8 mcg/mL, respectively. Results of studies in animals given radiolabeled clarithromycin or erythromycin indicate higher and more prolonged activity of clarithromycin in various body tissues, particularly the lung.

Clarithromycin is distributed into CSF following oral administration; however, there is no evidence that the drug would be effective in the treatment of meningitis.

Protein binding of clarithromycin in vitro has been reported to range from approximately 42-72% at usual therapeutic concentrations. In one study, protein binding of radiolabeled drug in human serum ranged from approximately 42-50% at clarithromycin concentrations of 0.25-5 mcg/mL. Protein binding of clarithromycin and 14-hydroxyclarithromycin decreases with increasing serum drug concentration.

Elimination

Elimination of clarithromycin appears to follow nonlinear, dose-dependent pharmacokinetics, possibly as a result of capacity-limited metabolism. Following oral administration of single 250-mg or 1.2-g doses of clarithromycin conventional tablets in healthy men, the elimination half-life averaged 4 or 11 hours, respectively. During multiple dosing every 12 hours, the elimination half-life of clarithromycin reportedly increased from 3-4 hours following a 250-mg dose (conventional tablets) every 12 hours to 5-7 hours following a 500-mg dose every 8-12 hours; the half-life of 14-hydroxyclarithromycin increased from 5-6 hours with a 250-mg dose to 7-9 hours with a 500-mg dose. When clarithromycin is administered as the oral suspension, the elimination half-life of the drug and of its 14-hydroxy metabolite appear to be similar to those observed at steady-state following administration of equivalent doses of clarithromycin as tablets.

In a single-dose study in healthy men, average total body clearance of clarithromycin decreased from 1116 mL/minute following a 250-mg dose to 403 mL/minute following a 1.2-g dose. This reduction in total body clearance was attributed principally to a reduction in metabolic (nonrenal) clearance, which declined from 913 mL/minute with the 250-mg dose to 289 mL/minute with the 1.2-g dose. The renal clearance of clarithromycin is relatively independent of dose and approximates the normal glomerular filtration rate.

Total body clearance and renal clearance of clarithromycin in healthy geriatric individuals are decreased compared with those in younger adults, apparently as a result of age-related reductions in renal function. However, since differences in pharmacokinetic values appear to be small and an increase in adverse effects has not been reported in geriatric versus younger adults, dosage adjustment solely on the basis of age generally is not required.

Clarithromycin is eliminated by both renal and nonrenal mechanisms. Clarithromycin is extensively metabolized in the liver, principally by oxidative N- demethylation and hydroxylation at the 14 position; hydrolytic cleavage of the cladinose sugar moiety also occurs in the stomach to a minor extent. Although at least 7 metabolites of clarithromycin have been identified, 14-hydroxyclarithromycin is the principal metabolite in serum and the only one with substantial antibacterial activity.(See Spectrum.) While both the R- and S-epimers of 14-hydroxyclarithromycin are formed in vivo, the R-epimer is present in greater amounts and has the greatest antimicrobial activity. Metabolism of clarithromycin appears to be saturable since the amount of 14-hydroxyclarithromycin after an 800-mg dose of the parent drug is only marginally greater than that after a 250-mg dose.

Following oral administration of a single 250-mg dose of radiolabeled clarithromycin in healthy men, approximately 38% of the dose (18% as clarithromycin) was excreted in urine, and 40% in feces (4% as clarithromycin), over 5 days. With oral administration of 250 or 500 mg of clarithromycin as tablets every 12 hours, approximately 20 or 30% of the respective dose is excreted unchanged in urine within 12 hours. After an oral clarithromycin dosage of 250 mg every 12 hours as the suspension, approximately 40% of the administered dose is excreted unchanged in urine. The principal metabolite found in urine is 14-hydroxyclarithromycin, which accounts for approximately 10-15% of the dose following administration of 250 or 500 mg of clarithromycin as tablets.

The serum half-life of clarithromycin is prolonged in patients with impaired renal function. Marked increases in peak serum concentration, AUC, and half- life of clarithromycin and 14-hydroxyclarithromycin have been reported in patients with creatinine clearances less than 30 mL/minute, and reduction of clarithromycin dosage may be required in such patients.(See Dosage and Administration: Dosage in Renal and Hepatic Impairment.) Moderate to severe hepatic impairment reportedly reduces the formation of 14-hydroxyclarithromycin but is accompanied by an increase in the renal clearance of the parent drug; therefore, a decrease in dosage would not be needed in patients with hepatic dysfunction unless renal function also is impaired. In fact, the total concentration of biologically active drug (clarithromycin plus 14-hydroxyclarithromycin) in circulation reportedly is decreased in patients with severe hepatic impairment.

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