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 Zambia HIV National Guidelines
 


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 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>Antiretrovirals>
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Ritonavir

Paul A. Pham, Pharm.D. and John G. Bartlett, M.D.
11-01-2010

Zambia Specific Information

  • Available formulation in Zambia: Oral liquid: 400 mg/5 ml. Oral capsules: 100 mg.
  • RTV (100-200mg/d) is generally used as a pharmacokinetic enhancer.
  • Minimum of RTV 400 mg twice-daily needed for antiviral activity, but GI intolerance and high cost limit routine use.
  • Store capsules in the refrigerator at 2-8º C (36-46º F). May store capsules out of refrigerator (at less than 25º C or 77º F) for up to 30 days. Protect from light and excessive heat.
  • Potent inhibitor of CYP3A4 with many drug-drug interactions. See contraindicated medications under the drug interaction section.
Zambia Information Author: Paul A. Pham, Pharm.D.

INDICATIONS

FDA

  • Treatment of HIV-infection in combination with other antiretrovirals.
  • Pharmacokinetic enhancement of APV, ATV, DRV, FPV, SQV, TPV, and LPV.
NON-FDA APPROVED USES

  • Pharmacokinetic enhancement of IDV

FORMS

brand 
name
 
generic 
Mfg 
brand 
forms
 
cost* 
Norvir Ritonavir (RTV)Abbottoral
soft gel capsule
100 mg
$10.29
      oral
solution
80 mg/mL
$216.03/80mL

*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

Pill burden: 1-8 caps/d (typically 1-4 caps/d based on doses of 100 mg once-daily to200 mg twice-daily used to enhance PK of other PIs).

  • RTV 600 mg po twice-daily (FDA approved dose; rarely used due to severe GI intolerance).
  • With IDV: RTV 100 mg twice-daily + IDV 800 mg twice-daily (less GI intolerance but more nephrolithiasis), or RTV 200 mg twice-daily + IDV 800 mg twice-daily (highest incidence of nephrolithiasis, use only if EFV co-administered), or RTV 400 mg twice-daily + IDV 400 mg twice-daily (more GI intolerance, rarely used).
  • With SQV: RTV 100 mg twice-daily + SQV 1000 mg twice-daily , or RTV 400 mg twice-daily + SQV 400 mg twice-daily or RTV 100 mg once-daily + SQV 2000 mg once-daily (dose being studied in ART-naive pts) or RTV 400 mg twice-daily + SQV 400 mg twice-daily (high rate of GI intolerance, rarely used).
  • With APV: RTV 100 mg twice-daily + APV 700 mg twice-daily (FPV liquid preferred), or RTV 200 mg once-daily + APV 1400 mg once-daily (FPV liquid preferred)
  • With FPV: RTV 100 mg twice-daily + FPV 700 mg twice-daily , or RTV 100 or 200 mg once-daily + FPV 1400 mg once-daily (once-daily dosing for PI-naive pts only). RTV 300 mg once-daily + FPV 1400 mg once-daily when co-administered with EFV.
  • With ATV: RTV 100 mg once-daily + ATV 300 mg once-daily . (with EFV and ATV, use RTV 100 mg once-daily + ATV 400 mg once-daily : for pts without PI resistance)
  • With NFV: Not recommended. Combination of RTV 400 mg twice-daily + NFV 500-750 mg twice-daily has been studied, but limited data; high rate of GI intolerance with only marginal PK enhancement of NFV levels.
  • With NVP: standard dose for both drugs, but rarely used due to high rate of GI intolerance
  • With TPV : RTV 200 mg twice-daily + TPV 500 mg twice-daily.
  • With DRV: RTV 100 mg twice-daily + DRV 600 mg twice-daily OR RTV 100 mg once-daily + DRV 800 mg once-daily (PI-naive pts only)
  • With MVC: decrease MVC to 150 mg twice-daily.
  • With ETR: High dose RTV not recommended, but DRV/r, SQV/r, and LPV/r, may be co-administered at standard dose.
  • With RAL: no interaction; use standard doses of both drugs.

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

600 mg twice-daily (FDA dose; rarely used).

DOSING FOR GLOMERULAR FILTRATION OF 10-50

600 mg twice-daily (FDA dose; rarely used).

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

600 mg twice-daily (FDA dose; rarely used).

DOSING IN HEMODIALYSIS

Usual dose, dose post-HD (small amount removed in HD).

DOSING IN PERITONEAL DIALYSIS

No data: Usual dose likely, dose post.

DOSING IN HEMOFILTRATION

No data.

ADVERSE DRUG REACTIONS

COMMON

  • Severe GI intolerance (nausea, vomiting, and diarrhea).
  • Abdominal pain, common with 600 mg twice-daily dosing.
  • Taste perversion.
  • Asthenia.
  • Circumoral and peripheral paresthesias.
  • Lower doses used for PI boosting better tolerated.
OCCASIONAL

  • Lipodystrophy, especially fat accumulation.
  • Insulin resistance, hyperglycemia, and diabetes.
  • Hyperlipidemia: increased triglycerides and/or cholesterol.
  • Transaminase elevation (more common with RTV 400-600 mg twice-daily).
  • Association between RTV (and other PIs) and osteonecrosis/avascular necrosis has not been confirmed.
  • QTc and PR interval prolongation (with RTV 400 mg twice-daily). Use with caution in pts with structural heart disease or at risk for conduction system abnormalities.

DRUG INTERACTIONS

Substrate, potent inhibitor, and inducer of CYP3A4, CYP1A2, possibly CYP2C19 and, phase II glucuronidation and a mild CYP2D inhibitor. Generally increases serum levels of drugs that are CYP3A4 substrates although in some cases its inducing effects may also decrease serum levels of drugs that are substrate of CYP3A4, CYP1A2 and possibly CYP2C19. RTV may increase serum levels of drugs that are CYP2D6 substrates.

Drug-to-Drug Interactions

Drug-to-Drug Interaction

DrugEffect of InteractionRecommendations/Comments
Clarithromycin Clarithromycin AUC increased by 77%, Cmin increased by 182%.Reduce clarithromycin dose by 50% in end stage renal disease. May increase risk of QTc prolongation with RTV 400 mg twice-daily. Consider using azithro.
IDV IDV AUC increased by 2 to 5-fold. Cmin increased by 400%.Dosing recommendation: IDV 400 mg twice-daily and RTV 400 mg twice-daily ( more GI intolerance but less nephrolithiasis). IDV 800 mg twice-daily + RTV 100 twice-daily (less GI intolerance but more nephrolithiasis). IDV 800 mg twice-daily + RTV 200 mg twice-daily (highest incidence of nephrolithiasis, use only if EFV is co-administered).
Metronidazole Disulfiram-like reaction.Applies to RTV (liquid). Warn pts of the alcohol content in RTV liquid. Use RTV capsule.
NFV NFV AUC increased by 1.5 fold (152%).NFV not generally coadministered since there is only a modest increase in NFV exposure.
Rifampin RTV AUC decreased by 35%.Recommended dose: Rifampin 600 mg once-daily with standard dose RTV.
SQV SQV AUC increased by 20-fold.Recommended doses: RTV 100 mg twice-daily + SQV 1000 mg twice-daily. RTV 400 mg twice-daily + SQV 400 mg twice-daily rarely used due to GI intolerance.SQV 2000 mg once-daily + RTV 100 mg once-daily under study.
FPV FPV AUC increased by 2-fold; Cmin increased by 4-fold with once-daily; and Cmin increased by 6-fold with twice-daily. RTV 100 mg twice-daily + FPV 700 mg twice-daily or RTV 200 mg once-daily + FPV 1400 mg once-daily (once-daily dosing for PI-naive only). RTV 300 mg once-daily + FPV 1400 mg once-daily with EFV co-administration. RTV 100 mg + FTP 1400 mg once-daily under study in PI-naive pts.
Fluconazole RTV AUC increased by 12%.Interaction not significant. Use standard doses for both drugs.
ATV ATV AUC and Cmin increased 238% and 1089%, respectively. Dose: RTV 100 mg once-daily + ATV 300 mg once-daily. With EFV, use RTV 100 mg once-daily + ATV 400 mg once-daily (only in pts without PI resistance).
EFV RTV AUC increased 18%. Efavirenz AUC increased 21%. Dose: standard dose for both drugs
 TPVTPV AUC increased 11-fold. Dose: RTV 200 mg twice-daily + TPV  500 mg twice-daily.
 Darunavir DRV AUC increased 14-fold. Dose: RTV 100 mg twice-daily + DRV 600 mg twice-daily
Nevirapine  RTV AUC decreased 11% Dose: standard dose for both drugs.
Maraviroc  Maraviroc AUC increased 161% Dose: decrease MVC to 150 mg twice-daily
Etravirine  ETR area under curve decreased 46% with high-dose RTV, not significant interaction with low-dose RTV. High-dose RTV not recommended, but DRV/r, FPV/r, SQV/r, LPV/r, and ATV/r  may be co-administered at standard dose.
ddI (buffered)Decreased RTV absorption.Use ddI EC or separate administration by >2 hrs.
Alfuzosin May significantly increase alfuzosin levels Contraindicated. Consider doxazosin and terazosin for BPH (with close monitoring).
Alfuzosin May increase alfuzosin serum concentrations. Avoid co-administration. Consider doxazosin and terazosin for BPH (with close monitoring).
Alprazolam Alprazolam clearance decreased by 59% (single dose study); alprazolam AUC decreased by 12% (steady-state).Use with caution. With co-administration alprazolam should be administered at the lowest possible dose with slow titration. Alternative benzodiazepine that can be used: temazepam, oxazepam, or lorazepam.
AmiodaroneMay significantly increase amiodarone serum levelsContraindicated.
Amitriptyline May increase serum levels of amitriptylineUse with caution. Consider an alternative antidepressant (i.e. SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
AmlodipineMay increase serum levels of amlodipineApplies to all PIs: Data limited to an interaction study conducted with ATV and diltiazem which resulted in doubling of diltiazem serum levels (this led to PR interval prolongation). All PIs have the potential of prolonging the PR interval with Ca channel blockers co-administration. Ca channel blockers should be started with 50% of the dose and slowly titrated with close monitoring of BP and pulse.
Amphetamine (including methamphetamine)May increase serum levels of amphetamineAvoid all illicit drug use with RTV.
APV APV AUC increase by 2.5 to 3.5-fold; RTV no effect. RTV 100 mg twice-daily + APV (liquid) 700 mg twice-daily or RTV 200 mg once-daily + APV (liquid) 1400 mg once-daily.
Artemether (artemisinin)May increase serum levels of artemetherCo-administration of EFV with artesunate plus amodaquine may result in significant LFT elevations. Unknown effect of artemeter on other Ps and NNRTIs. Close monitoring for artemether toxicity (bone marrow suppression, bradycardia, and seizure).
AstemizoleMay significantly increase astemizole serum levelsContraindicated due to the potential for cardiac arrhythmias. Recommended alternative antihistamine: loratadine, fexofenadine, desloratidine, or cetirizine.
Atorvastatin Atorvastatin AUC increased by 450% (studied with RTV/SQV).Use with caution. Begin with lowest possible dose of atorvastatin (10 mg/d), and avoid doses >40 mg/d. Consider pravastatin, fluvastatin or rosuvastatin.
AzathioprineInteraction unlikelyApplies to all PIs and NNRTIs: Use standard dose.
BepridilMay significantly increase bepridil serum levelsContraindicated.
Bosentan With LPV/r co-administration, bosentan AUC increased 48-fold (on day 4) and 5-fold (on day 10). Co-administer bosentan only after RTV has reached steady-state. In pts on RTV >10 days: start bosentan at 62.5 mg once daily or every other day. In pts already on bosentan: discontinue bosentan for >36 hrs prior to initiation of RTV-boosted PIs and restart bosentan at 62.5 mg once daily or every other day after RTV has reached steady-state (after 10 days).
Bupropion  May increase bupropion concentration (initially), but decrease concentrations (at steady-state).Titrate bupropion dose to therapeutic effect. In a small case series no seizures reported with co-administration.
CarbamazepineMay decrease serum levels of RTV. RTV may increase serum levels of carbamazepine.Consider alternative anticonvulsants (i.e. valproic acid, lamotrigine, levetiracetam, or topiramate). Carbamazepine toxicity has been reported with co-administration. With co-administration, monitor anticonvulsants levels closely.
CarvedilolMay increase carvedilol serum levelsCarvedilol levels may be increased with RTV. Monitor closely with co-administration. Consider alternative beta-blocker such as atenolol since it is primarily excreted unchanged in the urine with limited interaction with RTV.
Chlordiazepoxide May increase serum levels of chlordiazepoxideApplies to all PIs: Consider an alternative benzodiazepine (i.e lorazepam, oxazepam, or temazepam).
CisaprideMay significantly increase cisapride serum levelsContraindicated due to potential for cardiac arrhythmias. Recommended alternative: metoclopramide.
ClomipramineMay increase serum levels of clomipramineClinical significance unknown. Consider an alternative antidepressant (i.e SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
Clorazepate May increase serum levels of clorazepateApplies to all PIs: Consider an alternative benzodiazepine (i.e lorazepam, oxazepam, or temazepam).
CocaineMay theoretically increase serum levels of hepatotoxic metaboliteApplies to all PIs and NNRTIs. Illicit drug use should be avoided for the obvious reasons.
CyclophosphamideMay increase serum levels of cyclophosphamideApplies to all PIs: Data limited to an interaction study conducted with IDV resulting in a 50% increase in cyclophosphamide serum level. Since all PIs have the potential of increasing cyclophosphamide levels, close monitoring of cyclophosphamide-induced toxicity is recommended.
CyclosporineMay significantly increase serum levels of cyclosporineApplies to all PIs: Monitor serum level of cyclosporine closely with co-administration. Cyclosporine dose may need to be decreased.
Desipramine Desipramine AUC increased by 145%.If available, monitor desipramine levels. Consider escitalopram, citalopram, sertraline, or fluoxetine.
Digoxin Digoxin AUC increased 49%. Reduction in the digoxin dose may bee need with all boosted PI co-administration. Monitor for PR interval prolongation.
DiltiazemMay increase serum level of diltiazemData limited to an interaction study conducted with ATV which resulted in doubling of diltiazem serum levels (this led to PR interval prolongation). All PIs have the potential of prolonging the PR interval with diltiazem co-administration. Diltiazem should be started with 50% of the dose and slowly titrated with close monitoring of BP and pulse. 
DisopyramideMay increase disopyramide serum levelsApplies to all PIs: No data. Monitor disopyramide serum levels (target: 2 to 7.5 mcg/mL).
DocetaxelMay increase serum levels of docetaxelApplies to all PIs: No data. Close monitoring of chemotherapy-induced toxicity recommended.
DofetilideMay significantly increase serum level of dofetilideApplies to all PIs: No data. Use with caution. Monitor QTc closely and adjust dofetilide dosing based on QTc prolongation and renal function. Consider an alternative class III antiarrhythmic such as bretylium or ibutilide.
DolasetronMay increase serum levels of dolesetronDue to the large therapeutic index of dolasetron, potential interaction is unlikely to be clinically significant.
DoxepineMay increase serum levels of doxepineUse with caution. Consider an alternative antidepressant (i.e. SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
Echinacea May decrease RTV serum level. Echinacea (400 mg 4xd) decreased CYP3A4 substrate (midazolam) by 23%.Applies to all PIs and NNRTIs. Clinical significance unknown but should be avoided until the safety of this combination is further evaluated.
Ergot AlkaloidMay significantly increase ergotamine serum level. Acute ergotism has been reported with co-administration.Contraindicated. Consider alternative agent for migraine such as sumatriptan (but not eletriptan since it is a CYP3A4 substrate and significant drug-drug interaction occurred with CYP3A4 inhibitor).
EscitalopramNo significant change in serum levels.No significant interaction. Use standard dose.
Estazolam May increase serum levels of estazolamApplies to all PIs: Consider an alternative benzodiazepine (i.e lorazepam, temazepam, or flurazepam).
Ethinylestradiol Ethinylestradiol decreased by 40%. Use alternative method of contraception.
Ethinyl estradiolEthinyl estradiol AUC decreased by 41%.Warn pt of interaction. Use barrier method of contraception.
EthosuximideMay increase serum levels of ethosuximideApplies to all PIs: Consider switching to valproic acid for the treatment of absence seizure.
EtoposideMay increase serum levels of etoposideApplies to all PIs: No data. Close monitoring of chemotherapy- induced toxicity recommended.
FelodipineMay increase serum levels of felodipineApplies to all PIs: Data limited to an interaction study conducted with ATV and diltiazem which resulted in doubling of diltiazem serum levels (this led to PR interval prolongation). All PIs have the potential of prolonging the PR interval with Ca channel blocker co-administration. Ca channel blockers should be started with 50% of the dose and slowly titrated with close monitoring of BP and pulse.
Fentanyl Fentanyl clearance decreased by 67%.Avoid concurrent administration of fentanyl. Morphine may be a safer alternative.
FlecainideMay significantly increase flecainide serum levelContraindicated.
FluoxetineRTV AUC increased by 19%.Use standard dose. Serotonin syndrome has been reported but clear association is unclear [AIDS 2001;15:1281].
Flurazepam May increase serum levels of flurazepamApplies to all PIs: Consider an alternative benzodiazepine (i.e lorazepam, temazepam, or flurazepam).
Fluticasone
Fluticasone AUC and Cmax increased by 350-fold and 25-fold, respectively. With chronic administration plasma cortisol AUC decreased by 86%. Cushing's syndrome and adrenal suppression have been reported. Co-administration not recommended by manufacturer. Avoid long-term co-administration.
FluvoxamineMay increase serum levels of fluvoxamineClinical significance unknown. Consider an alternative antidepressant (i.e SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
Food (with 15g fat)RTV AUC increased by 15%.Minimal PK benefit with food; improves GI tolerance.
Garlic supplement 49% and 51% reduction of SQV AUC Cmin and AUC, respectively. Studies only done with SQV but garlic supplements may effect serum levels of other PIs or NNRTIs. Avoid co-administration of garlic supplements with PIs and NNRTIs.
GHB (gamma-hydroxybutyrate)Case report of prolonged and severe agitation attributed to interaction between GHB and RTV.All Illicit drug use should be avoided for obvious reasons. Warn patients of severe drug interaction with RTV.
GranisetronMay increase serum level of granisetron.Applies to all PIs: Due to the large therapeutic index of granisetron, potential interaction is unlikely to be clinically significant.
HaloperidolMay increase serum level of haloperidolConsider an alternative neuroleptic: olanzapine.
Heroin (Diamorphine)Drug interactions unlikely.Applies to PIs and NNRTIs: Interaction unlikely but illicit drug use should be avoided for obvious reasons.
IfosphamideMay increase serum levels of ifosphamideApplies to all PIs: No data. Close monitoring of chemotherapy-induced toxicity recommended.
Imipramine May increase serum levels of imipramineUse with caution. Consider an alternative antidepressant (i.e SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
IrinoteacanMay increase irinoteacan serum levelsApplies to all PIs: Co-administration of ATV is contraindicated by manufacturer. All PIs also have the potential for significant interaction with irinotecan, therefore co-administration should be done with extreme caution.
Itraconazole CYP3A4 inhibitor and substrate - bidirectional inhibition with increase levels of PIs and itraconazole. Monitor itraconazole serum level with RTV co-administration. May need itraconazole dose reduction.
KetamineMay cause chemical hepatitisAvoid all illicit drug use should be avoided for obvious reasons.
Ketoconazole Ketoconazole AUC increased by greater than 3-fold.May need to decrease ketoconazole dose (do not exceed 200 mg/d).
LidocaineMay increase antiarrhythmic serum levelsApplies to all PIs: No data. Use with caution, monitor lidocaine serum level (target:1.5 to 6 mcg/mL) with co-administration.
Lovastatin May significantly increase lovastatin levelsContraindicated. Recommended alternatives include pravastatin, rosuvastatin, and fluvastatin (and possibly atorvastatin - start with 10 mg/day). Monitor for adverse effect due to limited clinical data.
MDMA (ecstasy)Fatal case report attributed to drug interactions with RTV resulting in 10-fold increase in MDMA serum levels.Case report limited to RTV. Unknown effect of other PIs and NNRTIs on MDMA serum levels. Avoid all illicit drug use for obvious reason.
Mefloquine RTV AUC decreased by 31% and Cmin by 43% (with RTV 200 mg at steady-state).Clinical significance unknown but may consider increasing RTV dose.
Meperidine Meperidine AUC decreased by 67%, nor-meperidine AUC increased by 47%.Avoid concurrent administration of meperidine. Morphine may be a safer alternative.
Methadone Methadone levels decreased by 37%, S-Methadone AUC decreased by 25%, R-Methadone AUC decreased by 20%. Decrease in methadone AUC is unlikely to be significant since
S-methadone (inactive) is more affected. No withdrawal symptoms observed. Use standard methadone dose.
MetoclopramideMay increase serum level of metoclopramideNo data. Start with a low dose and titrate to effect.
MetoprololMay increase metoprolol serum levelMonitor closely with co-administration. It is unknown whether other PIs and NNRTIs can affect metoprolol serum concentrations. Consider alternative beta-blocker such as atenolol since it is primarily excreted unchanged in the urine with limited interaction with RTV.
MexiletineMay increase antiarrhythmic serum levelsApplies to all PIs: No data. Use with caution. Monitor EKG and serum levels. Serum levels exceeding 1.5 to 2 mcg/mL have been associated with an increased risk of toxicity.
Midazolam May significantly increase midazolam levelsConcurrent administration of midazolam is contraindicated. Alternative benzodiazepine that can be used (temazepam, oxazepam, and lorazepam).
Milk thistle Data limited to an interaction study with milk thistle and IDV. IDV AUC: unchanged; IDV Cmin: decreased by 47%. Clinical significance unknown. Unknown effect of the metabolism of other PIs or NNRTIs. Avoid co-administration with PIs and NNRTIs until it can be further evaluated.
MirtazapineMay increase serum levels of mirtazapineUse with caution. Consider an alternative antidepressant (i.e. SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
MycophenolateInteraction unlikely. No significant interaction observed with NVP.Applies to all PIs and NNRT:No significant interaction observed with NVP. Use standard dose.
NefazodoneMay increase serum levels of nefazodoneApplies to all PIs: Use with caution. Consider an alternative antidepressant (i.e SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
NifedipineMay increase serum level of nifedipineApplies to all PIs: Data limited to an interaction study conducted with ATV and diltiazem which resulted in doubling of diltiazem serum levels (this led to PR interval prolongation). All PIs have the potential of prolonging the PR interval with Ca channel blocker co-administration. Ca channel blockers should be started with 50% of the dose and slowly titrated with close monitoring of BP and pulse.
NisoldipineMay increase serum levels of nisoldipineApplies to all PIs: Data limited to an interaction study conducted with ATV and diltiazem which resulted in doubling of diltiazem serum levels (this led to PR interval prolongation). All PIs have the potential of prolonging PR interval with Ca channel blockers co-administration. Ca channel blockers should be started with 50% of the dose and slowly titrated with close monitoring of BP and pulse.
Nortriptyline May increase serum levels of nortriptylineUse with caution. Consider an alternative antidepressant (i.e. SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
OlanzapineOlanzapine AUC decreased by 53%.Olanzapine dose may need to be increased. Monitor and adjust as necessary.
OndansetronMay increase serum levels of ondansetronDue to the large therapeutic index of ondansetron, potential interaction is unlikely to be clinically significant.
Paclitaxel May increase paclitaxel serum levelsApplies to all PIs: Since all PIs have have the potential of significantly increasing paclitaxel serum level, close monitoring of paclitaxel-induced toxicity is recommended.
ParoxetineMay increase serum levels of paroxetineClinical significance unknown. Consider an alternative antidepressant (i.e SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
PCPMay significantly increase serum levels of PCPApplies to all PIs. Illicit drug use should be avoided for the obvious reason.
PerphenazineMay increase serum levels of perphenazineConsider an alternative neuroleptic: olanzapine.
PhenobarbitalMay decrease serum levels of RTV. RTV may increase serum levels of phenobarbital.Consider alternative anticonvulsants (i.e valproic acid, levetiracetam, lamotrigine, topiramate). Monitor anticonvulsants levels and consider TDM of RTV.
PhenytoinMay decrease serum levels of RTV. RTV may increase serum levels of phenytoin.Consider alternative anticonvulsants (i.e valproic acid, lamotrigine, levetiracetam, or topiramate). Monitor anticonvulsant levels and consider TDM of RTV.
PimozideMay significantly increase pimozide serum levels resulting in QTc prolongationContraindicated. Consider alternative: Olanzapine.
Pravastatin No change in RTV AUC, but pravastatin levels decreased by 50% with SQV/RTV.Clinical significance unknown. Start with standard dose of pravastatin; titrate to effect.
Prednisone Prednisolone AUC increase 30-40% with with RTV (200 mg twice-daily) co-administration. Dose adjustment may be needed with long-term co-administration.
PropafenoneMay significantly increase propafenone serum levels.Contraindicated.
Propoxyphene May significantly increase propoxyphene serum levelsAvoid concurrent administration.
PropranololMay increase propranolol serum levelsMonitor closely with coadministration. It is unknown whether other PIs and NNRTIs affect propranolol serum levels. Consider alternative beta-blocker such as atenolol since it is primarily excreted unchanged in the urine with limited interaction with RTV.
Quinidine May significantly increase quinidine levelsContraindicated.
 Raltegravir No interactions Dose: standard dose for both drugs
Ranolazine May significantly increase ranolazine serum concentrations. Contraindicated. May increase risk of QTc prolongation.
Rifabutin RFB AUC increased by 400%.Recommended dose: RFB 150 mg every other day or 150 mg 3x/week with standard dose RTV.
Rifapentine RTV serum levels may be significantly decreased.Avoid co-administration. Consider using RFB or rifampin with SQV 400 mg + RTV 400 mg twice-daily.
RisperidoneRisperidone serum levels may be increased.A case report of reversible coma associated with RTV-risperidone co-administration. Consider risperidone dose reduction with co-administration or use alternative neuroleptic (i.e olanzapine).
Rosuvastatin Other CYP3A4 inhibitor (i.e erythromycin) did not affect rosuvastatin serum levels. Rosuvastatin AUC and Cmax were increased 2.1 to 4.7-fold, respectively. LPV and RTV PK parameters were not significantly affected.Clinical significance of rosuvastatin effects on RTV PK unknown. This drug interaction study had important design limitations that could had affected the results. Unknown effect of rosuvastatin on other PIs and NNRTIs. Close monitoring recommended due to limited clinical data.
Salmeterol May increase salmeterol serum concentrations. Avoid co-administration. Consider formoterol
SildenafilSildenafil AUC increased by 11- fold, Cmax increased by 300%.Caution with concurrent use. Do not exceed 25 mg of sildenafil in a 48-hr period.
Simvastatin May significantly increase simvastatin levelsContraindicated. Alternatives that may be used include atorvastatin (start with10 mg/day), pravastatin, rosuvastatin, or fluvastatin. Monitor for adverse effect due to limited clinical data.
SirolimusMay significantly increase serum levels of sirolimuApplies to all PIs: Dose sirolimus based on serum levels. A significantly reduction of sirolimus dose with all PIs co-administration is highly likely.
St. John's wortMay decrease RTV serum levelsContraindicated. Studies done with IDV and NVP but St. John's wort likely to increase the metabolism of other PIs and NNRTIs. Use an alternative (more effective) antidepressant.
TacrolimusMay significantly increase serum levels of tacrolimuApplies to all PIs: Dose tacrolimus based on serum levels. A significantly reduction of tacrolimus dose with all PIs
co-administration is recommended.
TadalafilTadalafil AUC increased by 124% (with RTV 200 mg twice-daily).Start with 5 mg. Do not exceed 10 mg in 72 hrs. Consider sildenafil due to more clinical data and shorter half-life allowing for easier titration.
TamoxifenMay increase serum levels of tamoxifenApplies to all PIs: No data. Close monitoring of tamoxifen- induced toxicity recommended.
TeniposideMay increase serum levels of teniposideApplies to all PIs: No data. Close monitoring of teniposide-induced toxicity recommended.
TerfenadineMay significantly increase terfenadine serum levelsContraindicated due to the potential for cardiac arrhythmias. Recommended alternative antihistamine: loratadine, fexofenadine, desloratidine, or cetirizine.
THCBased on data with NFV and IDV, interactions are unlikely.Applies to PIs and NNRTIs: Interactions are unlikely but illicit drug use should be avoided for obvious reasons.
TheophyllineTheophylline AUC: decreased by 43%; Cmin: decreased by 57%.Monitor theophylline levels; dose may need to be increased if sub therapeutic.
ThioridazineMay increase serum levels of thioridazineConsider an alternative neuroleptic: olanzapine.
Trazodone Trazodone AUC increased by 2.4-fold and Cmax by 34%.Monitor for CNS and CV adverse effects. Consider decreasing trazadone dose by 50% with slow dose titration.
Trazodone RTV increased trazodone AUC by 2.4 fold. Use with caution. Nausea, dizziness, hypotension and syncope have been reported with co-administration. Consider decreasing trazodone dose by 50% with co-administration.
Triazolam May significantly increase serum levels of triazolamApplies to all PIs: Avoid co-administration. Consider alternative benzodiazepine (lorazepam, oxazepam, or temazepam).
VardenafilVardenafil AUC increased by 49-fold. RTV AUC decreased by 20%.Do not exceed vardenafil 2.5 mg in 72 hrs. Consider sildenafil due to more clinical data and less pronounced interaction.
VenlafaxineMay increase serum levels of venlafaxineConsider an alternative antidepressant (i.e SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
VerapamilMay increase serum levels of verapamilApplies to all PIs: Data limited to an interaction study conducted with ATV and diltiazem which resulted in doubling of diltiazem serum levels (this led to PR interval prolongation). All PIs have the potential of prolonging the PR interval with Ca channel blocker co-administration. Ca channel blockers should be started with 50% of the dose and slowly titrated with close monitoring of BP and pulse.
VinblastineMay increase serum levels of vinblastineApplies to all PIs: No data. Close monitoring of vinblastine-induced toxicity recommended.
VincristineMay increase serum levels of vincristineApplies to all PIs: No data. Close monitoring of vincristine-induced toxicity recommended.
Vitamin C Data limited to interaction study with IDV and vitamin C (1 g/d): IDV AUC decreased by 14% and Cmin by 32%. Clinical significance unknown. Other PIs and NNRTIs serum concentrations may be affected when co-administered with similar dose of vitamin C.
Voriconazole  RTV (400 mg twice-daily) decreased steady-state voriconazole AUC by 82%. RTV levels was not affected by voriconazole. RTV (100 mg twice-daily) decreased steady-state voriconazole AUC by 39%.RTV (400 mg twice-daily) contraindicated with voriconazole. . Avoid co-administration with boosted PI. Consider another antifungal for aspergillosis (i.e ambisome or caspofungin) or use with TDM.
WarfarinCase report of increased warfarin requirement after RTV initiation.Other PIs and NNRTIs may also affect warfarin requirements. Monitor INR closely with co-administration.

SPECTRUM

HIV

RESISTANCE

  • 82A/F/T/S: Intermediate resistance.
  • PI Mutations: 10, 20, 32, 33, 36, 46, 71, 77: secondary PI mutations that increase RTV resistance inpresence of primary mutations.
  • 50V, 54V, 90M: low-level resistance when present as single mutations.
  • Unclear whether low "boosting" doses select for resistance mutations. PI resistance uncommon in pts failing boosted PIs without pre-existing PI mutations.

PHARMACOLOGY

Pharmacology

COMMENTS

  • Pros: The most reliable PI "booster": typically used to enhance pharmacokinetics of all PIs except NFV, resulting in higher drug levels, longer half-lives, decrease dose and/or dosing frequency, greater activity against PI-resistant virus, and lower likelihood of resistance with failure
  • Cons: Costly; dose-dependent GI side effects, hepatitis, cholesterol and triglyceride elevation; many drug interactions.

REFERENCES

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