Clarithromycin

	Zambia HIV National Guidelines
	Introduction HIV Counseling and Testing Sexually Transmitted Infections (STIs) General Principles of Antiretroviral Therapy for Chronic HIV Infection in Adults and Adolescents When to Start ARV Therapy for Chronic HIV Infection in Adults and Adolescents Initial Regimen for ARV Therapy Adherence Baseline evaluation and Monitoring Calculations: Ideal Body Weight, Body Mass Index and Creatinine Clearance ARV Therapy for Individuals with Tuberculosis Co-Infection Adverse Effects and Toxicity Immune Reconstitution Inflammatory Syndrome (IRIS) Changing or Stopping ART Treatment Failure Stopping ARV Therapy Post Exposure Prophylaxis Cotrimoxazole Prophylaxis WHO Staging in Adults and Adolescents Nutrition Care and Support Palliative Care in HIV and AIDS
	Guide Editors
	Editor In Chief Joel E. Gallant, MD, MPH Pharmacology Editor Paul Pham, PharmD, BCPS Zambia Guideline Team Peter Mwaba MMed PhD FRCP Alywn Mwinga MMed Isaac Zulu MMed MPH Velepie Mtonga MMed Albert Mwango MBChB Jabbin Mulwanda MMed FCS

Drugs>Antimicrobial Agents>

Clarithromycin

Paul A. Pham Pharm.D, and John G. Bartlett M.D.
03-18-2009

Zambia Specific Information

Available formulation in Zambia: 250 mg; 500 mg tablets.
MAC: clarithromycin 500 mg PO q12h plus ethambutol. Rifabutin not routinely available or recommended.

REFERENCES

Zambia Information Author: Paul A. Pham, Pharm. D.

INDICATIONS

FDA

Pharyngitis and tonsillitis
Acute maxillary sinusitis
Acute bacterial exacerbation of chronic bronchitis
Community acquired pneumonia
Acute otitis media
Uncomplicated skin and skin structure infections
Treatment of disseminated mycobacterial infections due to complex
Prophylaxis of Mycobacterium avium complex
Treatment of active duodenal ulcer associated with H. pylori infection (in combination with omeprazole or ranitidine bismuth citrate; amoxicillin and lansoprazole or omeprazole as triple therapy)

NON-FDA APPROVED USES

Bartonella infection

FORMS

brand name	generic	Mfg	brand forms	cost*
Biaxin	Clarithromycin	Abbott, Ranbaxy	oral tablet 250 mg	$4.52
			oral tablet 500 mg	$5.86
			oral suspension 125 mg/5 ml (50 ml and 100 ml bottle)	$43.02 (100 ml bottle)
			oral suspension 250 mg/5 ml (50 ml and 100 ml bottle)	$81.99 (100 ml bottle)
Biaxin XL	Clarithromycin	Abbott	oral XL tablet 500 mg	$6.62
Clarithromycin	Clarithromycin	Various generic manufacturers	oral tablet 250 mg	$5.86
			oral tablet 500 mg	$5.86
			oral suspension 125 mg/5ml (50 ml and 100 ml bottle)	$43.02 (100 ml bottle)
			oral suspension 250 mg/5ml (50 ml and 100 ml bottle)	$81.99 (100 ml bottle)

*Prices represent cost per unit specified and are representative of "Average Wholesale Price" (AWP). AWP Prices were obtained and gathered by Lakshmi Vasist Pharm D using the Red Book, manufacturer's information, and the McKesson database.

^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

MAC prophylaxis: 500 mg PO twice-daily (azithromycin 1200 mg q wk preferred)
MAC treatment: 500 mg PO twice-daily or 1000 mg XL once-daily (in combination with ethambutol) x 1 yr and treat until immune reconstitution (CD4 >100 x 6 mos)
Infections due to H influenzae and H. parainfluenzae: 500 mg twice-daily x 7-14d.
Community acquired pneumonia, pharyngitis, tonsillitis, otitis media, and uncomplicated soft tissue infections: 250-500 mg twice-daily or 1000 mg XL once-daily x 7d.
Peptic ulcer disease due to H. pylori: 500 mg in combination with PPI and amoxicillin twice-daily x 10-14 d.
Acute bacterial sinusitis: 500 mg twice-daily or 1000 mg XL once-daily w/ food x 7-14d
Acute exacerbation of chronic bronchitis: 500 mg twice-daily or 1000 mg XLonce-daily w/ food x 7d

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

Usual dose

DOSING FOR GLOMERULAR FILTRATION OF 10-50

50% of dose (500 mg q24h) with Cr clearance <30ml/min; especially important with boosted-PI co-administration.

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

0.25-0.5 gm q24h

DOSING IN HEMODIALYSIS

500 mg every day; on days of dialysis dose post-dialysis

DOSING IN PERITONEAL DIALYSIS

No data. Consider 250-500mg po q24h .

DOSING IN HEMOFILTRATION

No data. Consider 500 mg po q24h .

ADVERSE DRUG REACTIONS

OCCASIONAL

GI intolerance (diarrhea, nausea, vomiting)
Metallic taste
Transaminases elevation

RARE

Headache
Reversible hearing loss and tinnitus
C. difficile colitis
Rash

DRUG INTERACTIONS

Clarithromycin is a substrate and inhibitor of CYP3A4.

APV or FPV: APV AUC increased by 18% (studied with APV). Clarithromycin not affected by unboosted APV. No dose adjustment needed. See RTV for dose adjustment with FPV/r.
ATV: ATV AUC increased by 28%. Clarithromycin AUC increased by 94%. QTc prolongation observed with co-administration. 50% of clarithromycin dose recommended when co-administered with ATV. Use azithromycin. Further dose adjustment needed with moderate to severe renal insufficiency and ESRD, no specific dosing guidelines consider:Cr clearance 30-60ml/min: 250 mg q24h. Cr clearance <30ml/min: 250 mg every other day.
DLV: Clarithromycin AUC increased by 100%. DLV AUC increased by 44%. Dose adjustment recommended with impaired renal function. Clarithromycin dose: Cr clearance 30-60ml/min=500 mg q24. Cr clearance <30ml/min=250 mg q24.
EFV: clarithromycin AUC decreased by 39%. Clinical significance unknown. High incidence of rash seen in healthy volunteer receiving this combination. Consider azithromycin.
NVP: clarithromycin AUC decreased by 29% but 14-hydroxy clarithromycin (active metabolite) AUC increased by 27%. NVP AUC increased by 26%. No dose adjustment needed.
RTV: clarithromycin AUC increased by 77%, Cmin increased by 182%. Reduce clarithromycin dose by 50% in end stage renal disease. Consider using azithromycin.
SQV: clarithromycin increases SQV AUC by 177% and SQV increases clarithromycin AUC by 45%. See RTV for dose adjustment with SQV/r.
LPV/r: may increase clarithromycin serum level. Decrease dose of clarithromycin by 50% in ESRD.
Theophylline: may increase theophylline serum levels. Monitor serum level with dose adjustment.
Alfuzosin, ranolazine, pimozide, cisapride, astemizole and terfenadine: contraindicated
Ergot Alkaloid: avoid co-administration
Warfarin: may increase anticoagulant effect of warfarin. Monitor INR closely.
Cyclosporine: may increase cyclosporine serum levels. Monitor closely.
Benzodiazepines (alprazolam, diazepam, midazolam, triazolam): may increase benzodiazepines serum concentrations. Use alternative benzodiazepines (i.e lorazepam, oxazepam, temazepam).
Carbamazepine: carbamazepine serum levels increased by 60%. Avoid or use with close monitoring of carbamazepine levels with appropriate dose adjustment.
Rifampin: contraindicated
Rifabutin: clarithromycin AUC decreased by 44% and 14-hydroxy-clarithromycin increased by 57%. 14-hydroxy metabolite has less activity against MAC. Rifabutin AUC increased by 56%. Consider using azithromycin.
Digoxin: case reports of digoxin toxicity. Monitor closely with co-administration.
Amiodarone: may increase amiodarone serum levels. Monitor closely with proper dose adjustment.
TPV/r: clarithromycin increases TPV AUC by 66% and TPV/r increases clarithromycin AUC by 19%. Adjust clarithromycin dose according to renal function: CrCl >60 ml/min=500 mg q12h; CrCl 30-60 ml/min=500 mg po q24h; CrCl <30 ml.min=250 mg po q24h. Consider azithromycin.
DRV/r: clarithromycin did not affect DRV AUC, but DRV increases clarithromycin AUC by 57%. Adjust clarithromycin dose according to renal function: CrCl >60 ml/min=500 mg q12h; CrCl 30-60 ml/min=500 mg po q24h; CrCl <30 ml.min=250 mg po q24h. Consider azithromycin.
Lovastatin and simvastatin: may significantly increase lovastatin and simvastatin serum concentrations. Consider pravastatin with co-administration.
Fentanyl: may significantly increase fentanyl serum concentrations. Avoid co-administration. Consider morphine.
Tacrolimus, sirolimus, cyclosporine: may significantly increase immunosuppressants serum concentrations. Monitor closely with dose adjustments.
Etravirine (ETR): clarithromycin AUC decreased 39%, but active OH-clarithromycin increased 21%. ETR AUC increased 42%. Consider azithromycin for MAC infection.
Maraviroc (MVC): clarithromycin serum concentrations not affected. MVC may be increased. Dose: MVC 150 mg twice-daily.
NFV: no data.
IDV: clarithromycin AUC increased 53% and IDV AUC increased 29%. Reduce clarithromycin dose by 50% in end stage renal disease.
Raltegravir: interaction unlikely. Use standard dose.

Drug-to-Drug Interactions

Drug-to-Drug Interaction

Drug	Effect of Interaction	Recommendations/Comments
Atazanavir (ATV)	ATV AUC increased by 28%. Clarithromycin AUC increased by 94%. QTc prolongation has been observed with co-administration.	Consider azithromycin or reduce clarithromycin dose by 50%. Further renal dose adjustment is required but not outlined by specific guidelines. Suggestion: CrCl 30-60 mL/min, 250 mg q24h; CrCl < 30 mL/min, 250 mg q48h.
Efavirenz (EFV)	Clarithromycin AUC decreased by 39%. Clinical significance unknown although high incidence of rash was observed in healthy volunteers with co-administration.	Consider azithromycin .
Fosamprenavir (FPV)	FPV AUC increased by 18% (studied with APV). Clarithromycin AUC not affected.	No dose adjustment necessary.
Nevirapine (NVP)	NVP AUC increased by 26%. Clarithromycin AUC decreased by 29%. 14-hydroxyclarithromycin (active metabolite, though not as effective against MAC ) AUC increased by 27%.	No dose adjustment necessary.
Ritonavir (RTV)	Clarithromycin AUC increased by 77% and Cmin increased by 182%.	Consider azithromycin or reduce clarithromycin dose by 50%. Further renal dose adjustment is required but not outlined by specific guidelines.
Saquinavir (SQV)	SQV AUC increased by 177%. Clarithromycin AUC increased by 45%.	No dose adjustment necessary. See RTV for SQV/r.
Alfuzosin	Risk of QTc prolongation increased.	Contraindicated.
Alprazolam	Alprazolam serum levels may be increased.	Consider lorazepam , oxazepam , or temazepam.
Amiodarone	Amiodarone serum levels may be increased.	Monitor.
Amprenavir (APV)	APV AUC increased by 18%. Clarithromycin AUC not affected.	No dose adjustment necessary.
Astemizole	Risk of QTc prolongation increased.	Contraindicated.
Carbamazepine	Carbamazepine serum levels increased by 60%.	Avoid co-administration or monitor serum level.
Cisapride	Risk of QTc prolongation increased.	Contraindicated.
Cyclosporine	Cyclosporine serum levels may be increased.	Monitor.
Delavirdine (DLV)	DLV AUC increased by 44%. Clarithromycin AUC increased by 100%.	Consider azithromycin or reduce clarithromycin dose by 50%. Further renal dose adjustment is required but not outlined by specific guidelines. Suggestion: CrCl 30-60 mL/min, 500 mg q24h; CrCl < 30 mL/min, 250 mg q24h.
Diazepam	Diazepam serum levels may be increased.	Consider lorazepam , oxazepam , or temazepam.
Digoxin	Digoxin serum levels may be increased. Increased digoxin toxicity has been reported with co-administration.	Monitor serum level.
DRV/r	Clarithromycin AUC increased by 57%.	Consider azithromycin .
Ergot alkaloids	Risk of ergotism increased.	Avoid co-administration.
ETR	ETR AUC increased 42%. Clarithromycin AUC decreased 39%. 14-hydroxyclarithromycin (active metabolite, though not as effective against MAC ) AUC increased 21%.	Consider azithromycin .
Fentanyl	Fentanyl serum levels may be increased.	Consider morphine .
IDV	IDV AUC increased 295%. Clarithromycin AUC increased 53%.	No dose adjustment necessary.
Lopinavir (LPV)	Clarithromycin AUC may be increased.	No dose adjustment necessary. See RTV for LPV/r.
Lovastatin	Lovastatin serum levels may be increased.	Consider pravastatin .
Midazolam	Midazolam serum levels may be increased.	Consider lorazepam , oxazepam , or temazepam.
MVC	MVC serum levels may be increased.	MVC 150 mg bid.
Pimozide	Risk of QTc prolongation increased.	Contraindicated.
Raltegravir	No data but an interaction is unlikely.	No dose adjustment necessary.
Ranolazine	Risk of QTc prolongation increased.	Contraindicated.
Rifabutin	Rifabutin AUC increased by 56%. Clarithromycin AUC decreased by 44%. 14-hydroxyclarithromycin (active metabolite, though not as effective against MAC ) AUC increased by 57%.	Consider azithromycin .
Rifampin	Rifampin AUC increased 99% and Cmax increased 69%. Clarithromycin AUC decreased 44% and Cmax decreased 41%. Increased rifampin toxicity has been observed with co-administration.	Avoid co-administration.
Simvastatin	Simvastatin serum levels may be increased.	Consider pravastatin .
Sirolimus	Sirolimus serum levels may be increased.	Monitor serum level.
Tacrolimus	Tacrolimus serum levels may be increased.	Monitor serum level.
Terfenadine	Risk of QTc prolongation increased.	Contraindicated.
Theophylline	Theophylline serum levels may be increased.	Monitor serum level.
TPV/r	TPV AUC increased by 66%. Clarithromycin AUC increased by 19%.	Consider azithromycin .
Triazolam	Triazolam serum levels may be increased.	Consider lorazepam , oxazepam , or temazepam.
Warfarin	Anticoagulation may be increased.	Monitor INR.

SPECTRUM

Detailed Spectrum of Activity

RESISTANCE

S. pneumoniae macrolide resistance ~26% but clinical significance unclear (esp. with intermediate resistance); treatment failures reported.
Use of clarithromycin monotherapy for MAC infection in HIV associated with high rates of resistance. Combination therapy (usually with ethambutol +/- rifabutin) recommended. Drug sensitivity testing may help guide therapy but clinical significance unclear.

PHARMACOLOGY

Pharmacology

COMMENTS

Clarithromycin important component in treatment of MAC and other MOTT infections. More active than azithromycin against MAC and is preferred macrolide for treatment of disseminated MAC infection, but azithromycin can be considered if intolerant to clarithromycin. Weekly azithromycin preferred for MAC prophylaxis because of weekly dosing and lower cost.

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Abbreviations