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Clarithromycin

Pronunciation

Pronunciation

(kla RITH roe mye sin)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension Reconstituted, Oral:

Biaxin: 250 mg/5 mL (50 mL, 100 mL) [fruit punch flavor]

Generic: 125 mg/5 mL (50 mL, 100 mL); 250 mg/5 mL (50 mL, 100 mL)

Tablet, Oral:

Biaxin: 250 mg [contains brilliant blue fcf (fd&c blue #1), fd&c yellow #10 (quinoline yellow)]

Biaxin: 500 mg [contains fd&c yellow #10 (quinoline yellow)]

Generic: 250 mg, 500 mg

Tablet Extended Release 24 Hour, Oral:

Biaxin XL: 500 mg [contains fd&c yellow #10 (quinoline yellow)]

Biaxin XL Pac: 500 mg [contains fd&c yellow #10 (quinoline yellow)]

Generic: 500 mg

Brand Names: U.S.

  • Biaxin
  • Biaxin XL
  • Biaxin XL Pac

Pharmacologic Category

  • Antibiotic, Macrolide

Pharmacology

Exerts its antibacterial action by binding to 50S ribosomal subunit resulting in inhibition of protein synthesis. The 14-OH metabolite of clarithromycin is twice as active as the parent compound against certain organisms.

Absorption

Immediate release: Rapid; food delays rate, but not extent of absorption

Extended-release: Fasting is associated with ~30% lower AUC relative to administration with food

Distribution

Widely distributes into most body tissues; manufacturer reports no data in regards to CNS penetration

Metabolism

Partially hepatic via CYP3A4; converted to 14-OH clarithromycin (active metabolite); undergoes extensive first-pass metabolism

Excretion

Primarily urine (20% to 40% as unchanged drug; additional 10% to 15% as metabolite); feces (29% to 40% mostly as metabolites) (Ferrero, 1990)

Clearance: Approximates normal GFR

Time to Peak

Immediate release: 2-3 hours; Extended release: 5-8 hours

Half-Life Elimination

Immediate release: Clarithromycin: 3-7 hours; 14-OH-clarithromycin: 5-9 hours

Protein Binding

42% to 70% (Peters, 1992)

Special Populations: Renal Function Impairment

The pharmacokinetics of clarithromycin were altered in subjects with impaired renal function.

Special Populations: Hepatic Function Impairment

The 14-OH clarithromycin concentrations were lower in subjects with hepatic impairment but may be partially offset by an increase in renal clearance of clarithromycin.

Special Populations: Elderly

The Cmax and AUC of clarithromycin and 14-OH clarithromycin were increased in elderly patients because of age-related decreases in renal function.

Use: Labeled Indications

Infants and Children 6 months and older:

Acute maxillary sinusitis due to susceptible H. influenzae, S. pneumoniae, or Moraxella catarrhalis

Acute otitis media due to susceptible H. influenzae, M. catarrhalis, or S. pneumoniae

Community-acquired pneumonia due to susceptible Mycoplasma pneumoniae, S. pneumoniae, or Chlamydophila (also known as Chlamydia) pneumoniae (TWAR)

Disseminated mycobacterial infections due to M. avium or M. intracellulare

Pharyngitis/tonsillitis due to susceptible S. pyogenes

Prevention of disseminated mycobacterial infections due to M. avium complex (MAC) disease in patients with advanced HIV infection (20 months of age and older)

Uncomplicated skin/skin structure infection due to susceptible S. aureus or S. pyogenes

Adults:

Pharyngitis/tonsillitis due to susceptible S. pyogenes

Acute maxillary sinusitis due to susceptible H. influenzae, M. catarrhalis, or S. pneumoniae

Acute exacerbation of chronic bronchitis due to susceptible H. influenzae, H. parainfluenzae, M. catarrhalis, or S. pneumoniae

Community-acquired pneumonia due to susceptible H. influenzae, H. parainfluenzae, M. catarrhalis, Mycoplasma pneumoniae, S. pneumoniae, or Chlamydophila (also known as Chlamydia) pneumoniae (TWAR)

Uncomplicated skin/skin structure infections due to susceptible S. aureus or S. pyogenes

Disseminated mycobacterial infections due to M. avium or M. intracellulare

Prevention of disseminated mycobacterial infections due to MAC disease in patients with advanced HIV infection

Duodenal ulcer disease due to H. pylori in regimens with other drugs including amoxicillin and lansoprazole or omeprazole, or in combination with omeprazole or ranitidine bismuth citrate (no longer marketed in the U.S.). Note: Regimens that contain clarithromycin as the single antimicrobial agent are more likely to be associated with the development of clarithromycin resistance.

Use: Unlabeled

Pertussis (CDC guidelines); alternate antibiotic for prophylaxis of infective endocarditis in patients who are allergic to penicillin and undergoing dental procedures (ACC/AHA guidelines); alternate antibiotic for treatment and secondary prophylaxis of bartonellosis infection in HIV-exposed/-positive infants and children (CDC guidelines) and in HIV-positive adolescents and adults (DHHS guidelines); Lyme disease (IDSA guidelines)

Contraindications

Hypersensitivity to clarithromycin, erythromycin, any of the macrolide antibiotics, or any component of the formulation; history of cholestatic jaundice/hepatic dysfunction associated with prior use of clarithromycin; history of QT prolongation or ventricular cardiac arrhythmia, including torsade de pointes; concomitant use with cisapride, pimozide, ergot alkaloids (eg, ergotamine, dihydroergotamine), HMG-CoA reductase inhibitors extensively metabolized by CYP3A4 (eg, lovastatin, simvastatin), astemizole or terfenadine (not available in the U.S.); concomitant use with colchicine in patients with renal or hepatic impairment

Canadian labeling: Additional contraindications (not in US labeling): Severe hepatic failure in combination with renal impairment; hypokalemia; concomitant use with midazolam (oral), colchicine (regardless of hepatic/renal impairment), ticagrelor, or ranolazine (not available in Canada)

Dosing: Adult

Usual dosage range: Oral: 250 to 500 mg every 12 hours or 1000 mg (two 500 mg extended-release tablets) once daily for 7 to 14 days

Acute exacerbation of chronic bronchitis: Oral:

M. catarrhalis and S. pneumoniae: 250 mg every 12 hours for 7 to 14 days or 1,000 mg (two 500 mg extended-release tablets) once daily for 7 days (US labeling) or 5 to 7 days (Canadian labeling)

H. influenzae: 500 mg every 12 hours for 7 to 4 days or 1,000 mg (two 500 mg extended-release tablets) once daily for 7 days (US labeling) or 5 to 7 days (Canadian labeling)

H. parainfluenzae: 500 mg every 12 hours for 7 days or 1,000 mg (two 500 mg extended-release tablets) once daily for 7 days (US labeling) or 5 to 7 days (Canadian labeling)

Acute maxillary sinusitis: Oral: 500 mg every 12 hours for 14 days (US labeling) or 7 to 14 days (Canadian labeling) or 1,000 mg (two 500 mg extended-release tablets) once daily for 14 days

Bartonellosis in HIV-infected patients (excluding CNS infections and endocarditis) (off-label use; HHS [OI adult 2015]): Oral:

Treatment (alternative to preferred): 500 mg twice daily for at least 3 months

Long-term suppressive therapy: 500 mg twice daily; may discontinue if completed 3 to 4 months therapy and CD4 >200 cells/mm3 for at least 6 months Note: Some clinicians would discontinue only if Bartonella titers have also decreased four-fold

Lyme disease (off-label use): Oral: 500 mg twice daily for 14 to 21 days (not recommended for pregnant women) (Wormser 2006)

Mycobacterial infection, disseminated (prevention and treatment): Oral:

Manufacturer's labeling: 500 mg twice daily (use with other antimycobacterial drugs, eg, ethambutol or rifampin). Continue therapy if clinical response is observed; may discontinue when patient is considered at low risk of disseminated infection.

Alternate dosing: Mycobacterium avium complex disease (MAC) in HIV-infected patients (HHS [OI adult 2015]):

Primary prophylaxis: 500 mg twice daily; may discontinue when CD4 count >100 cells/mm3 for ≥3 months in response to ART

Treatment and chronic maintenance therapy: 500 mg twice daily plus ethambutol; consider additional agents (eg, rifabutin, aminoglycoside, fluoroquinolone) for CD4 <50 cells/mm3, high mycobacterial load, or ineffective antiretroviral therapy; may discontinue chronic maintenance if no signs/symptoms of MAC disease, have maintained a CD4 count >100 cells/mm3 for >6 months in response to ART, and completed at least 12 months of therapy

Peptic ulcer disease: Eradication of Helicobacter pylori: Dual or triple combination regimens with bismuth subsalicylate, amoxicillin, an H2-receptor antagonist, or proton-pump inhibitor: Oral: 500 mg every 8 to 12 hours for 10 to 14 days

Pertussis (off-label use): Oral: 500 mg twice daily for 7 days (CDC 2005)

Pharyngitis, tonsillitis: Oral: 250 mg every 12 hours for 10 days. Note: Recommended by the Infectious Disease Society of America (IDSA) as an alternative agent for group A streptococcal pharyngitis in penicillin-allergic patients (Shulman 2012).

Pneumonia: Oral:

C. pneumoniae, M. pneumoniae, and S. pneumoniae: 250 mg every 12 hours for 7 to 14 days or 1,000 mg (two 500 mg extended-release tablets) once daily for 7 days

H. influenzae: 250 mg every 12 hours for 7 days or 1,000 mg (two 500 mg extended-release tablets) once daily for 7 days

H. parainfluenzae and M. catarrhalis: 1000 mg (two 500 mg extended-release tablets) once daily for 7 days

Prophylaxis against infective endocarditis (off-label use): Oral: 500 mg 30 to 60 minutes prior to procedure. Note: American Heart Association (AHA) guidelines now recommend prophylaxis only in patients undergoing invasive procedures and in whom underlying cardiac conditions may predispose to a higher risk of adverse outcomes should infection occur. As of April 2007, routine prophylaxis for GI/GU procedures is no longer recommended by the AHA (Wilson 2007).

Skin and skin structure infection, uncomplicated: Oral: 250 mg every 12 hours for 7 to 4 days

Dosing: Geriatric

Refer to adult dosing. May have age-related reductions in renal function; monitor and adjust dose if necessary.

Dosing: Pediatric

Usual dosage range: Note: All pediatric dosing recommendations based on immediate release product formulations (tablet and oral suspension):

Infants ≥6 months, Children, and Adolescents: Oral: 7.5 mg/kg every 12 hours (maximum: 500 mg/dose) for 10 days

Acute otitis media: Infants ≥6 months, Children, and Adolescents: Oral: 7.5 mg/kg/dose (maximum: 500 mg/dose) every 12 hours for 10 days. Note: Due to increased S. pneumoniae and H. influenzae resistance, macrolides are not routinely recommended as a treatment option (Lieberthal 2013)

Bartonellosisin (treatment/long-term suppressive therapy) HIV-infected patients (excluding CNS infections and endocarditis) (off-label use): Adolescents: Oral: Refer to adult dosing.

Community-acquired pneumonia (CAP): Infants >3 months and Children: Oral: Note: A beta-lactam antibiotic should be added if typical bacterial pneumonia cannot be ruled out.

Presumed atypical (M. pneumoniae, C. pneumoniae, C. trachomatis) infection, mild-to-severe atypical infection or step-down therapy (alternative to azithromycin): 7.5 mg/kg/dose (maximum dose: 500 mg) every 12 hours (Bradley 2011)

Lyme disease (off-label use): Infants, Children, and Adolescents: Oral: 7.5 mg/kg/dose (maximum dose: 500 mg) twice daily for 14-21 days (Wormser 2006)

Mycobacterial infection, disseminated (prevention and treatment): Oral:

Manufacturer's labeling: 7.5 mg/kg/dose (maximum: 500 mg/dose) twice daily; use in combination with other antimycobacterial agents for the treatment of disseminated MAC. Note: Safety of clarithromycin for MAC not studied in children <20 months.

Alternative recommendations: Disseminated Mycobacterium avium complex (MAC) disease in HIV-exposed/-positive patients:

Infants and children (CDC 2009):

Primary prophylaxis: 7.5 mg/kg/dose (maximum: 500 mg/dose) twice daily

Secondary prophylaxis: 7.5 mg/kg/dose (maximum: 500 mg/dose) twice daily, plus ethambutol, with or without rifabutin

Treatment: 7.5-15 mg/kg/dose (maximum: 500 mg/dose) twice daily plus ethambutol, plus rifabutin (for severe disease)

Adolescents: Refer to adult dosing.

Pertussis (off-label use): Infants ≥1 month, Children, and Adolescents: Oral: 7.5 mg/kg/dose (maximum: 500 mg/dose) every 12 hours for 7 days (CDC 2005)

Pharyngitis/tonsillitis: Oral: 7.5 mg/kg/dose (maximum: 250 mg/dose) every 12 hours for 10 days. Note: Recommended by the Infectious Disease Society of America (IDSA) as an alternative agent for group A streptococcal pharyngitis in penicillin-allergic patients (Shulman 2012).

Prophylaxis against infective endocarditis (off-label use): Children and Adolescents: Oral: 15 mg/kg/dose (maximum: 500 mg/dose) 30-60 minutes before procedure (maximum: 500 mg). Note: American Heart Association (AHA) guidelines now recommend prophylaxis only in patients undergoing invasive procedures and in whom underlying cardiac conditions may predispose to a higher risk of adverse outcomes should infection occur. As of April 2007, routine prophylaxis for GI/GU procedures is no longer recommended by the AHA (Wilson 2007).

Sinusitis: Infants ≥6 months, Children, and Adolescents: Oral: 7.5 mg/kg/dose (maximum: 500 mg/dose) every 12 hours for 10 days

Skin/skin structure infections, uncomplicated: Infants ≥6 months, Children, and Adolescents: Oral: 7.5 mg/kg/dose (maximum: 250 mg dose) every 12 hours for 10 days

Dosing: Renal Impairment

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: Decrease clarithromycin dose by 50%

Hemodialysis: Administer after HD session is completed (Aronoff 2007).

In combination with atazanavir or ritonavir:

CrCl 30 to 60 mL/minute: Decrease clarithromycin dose by 50%.

CrCl <30 mL/minute: Decrease clarithromycin dose by 75%.

Dosing: Hepatic Impairment

US labeling: No dosing adjustment necessary if renal function is normal; however, in patients with hepatic impairment and concomitant severe renal impairment, a dosage reduction or prolonged dosing intervals may be appropriate.

Canadian labeling: No dosage adjustment necessary if renal function is normal.

Mild or moderate hepatic impairment with concomitant renal impairment: There are no specific dosage adjustments provided in the manufacturer’s labeling; however, a dosage reduction or prolonged dosing intervals may be appropriate.

Severe hepatic impairment with concomitant renal impairment: Use is contraindicated.

Administration

Immediate release tablets and granules for suspension: Administer with or without meals. Administer every 12 hours rather than twice daily to avoid peak and trough variation. Shake suspension well before each use.

Extended release tablets: Administer with food. Do not crush or chew.

Dietary Considerations

Extended release tablets should be taken with food.

Storage

Extended release tablets: Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Immediate release tablets:

250 mg: Store at 15°C to 30°C (59°F to 86°F). Protect from light.

500 mg: Store at 20°C to 25°C (68°F to 77°F).

Granules for suspension: Store at 15°C to 30°C (59°F to 86°F) prior to and following reconstitution. Do not refrigerate. Use within 14 days of reconstitution.

Drug Interactions

Ado-Trastuzumab Emtansine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Ado-Trastuzumab Emtansine. Specifically, strong CYP3A4 inhibitors may increase concentrations of the cytotoxic DM1 component. Avoid combination

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Alfentanil: Macrolide Antibiotics may increase the serum concentration of Alfentanil. Management: For patients receiving an interacting macrolide antibiotic, caution should be used in administering alfentanil; monitor for increased anesthetic and respiratory depressant effects. Consider using lower doses of alfentanil or an alternative anesthetic. Consider therapy modification

Alfuzosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alfuzosin. Avoid combination

Alitretinoin (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alitretinoin (Systemic). Monitor therapy

Almotriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Almotriptan. Management: Limit initial almotriptan adult dose to 6.25 mg and maximum adult dose to 12.5 mg/24-hrs when used with a strong CYP3A4 inhibitor. Avoid concurrent use in patients with impaired hepatic or renal function. Consider therapy modification

Alosetron: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alosetron. Monitor therapy

ALPRAZolam: Macrolide Antibiotics may increase the serum concentration of ALPRAZolam. Management: Consider an alternative less likely to interact. Azithromycin is likely a lower-risk macrolide, and benzodiazepines less dependent on CYP3A metabolism (e.g., lorazepam, oxazepam) are similarly less likely to interact. Consider therapy modification

Antihepaciviral Combination Products: May increase the serum concentration of Clarithromycin. Management: Avoid clarithromycin doses greater than 1000 mg/day when used with an antihepaciviral combination product. Further dose reductions may be needed in patients with impaired renal function. Consider an alternative antimicrobial for any non-MAC infection. Consider therapy modification

Antineoplastic Agents (Vinca Alkaloids): Macrolide Antibiotics may increase the serum concentration of Antineoplastic Agents (Vinca Alkaloids). Macrolides may also increase the distribution of Vinca Alkaloids into certain cells and/or tissues. Management: Consider an alternative to using a macrolide antibiotic when possible in order to avoid the potential for increased vinca alkaloid toxicity. Consider therapy modification

Apixaban: Inhibitors of CYP3A4 (Strong) and P-glycoprotein may increase the serum concentration of Apixaban. Management: US labeling recommends a 50% apixaban dose reduction in patients who would otherwise receive 5 or 10 mg twice daily, and avoiding in patients who would otherwise receive 2.5 mg twice daily. Canadian labeling lists any combined use as contraindicated. Consider therapy modification

Aprepitant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Aprepitant. Avoid combination

ARIPiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole. Management: See full interaction monograph for details. Consider therapy modification

ARIPiprazole Lauroxil: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Please refer to the full interaction monograph for details concerning the recommended dose adjustments. Consider therapy modification

Astemizole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Astemizole. Avoid combination

Asunaprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Asunaprevir. Avoid combination

AtorvaSTATin: Clarithromycin may increase the serum concentration of AtorvaSTATin. Management: Limit atorvastatin to a maximum dose of 20 mg/day (for adults) when used with clarithromycin. If this combination is used, monitor patients more closely for evidence of atorvastatin toxicity. Consider therapy modification

Avanafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil. Avoid combination

Axitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Axitinib. Management: Avoid concurrent use of axitinib with any strong CYP3A inhibitor whenever possible. If a strong CYP3A inhibitor must be used with axitinib, a 50% axitinib dose reduction is recommended. Avoid combination

Barnidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Barnidipine. Avoid combination

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Bedaquiline: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bedaquiline. Management: Limit the duration of concomitant administration of bedaquiline with CYP3A4 inhibitors to no more than 14 days, unless the benefit of continued administration is judged to outweigh the possible risks. Monitor for toxic effects of bedaquiline. Consider therapy modification

Blonanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Blonanserin. Avoid combination

Boceprevir: Clarithromycin may increase the serum concentration of Boceprevir. Boceprevir may increase the serum concentration of Clarithromycin. Monitor therapy

Bortezomib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bortezomib. Monitor therapy

Bosentan: May increase serum concentrations of the active metabolite(s) of Clarithromycin. Specifically, bosentan may increase concentrations of 14-hydroxyclarithromycin. Bosentan may decrease the serum concentration of Clarithromycin. Clarithromycin may increase the serum concentration of Bosentan. Management: Consider alternative antimicrobial if possible. The clinical activity of clarithromycin may be altered, and increased bosentan toxicity may be expected. Consider therapy modification

Bosutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bosutinib. Avoid combination

Bosutinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bosutinib. Avoid combination

Brentuximab Vedotin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Brexpiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual with a strong CYP3A4 inhibitor; reduce to 25% of usual if used with both a moderate CYP3A4 inhibitor and a CYP2D6 inhibitor, or if a strong CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Consider therapy modification

Brinzolamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brinzolamide. Monitor therapy

Bromocriptine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bromocriptine. Avoid combination

Budesonide (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Nasal). Monitor therapy

Budesonide (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Oral Inhalation). Monitor therapy

Budesonide (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Systemic). Management: Consider reducing the oral budesonide dose when used together with a CYP3A4 inhibitor or temporarily stopping budesonide therapy during CYP3A4 inhibitor use. Monitor patients closely for signs/symptoms of corticosteroid excess. Consider therapy modification

Budesonide (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification

BusPIRone: Macrolide Antibiotics may decrease the metabolism of BusPIRone. Consider therapy modification

Cabazitaxel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabazitaxel. Management: Concurrent use of cabazitaxel with strong inhibitors of CYP3A4 should be avoided when possible. If such a combination must be used, consider a 25% reduction in the cabazitaxel dose. Consider therapy modification

Cabergoline: Clarithromycin may increase the serum concentration of Cabergoline. Monitor therapy

Cabozantinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabozantinib. Avoid combination

Calcium Channel Blockers: Macrolide Antibiotics may decrease the metabolism of Calcium Channel Blockers. Management: Consider using a noninteracting macrolide. Felodipine Canadian labeling specifically recommends avoiding its use in combination with clarithromycin. Exceptions: Clevidipine. Consider therapy modification

Cannabis: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy

CarBAMazepine: May increase serum concentrations of the active metabolite(s) of Clarithromycin. Clarithromycin may increase the serum concentration of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Clarithromycin. Management: Consider alternatives to this combination when possible. If combined, monitor for increased carbamazepine effects/toxicities and for reduced clarithromycin efficacy. Consider therapy modification

Cardiac Glycosides: Macrolide Antibiotics may increase the serum concentration of Cardiac Glycosides. Monitor therapy

Cariprazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cariprazine. Management: Cariprazine dose reductions of 50% are required; specific recommended management varies slightly for those stable on cariprazine versus those just starting cariprazine. See prescribing information or full interaction monograph for details. Consider therapy modification

Ceritinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ceritinib. Management: If such combinations cannot be avoided, the ceritinib dose should be reduced by approximately one-third (to the nearest 150 mg). Resume the prior ceritinib dose after cessation of the strong CYP3A4 inhibitor. Avoid combination

Cilostazol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving strong inhibitors of CYP3A4. Consider therapy modification

Cisapride: Macrolide Antibiotics may decrease the metabolism of Cisapride. Avoid combination

Cobicistat: Clarithromycin may increase the serum concentration of Cobicistat. Cobicistat may increase the serum concentration of Clarithromycin. Management: Consider alternative antibiotics. Reduce clarithromycin dose by 50% in patients receiving elvitegravir/cobicistat/emtricitabine/tenofovir with estimated creatinine clearance 50 to 60 mL/min. Closely monitor for clarithromycin toxicity. Consider therapy modification

Cobimetinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cobimetinib. Avoid combination

Colchicine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Colchicine. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a strong CYP3A4 inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

Conivaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Conivaptan. Avoid combination

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Corticosteroids (Orally Inhaled): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Orally Inhaled). Management: Orally inhaled fluticasone propionate with a strong CYP3A4 inhibitor is not recommended. Exceptions: Beclomethasone (Oral Inhalation); Triamcinolone (Systemic). Monitor therapy

Corticosteroids (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Systemic). Exceptions: MethylPREDNISolone; PrednisoLONE (Systemic); PredniSONE. Monitor therapy

Crizotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Crizotinib. Avoid combination

CYP3A4 Inducers (Moderate): May increase serum concentrations of the active metabolite(s) of Clarithromycin. CYP3A4 Inducers (Moderate) may decrease the serum concentration of Clarithromycin. Management: Consider alternative antimicrobial therapy for patients receiving a CYP3A inducer. Drugs that enhance the metabolism of clarithromycin into 14-hydroxyclarithromycin may alter the clinical activity of clarithromycin and impair its efficacy. Consider therapy modification

CYP3A4 Inducers (Strong): May increase serum concentrations of the active metabolite(s) of Clarithromycin. Clarithromycin may increase the serum concentration of CYP3A4 Inducers (Strong). CYP3A4 Inducers (Strong) may decrease the serum concentration of Clarithromycin. Management: Consider alternative antimicrobial therapy for patients receiving a CYP3A inducer. Drugs that enhance the metabolism of clarithromycin into 14-hydroxyclarithromycin may alter the clinical activity of clarithromycin and may impair clarithromycin efficacy. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

CYP3A4 Substrates: CYP3A4 Inhibitors (Strong) may decrease the metabolism of CYP3A4 Substrates. Exceptions: Buprenorphine; Gefitinib; Hydrocodone. Consider therapy modification

Dabigatran Etexilate: Clarithromycin may increase the serum concentration of Dabigatran Etexilate. Management: Dose reductions and/or avoidance of this combination may be necessary. Specific recommendations vary by U.S. vs. Canadian labeling, renal function, and indication for dabigatran. Refer to full monograph or dabigatran labeling. Consider therapy modification

Dabrafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dabrafenib. Avoid combination

Daclatasvir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Daclatasvir. Management: Decrease the daclatasvir dose to 30 mg once daily if combined with a strong CYP3A4 inhibitor. No dose adjustment is needed when daclatasvir is used with darunavir/cobicistat. Consider therapy modification

Dapoxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dapoxetine. Avoid combination

Dasatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dasatinib. Management: Use of this combination should be avoided; consider reducing dasatinib dose if a strong CYP3A4 inhibitor must be used. If using dasatinib 100 mg/day, consider reduction to 20 mg/day; if using dasatinib 140 mg/day, consider reduction to 40 mg/day. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Dienogest: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dienogest. Monitor therapy

Dihydroergotamine: Clarithromycin may increase the serum concentration of Dihydroergotamine. Avoid combination

Disopyramide: Clarithromycin may enhance the hypoglycemic effect of Disopyramide. Clarithromycin may enhance the QTc-prolonging effect of Disopyramide. Clarithromycin may increase the serum concentration of Disopyramide. Avoid combination

Domperidone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Domperidone. Avoid combination

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronabinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronabinol. Monitor therapy

Dronedarone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronedarone. Avoid combination

Drospirenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Drospirenone. Monitor therapy

Dutasteride: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dutasteride. Monitor therapy

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Efavirenz: May decrease the serum concentration of Clarithromycin. Management: Consider using an alternative antibiotic, such as azithromycin, for patients taking efavirenz. If concomitant therapy cannot be avoided, monitor for decreased therapeutic effect of clarithromycin and increased incidence of skin rash. Consider therapy modification

Eletriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eletriptan. Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Eplerenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone. Avoid combination

Ergot Derivatives: Macrolide Antibiotics may increase the serum concentration of Ergot Derivatives. Cabergoline and Clarithromycin may interact, see specific monograph for full details. Exceptions: Cabergoline. Consider therapy modification

Ergotamine: Clarithromycin may increase the serum concentration of Ergotamine. Avoid combination

Erlotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Erlotinib. Management: Avoid use of this combination when possible. When the combination must be used, monitor the patient closely for the development of severe adverse reactions, and if such severe reactions occur, reduce the erlotinib dose (in 50 mg decrements). Consider therapy modification

Estazolam: Macrolide Antibiotics may increase the serum concentration of Estazolam. Management: Consider an alternative less likely to interact. Azithromycin is likely a lower-risk macrolide, and benzodiazepines less dependent on CYP3A metabolism (e.g., lorazepam, oxazepam) are similarly less likely to interact. Consider therapy modification

Etizolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Etizolam. Management: Consider use of lower etizolam doses when using this combination; specific recommendations concerning dose adjustment are not available. Monitor clinical response to the combination closely. Consider therapy modification

Etravirine: May decrease the serum concentration of Macrolide Antibiotics. Clarithromycin AUC is reduced and levels of the active metabolite (14-hydroxy-clarithromycin) are modestly increased. Management: For the treatment of Mycobacterium avium complex, consider changing to alternative agent, such as azithromycin. Consider therapy modification

Everolimus: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Everolimus. Avoid combination

FentaNYL: CYP3A4 Inhibitors (Strong) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary. Consider therapy modification

Fesoterodine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine. Management: Avoid fesoterodine doses greater than 4 mg daily in adult patients who are also receiving strong CYP3A4 inhibitors. Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Flibanserin. Avoid combination

FLUoxetine: Clarithromycin may enhance the QTc-prolonging effect of FLUoxetine. Clarithromycin may increase the serum concentration of FLUoxetine. Avoid combination

Fluticasone (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Nasal). Monitor therapy

Fluticasone (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Oral Inhalation). Management: Use of orally inhaled fluticasone propionate with strong CYP3A4 inhibitors is not recommended. Use of orally inhaled fluticasone furoate with strong CYP3A4 inhibitors should be done with caution. Monitor patients using such a combination more closely. Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Gefitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Gefitinib. Monitor therapy

GlipiZIDE: Clarithromycin may increase the serum concentration of GlipiZIDE. Monitor therapy

GlyBURIDE: Clarithromycin may increase the serum concentration of GlyBURIDE. Monitor therapy

GuanFACINE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when starting this combination. Consider therapy modification

Halofantrine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine. Avoid combination

Highest Risk QTc-Prolonging Agents: Moderate Risk QTc-Prolonging Agents may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Hydrocodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Hydrocodone. Monitor therapy

Ibrutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ibrutinib. Management: If a strong CYP3A inhibitor must be used short-term (e.g. antifungals and antibiotics for 7 days or less), consider stopping ibrutinib until the CYP3A inhibitor is no longer needed. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ifosfamide: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Imatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imatinib. Monitor therapy

Imidafenacin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imidafenacin. Monitor therapy

Irinotecan Products: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Irinotecan Products. Avoid combination

Isavuconazonium Sulfate: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inhibitors (Strong) may increase isavuconazole serum concentrations. Management: Combined use is considered contraindicated per US labeling. Lopinavir/ritonavir (and possibly other uses of ritonavir doses less than 400 mg every 12 hours) is treated as a possible exception to this contraindication despite strongly inhibiting CYP3A4. Avoid combination

Ivabradine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivabradine. Avoid combination

Ivabradine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Ivacaftor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult prescribing information for specific age- and weight-based recommendations. Consider therapy modification

Ixabepilone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ixabepilone. Consider therapy modification

Lacosamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lacosamide. Monitor therapy

Lapatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lapatinib. Management: If an overlap in therapy cannot be avoided, consider reducing lapatinib adult dose to 500 mg/day during, and within 1 week of completing, treatment with the strong CYP3A4 inhibitor. Avoid combination

Ledipasvir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ledipasvir. Monitor therapy

Lercanidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lercanidipine. Avoid combination

Levobupivacaine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine. Monitor therapy

Levomilnacipran: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levomilnacipran. Management: Do not exceed a maximum adult levomilnacipran dose of 80 mg/day in patients also receiving strong CYP3A4 inhibitors. Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lomitapide. Avoid combination

Lopinavir: Clarithromycin may enhance the QTc-prolonging effect of Lopinavir. Lopinavir may diminish the therapeutic effect of Clarithromycin. Specifically, lopinavir may decrease the formation of the active 14-hydroxy-clarithromycin metabolite, which may negatively impact clarithromycin effectiveness. Lopinavir may increase the serum concentration of Clarithromycin. Clarithromycin may increase the serum concentration of Lopinavir. Avoid combination

Lovastatin: Clarithromycin may increase the serum concentration of Lovastatin. Avoid combination

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Lurasidone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lurasidone. Avoid combination

Macitentan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Macitentan. Avoid combination

Maraviroc: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Maraviroc. Management: Reduce the adult dose of maraviroc to 150 mg twice daily when used with a strong CYP3A4 inhibitor. Do not use maraviroc with strong CYP3A4 inhibitors in patients with Clcr less than 30 mL/min. Consider therapy modification

MedroxyPROGESTERone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MedroxyPROGESTERone. Monitor therapy

MethylPREDNISolone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose reduction in patients receiving strong CYP3A4 inhibitors and monitor for increased steroid related adverse effects. Consider therapy modification

Midazolam: Macrolide Antibiotics may increase the serum concentration of Midazolam. Management: Consider an alternative less likely to interact. Azithromycin is likely a lower-risk macrolide, and benzodiazepines less dependent on CYP3A metabolism (e.g., lorazepam, oxazepam) are similarly less likely to interact. Consider therapy modification

Mifepristone: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Moderate Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Naloxegol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naloxegol. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Nilotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nilotinib. Avoid combination

NiMODipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of NiMODipine. Avoid combination

Nintedanib: Combined Inhibitors of CYP3A4 and P-glycoprotein may increase the serum concentration of Nintedanib. Monitor therapy

Nisoldipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nisoldipine. Avoid combination

Olaparib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Olaparib. Management: Avoid use of strong CYP3A4 inhibitors in patients being treated with olaparib. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 150 mg twice daily. Avoid combination

Osimertinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Osimertinib. Avoid combination

Ospemifene: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ospemifene. Monitor therapy

Oxybutynin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Oxybutynin. Monitor therapy

OxyCODONE: CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Strong) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite oxymorphone may also be increased. Consider therapy modification

Palbociclib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Palbociclib. Avoid combination

Panobinostat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Panobinostat. Management: Reduce the panobinostat dose to 10 mg when it must be used with a strong CYP3A4 inhibitor. Consider therapy modification

Parecoxib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Parecoxib. Monitor therapy

Paricalcitol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Paricalcitol. Monitor therapy

PARoxetine: Clarithromycin may enhance the adverse/toxic effect of PARoxetine. Clarithromycin may enhance the QTc-prolonging effect of PARoxetine. Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Pimecrolimus: CYP3A4 Inhibitors (Strong) may decrease the metabolism of Pimecrolimus. Monitor therapy

Pimozide: Macrolide Antibiotics may enhance the QTc-prolonging effect of Pimozide. Macrolide Antibiotics may decrease the metabolism of Pimozide. This mechanism may not apply to azithromycin. Avoid combination

Pimozide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimozide. Avoid combination

Pitavastatin: Clarithromycin may increase the serum concentration of Pitavastatin. Monitor therapy

PONATinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PONATinib. Management: Per ponatinib U.S. prescribing information, the adult starting dose of ponatinib should be reduced to 30 mg daily during treatment with any strong CYP3A4 inhibitor. Consider therapy modification

Pranlukast: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pranlukast. Monitor therapy

Prasugrel: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel. Monitor therapy

Pravastatin: Clarithromycin may increase the serum concentration of Pravastatin. Management: Limit pravastatin to a maximum of 40 mg/day (for adults) when used in combination with clarithromycin. If this combination is used, monitor patients more closely for evidence of pravastatin toxicity. Consider therapy modification

PrednisoLONE (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of PrednisoLONE (Systemic). Monitor therapy

PredniSONE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PredniSONE. Monitor therapy

Protease Inhibitors: May diminish the therapeutic effect of Clarithromycin. Specifically, certain protease inhibitors may decrease formation of the active 14-hydroxy-clarithromycin metabolite, which may negatively impact clarithromycin effectiveness vs. H. influenzae and other non-MAC infections. Protease Inhibitors may increase the serum concentration of Clarithromycin. Clarithromycin dose adjustment in renally impaired patients may be needed. Clarithromycin may increase the serum concentration of Protease Inhibitors. Management: Avoid clarithromycin adult doses greater than 1000 mg/day when used with a protease inhibitor. Further dose reductions may be needed in patients with impaired renal function. Consider alternative antimicrobial for any non-MAC infection. Consider therapy modification

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

QUEtiapine: Clarithromycin may enhance the QTc-prolonging effect of QUEtiapine. Clarithromycin may increase the serum concentration of QUEtiapine. Avoid combination

QuiNINE: Macrolide Antibiotics may increase the serum concentration of QuiNINE. Avoid combination

Ramelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ramelteon. Monitor therapy

Ranolazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ranolazine. Avoid combination

Reboxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Reboxetine. Consider therapy modification

Red Yeast Rice: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Red Yeast Rice. Specifically, concentrations of lovastatin and related compounds found in Red Yeast Rice may be increased. Avoid combination

Regorafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Regorafenib. Avoid combination

Repaglinide: Macrolide Antibiotics may increase the serum concentration of Repaglinide. Monitor therapy

Repaglinide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Repaglinide. Management: The addition of a CYP2C8 inhibitor to this drug combination may substantially increase the magnitude of increase in repaglinide exposure. Monitor therapy

Retapamulin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Retapamulin. Management: Avoid this combination in patients less than 2 years old. No action is required in other populations. Monitor therapy

Rifaximin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Rifaximin. Monitor therapy

Rilpivirine: Macrolide Antibiotics may increase the serum concentration of Rilpivirine. Management: Consider the use of azithromycin or another non-macrolide alternative when appropriate to avoid this potential interaction. Consider therapy modification

Rivaroxaban: Clarithromycin may increase the serum concentration of Rivaroxaban. Management: In patients with impaired renal function, clarithromycin should not be used unless the potential benefits outweigh the potential risks. This interaction is unlikely clinically significant in patients with normal renal function. Consider therapy modification

RomiDEPsin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of RomiDEPsin. Monitor therapy

Ruxolitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ruxolitinib. Management: This combination should be avoided under some circumstances. See monograph for details. Consider therapy modification

Salmeterol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Salmeterol. Avoid combination

Saxagliptin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Saxagliptin. Management: Saxagliptin U.S. product labeling recommends limiting saxagliptin adult dose to 2.5 mg/day when used with a strong CYP3A4 inhibitor. Monitor for increased saxagliptin levels/effects. A similar recommendation is not made in the Canadian product labeling. Consider therapy modification

Sildenafil: Clarithromycin may increase the serum concentration of Sildenafil. Consider therapy modification

Silodosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Silodosin. Avoid combination

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simeprevir. Avoid combination

Simvastatin: Clarithromycin may increase the serum concentration of Simvastatin. Avoid combination

Sirolimus: Macrolide Antibiotics may decrease the metabolism of Sirolimus. Consider therapy modification

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

Sonidegib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sonidegib. Avoid combination

SORAfenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SORAfenib. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Suvorexant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Suvorexant. Avoid combination

Tacrolimus (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tacrolimus (Systemic). Management: Monitor clinical tacrolimus response closely and frequently monitor tacrolimus serum concentrations with concurrent use of any strong CYP3A4 inhibitor. Tacrolimus dose reductions and/or prolongation of the dosing interval will likely be required. Consider therapy modification

Tacrolimus (Topical): Macrolide Antibiotics may increase the serum concentration of Tacrolimus (Topical). Monitor therapy

Tadalafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tadalafil. Management: Recommendations regarding use of tadalafil in patients also receiving strong CYP3A4 inhibitors may vary based on indication and/or international labeling. Consult appropriate product labeling. Consider therapy modification

Tamsulosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Avoid combination

Tasimelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tasimelteon. Monitor therapy

Telaprevir: Clarithromycin may increase the serum concentration of Telaprevir. Telaprevir may increase the serum concentration of Clarithromycin. Monitor therapy

Temsirolimus: Macrolide Antibiotics may enhance the adverse/toxic effect of Temsirolimus. Levels of sirolimus, the active metabolite, may be increased, likely due to inhibition of CYP-mediated metabolism. Consider therapy modification

Terfenadine: Macrolide Antibiotics may enhance the QTc-prolonging effect of Terfenadine. Macrolide Antibiotics may increase the serum concentration of Terfenadine. Avoid combination

Terfenadine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Terfenadine. Avoid combination

Tetrahydrocannabinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Theophylline Derivatives: Macrolide Antibiotics may decrease the metabolism of Theophylline Derivatives. Exceptions: Dyphylline. Consider therapy modification

Ticagrelor: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ticagrelor. Avoid combination

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofacitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tofacitinib. Management: Reduce the adult dose of tofacitinib to 5 mg daily in patients receiving strong CYP3A4 inhibitors. Consider therapy modification

Tolterodine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolterodine. Management: The maximum recommended adult dose of tolterodine is 2 mg/day when used together with a strong CYP3A4 inhibitor. Consider therapy modification

Tolvaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolvaptan. Avoid combination

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Toremifene: CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of Toremifene. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Toremifene. Avoid combination

Trabectedin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Trabectedin. Avoid combination

TraMADol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of TraMADol. Monitor therapy

TraZODone: May enhance the QTc-prolonging effect of Clarithromycin. Clarithromycin may increase the serum concentration of TraZODone. Management: Consider an alternative to this combination whenever possible. If combined, use a lower trazodone dose and monitor for increased effects of trazodone. Consider therapy modification

Triazolam: Macrolide Antibiotics may increase the serum concentration of Triazolam. Management: Consider an alternative less likely to interact. Azithromycin is likely a lower-risk macrolide, and benzodiazepines less dependent on CYP3A metabolism (e.g., lorazepam, oxazepam) are similarly less likely to interact. Consider therapy modification

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Ulipristal: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combo should be monitored for ulipristal toxicity. Avoid combination

Vardenafil: Clarithromycin may increase the serum concentration of Vardenafil. Management: Recommendations regarding the concomitant use of vardenafil with clarithromycin vary between international labelings and between commercially available vardenafil brand name products (Levitra, Staxyn). Consult appropriate product labelings. Consider therapy modification

Vemurafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vemurafenib. Avoid combination

Vilazodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilazodone. Management: Limit maximum adult vilazodone dose to 20 mg/day in patients receiving strong CYP3A4 inhibitors. The original vilazodone dose can be resumed following discontinuation of the strong CYP3A4 inhibitor. Consider therapy modification

VinCRIStine (Liposomal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vitamin K Antagonists (eg, warfarin): Macrolide Antibiotics may increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Vorapaxar: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vorapaxar. Avoid combination

Zidovudine: Clarithromycin may enhance the myelosuppressive effect of Zidovudine. Clarithromycin may decrease the serum concentration of Zidovudine. Management: Monitor response to zidovudine closely when used with clarithromycin, and consider staggering zidovudine and clarithromycin doses when possible in order to minimize the potential for interaction. Consider therapy modification

Zopiclone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zopiclone. Management: The initial starting adult dose of zopiclone should not exceed 3.75 mg if combined with a strong CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification

Adverse Reactions

1% to 10%:

Central nervous system: Headache (2%), insomnia

Dermatologic: Skin rash (children 3%)

Gastrointestinal: Dysgeusia (adults 3% to 7%), vomiting (children 6%), diarrhea (3% to 6%), nausea (adults 3%), abdominal pain (2% to 3%), dyspepsia (adults 2%)

Hematologic & oncologic: Prolonged prothrombin time (adults 1%)

Hepatic: Abnormal hepatic function tests

Hypersensitivity: Anaphylactoid reaction

Infection: Candidiasis (including oral)

Renal: Increased blood urea nitrogen (4%)

<1% (Limited to important or life-threatening): Acne vulgaris, ageusia, altered sense of smell, anxiety, asthma, atrial fibrillation, behavioral changes, cardiac arrest, cellulitis, cholestatic hepatitis, Clostridium difficile associated diarrhea, Clostridium difficile (colitis), dental discoloration (reversible with dental cleaning), depression, disorientation, DRESS syndrome, drowsiness, dyskinesia, epistaxis, esophagitis, extrasystoles, gastritis, gastroesophageal reflux disease, glossitis, hallucination, hearing loss (reversible), hemorrhage, hepatic failure, hepatotoxicity (idiosyncratic) (Chalasani, 2014), hyperhidrosis, hypersensitivity, hypoglycemia, IgA vasculitis, increased gamma-glutamyl transferase, increased INR, increased lactate dehydrogenase, interstitial nephritis, leukopenia, loss of consciousness, malaise, manic behavior, neck stiffness, neutropenia, pancreatitis, parasominas, paresthesia, prolonged QT interval on ECG, pruritus, pseudomembranous colitis, pulmonary embolism, renal failure, rhabdomyolysis, seizure, Stevens-Johnson syndrome, stomatitis, thrombocytopenia, tinnitus, tongue discoloration, torsades de pointes, vaginal infection, ventricular arrhythmia, ventricular tachycardia

Warnings/Precautions

Concerns related to adverse effects:

• Altered cardiac conduction: Use has been associated with QT prolongation and infrequent cases of arrhythmias, including torsade de pointes; use with caution in patients at risk of prolonged cardiac repolarization; avoid use in patients with uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and patients receiving Class IA (eg, quinidine, procainamide) or Class III (eg, amiodarone, dofetilide, sotalol) antiarrhythmic agents.

• Hepatic effects: Elevated liver function tests and hepatitis (hepatocellular and/or cholestatic with or without jaundice) have been reported; usually reversible after discontinuation of clarithromycin. May lead to hepatic failure or death (rarely), especially in the presence of preexisting diseases and/or concomitant use of medications. Discontinue immediately if symptoms of hepatitis (eg, anorexia, jaundice, abdominal tenderness, pruritus, dark urine) occur.

• Hypersensitivity reactions: Severe acute reactions have been reported, including anaphylaxis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms (DRESS), and Henoch-Schönlein purpura (IgA vasculitis); discontinue therapy and initiate treatment immediately for severe acute hypersensitivity reactions.

• Superinfection: Use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Coronary artery disease (CAD): Use with caution in patients with CAD; postmarketing safety trial suggests increased risk of cardiovascular mortality with short-term clarithromycin use (vs placebo) in patients with stable CAD. However, more smokers were randomized to the clarithromycin arm (Jespersen 2006).

• Myasthenia gravis: Use with caution in patients with myasthenia gravis; exacerbation of symptoms and new onset of symptoms has occurred.

• Porphyria: Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of acute porphyria.

• Renal impairment: Dosage adjustment required with severe renal impairment. Clarithromycin in combination with ranitidine bismuth citrate is not recommended in patients with CrCl <25 mL/min.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution; systemic exposure is increased. Elderly patients may be at increased risk of torsade de pointes, particularly if concurrent severe renal impairment.

• HIV patients: Decreased survival has been observed in HIV patients with Mycobacterium avium complex (MAC) receiving clarithromycin doses above the maximum recommended dose; maximum recommended dosing should not be exceeded in this population. Development of resistance to clarithromycin has been observed when used as prophylaxis and treatment of MAC infection (Biaxin Canadian product labeling 2016).

Dosage form specific issues:

• Extended release formulation: The presence of extended release tablets in the stool has been reported, particularly in patients with anatomic (eg, ileostomy, colostomy) or functional GI disorders with decreased transit times. Consider alternative dosage forms (eg, suspension) or an alternative antimicrobial for patients with tablet residue in the stool and no signs of clinical improvement.

• Lactose: Some products may contain lactose

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007).

• Sucrose: Some products may contain sucrose; consider sucrose content when administering to diabetic patients.

Other warnings/precautions:

• Appropriate use: Helicobacter pylori eradication: Short-term combination therapy (≤7 days) has been associated with a higher incidence of treatment failure. Current guidelines recommend 10 to 14 days of therapy (triple or quadruple) for eradication of H. pylori in pediatric and adult patients (Chey 2007; NASPHGAN [Koletzko 2011]).

Monitoring Parameters

CBC with differential, BUN, creatinine; perform culture and sensitivity studies prior to initiating drug therapy as appropriate

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been documented in some animal reproduction studies. Clarithromycin crosses the placenta (Witt 2003). The manufacturer recommends that clarithromycin not be used in a pregnant woman unless there are no alternative therapies. Clarithromycin is generally not recommended for the treatment or prophylaxis of Mycobacterium avium complex (MAC) or bacterial respiratory disease in HIV-infected pregnant patients (HHS [opportunistic; adult] 2015).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience abdominal pain, change in taste, nausea, vomiting, or diarrhea. Have patient report immediately to prescriber rash, enlarged lymph nodes, muscle pain, joint pain, tachycardia, severe dizziness, passing out, muscle weakness, angina, signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of a severe pulmonary disorder (lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse), arrhythmia, signs of Clostridium difficile (C. diff)-associated diarrhea (stomach pain or cramps, very loose or watery stools, or bloody stools), signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), or tablet shell in stool (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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