Zambian HIV Guidelines:: Ritonavir

	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>Antiretrovirals>

Ritonavir

Paul A. Pham, Pharm.D. and John G. Bartlett, M.D.
03-31-2008

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 bid needed for antiviral activity, but GI intolerance and high cost limit routine use.
Store capsules in the refrigerator at 2-8^ºC (36-46^ºF). May store capsules out of refrigerator (at less than 25^º C or 77^º 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)	Abbott	oral soft gel capsule 100 mg	$10.71
			oral solution 80 mg/mL (240 mL)	$1800/240 mL

*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 (based on 100 mg qd-200 mg bid used to enhance the PK of other PIs).

RTV 600 mg po bid (FDA approved dose; rarely used due to severe GI intolerance).
With IDV: RTV 100 mg bid + IDV 800 mg bid (less GI intolerance but more nephrolithiasis), or RTV 200 mg bid + IDV 800 mg bid (highest incidence of kidney stonesnephrolithiasis, use only if EFV is co-administered), or RTV 400 mg bid + IDV 400 mg bid (more GI intolerance, rarely used).
With SQV: RTV 100 mg bid + SQV 1000 mg bid, or RTV 400 mg bid + SQV 400 mg bid or RTV 100 mg qd + SQV 2000 mg qd (dose being studied in ART-naive pts) or RTV 400 mg bid + SQV 400 mg bid (high rate of GI intolerance, rarely used).
With APV: RTV 100 mg bid + APV 700 mg bid (liquid), or RTV 200 mg qd + APV 1400 mg qd (liquid)
With FPV: RTV 100 mg bid + FPV 700 mg bid, or RTV 200 mg qd + FPV 1400 mg qd (qd dosing for PI-naive pts only). RTV 300 mg qd + FPV 1400 mg qd when co-administered with EFV. RTV 100 mg qd + FPV 1400 mg qd being studied in PI-naive pts.
With ATV: RTV 100 mg qd + ATV 300 mg qd.
With NFV: Not recommended. Combination of RTV 400 mg bid + NFV 500-750 mg bid has been studied, but limited data; high rate of GI intolerance with only marginal PK enhancement of NFV levels.
With NVP: standard doses for both drugs (rarely used).
With TPV : RTV 200 mg bid + TPV 500 mg bid
With DRV: RTV 100 mg bid + DRV 600 mg bid.
With maraviroc (MVC): decrease maraviroc's dose to 150 mg BID
With etravirine (ETV): High dose RTV not recommended, but DRV/r, FPV/r, SQV/r, LPV/r, and ATV/r may be co-administered at standard dose.
With raltegravir (RAL): no interaction; use standard dose of both drugs.

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

600 mg bid (FDA dose; rarely used).

DOSING FOR GLOMERULAR FILTRATION OF 10-50

600 mg bid (FDA dose; rarely used).

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

600 mg bid (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 bid 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 bid).
Association between RTV (and other PIs) and osteonecrosis/avascular necrosis has not been confirmed.

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

Drug	Effect of Interaction	Recommendations/Comments
TPV	TPV AUC increased 11-fold.	Dose: RTV 200 mg bid + TPV 500 mg bid.
Clarithromycin	Clarithromycin AUC increased by 77%, Cmin increased by 182%.	Reduce clarithromycin dose by 50% in end stage renal disease. Consider using azithro.
IDV	IDV AUC increased by 2 to 5-fold. Cmin increased by 400%.	Dosing recommendation: IDV 400 mg bid and RTV 400 mg bid ( more GI intolerance but less nephrolithiasis). IDV 800 mg bid + RTV 100 bid (less GI intolerance but more nephrolithiasis). IDV 800 mg bid + RTV 200 mg bid (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 qd with standard dose RTV.
SQV	SQV AUC increased by 20-fold.	Recommended doses: RTV 100 mg bid + SQV 1000 mg bid. RTV 400 mg bid + SQV 400 mg bid rarely used due to GI intolerance.SQV 2000 mg qd + RTV 100 mg qd under study.
FPV	FPV AUC increased by 2-fold; Cmin increased by 4-fold with qd; and Cmin increased by 6-fold with bid.	RTV 100 mg bid + FPV 700 mg bid or RTV 200 mg qd + FPV 1400 mg qd (qd dosing for PI-naive only). RTV 300 mg qd + FPV 1400 mg qd with EFV co-administration. RTV 100 mg + FTP 1400 mg qd under study in PI-naive pts.
Fluconazole	RTV AUC increased by 12%.	Interaction not significant. Use standard doses for both drugs.
ATV		Dose: RTV 100 mg qd + ATV 300 mg qd
EFV		Dose: standard dose for both drugs
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).
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.
Amiodarone	May significantly increase amiodarone serum levels	Contraindicated.
Amitriptyline	May increase serum levels of amitriptyline	Use with caution. Consider an alternative antidepressant (i.e. SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
Amlodipine	May increase serum levels of amlodipine	Applies to all PIs and DLV: 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 and DLV 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 amphetamine	Avoid all illicit drug use with RTV.
APV	APV AUC increase by 2.5 to 3.5-fold; RTV no effect.	RTV 100 mg bid + APV (liquid) 700 mg bid or RTV 200 mg qd + APV (liquid) 1400 mg qd.
Artemether (artemisinin)	May increase serum levels of artemether	Co-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).
Astemizole	May significantly increase astemizole serum levels	Contraindicated 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.
Azathioprine	Interaction unlikely	Applies to all PIs and NNRTIs: Use standard dose.
Bepridil	May significantly increase bepridil serum levels	Contraindicated.
Bupropion	May increase bupropion serum levels slightly	Not likely to be clinically significant. Start with the lowest possible dose of bupropion. In a small case series no seizures reported with co-administration.
Carbamazepine	May 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.
Carvedilol	May increase carvedilol serum levels	Carvedilol 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 chlordiazepoxide	Applies to all PIs and DLV: Consider an alternative benzodiazepine (i.e lorazepam, oxazepam, or temazepam).
Cisapride	May significantly increase cisapride serum levels	Contraindicated due to potential for cardiac arrhythmias. Recommended alternative: metoclopramide.
Clomipramine	May increase serum levelsof clomipramine	Clinical significance unknown. Consider an alternative antidepressant (i.e SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
Clorazepate	May increase serum levels of clorazepate	Applies to all PIs and DLV: Consider an alternative benzodiazepine (i.e lorazepam, oxazepam, or temazepam).
Cocaine	May theoretically increase serum levels of hepatotoxic metabolite	Applies to all PIs and NNRTIs. Illicit drug use should be avoided for the obvious reasons.
Cyclophosphamide	May increase serum levels of cyclophosphamide	Applies to all PIs and DLV: Data limited to an interaction study conducted with IDV resulting in a 50% increase in cyclophosphamide serum level. Since all PIs and DLV have the potential of increasing cyclophosphamide levels, close monitoring of cyclophosphamide-induced toxicity is recommended.
Cyclosporine	May significantly increase serum levels of cyclosporine	Applies 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 serum concentration may be significantly increased with RTV co-administration.	Reduction in the digoxin dose may bee need with all boosted PI co-administration.
Diltiazem	May increase serum level of diltiazem	Applies to all PIs and DLV: Data limited to an interaction study conducted with ATV which resulted in doubling of diltiazem serum levels (this led to PR interval prolongation). All PIs and DLV 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.
Disopyramide	May increase disopyramide serum levels	Applies to all PIs and DLV: No data. Monitor disopyramide serum levels (target: 2 to 7.5 mcg/mL).
DLV		Dose: no dosing recommendation
Docetaxel	May increase serum levels of docetaxel	Applies to all PIs and DLV: No data. Close monitoring of chemotherapy-induced toxicity recommended.
Dofetilide	May significantly increase serum level of dofetilide	Applies to all PIs and DLV: 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.
Dolasetron	May increase serum levels of dolesetron	Due to the large therapeutic index of dolasetron, potential interaction is unlikely to be clinically significant.
Doxepine	May increase serum levels of doxepine	Use with caution. Consider an alternative antidepressant (i.e. SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
DRV	DRV AUC increased 14-fold.	Dose: RTV 100 mg bid + DRV 600 mg bid
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 Alkaloid	May 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).
Escitalopram	No significant change in serum levels.	No significant interaction. Use standard dose.
Estazolam	May increase serum levels of estazolam	Applies to all PIs and DLV: Consider an alternative benzodiazepine (i.e lorazepam, temazepam, or flurazepam).
Ethinylestradiol	Ethinylestradiol decreased by 40%.	Use alternative method of contraception.
Ethinyl estradiol	Ethinyl estradiol AUC decreased by 41%.	Warn pt of interaction. Use barrier method of contraception.
Ethosuximide	May increase serum levels of ethosuximide	Applies to all PIs and DLV: Consider switching to valproic acid for the treatment of absence seizure.
Etoposide	May increase serum levels of etoposide	Applies to all PIs and DLV: No data. Close monitoring of chemotherapy- induced toxicity recommended.
ETV	Etravirine area under the 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.
Felodipine	May increase serum levels of felodipine	Applies to all PIs and DLV: 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 and DLV 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.
Flecainide	May significantly increase flecainide serum level	Contraindicated.
Fluoxetine	RTV 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 flurazepam	Applies to all PIs and DLV: 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.
Fluvoxamine	May increase serum levels of fluvoxamine	Clinical 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.
Granisetron	May increase serum level of granisetron.	Applies to all PIs and DLV: Due to the large therapeutic index of granisetron, potential interaction is unlikely to be clinically significant.
Haloperidol	May increase serum level of haloperidol	Consider 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.
Ifosphamide	May increase serum levels of ifosphamide	Applies to all PIs and DLV: No data. Close monitoring of chemotherapy-induced toxicity recommended.
Imipramine	May increase serum levels of imipramine	Use with caution. Consider an alternative antidepressant (i.e SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
Irinoteacan	May increase irinoteacan serum levels	Applies to all PIs and DLV: Co-administration of ATV is contraindicated by manufacturer. All PIs and DLV 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.
Ketamine	May cause chemical hepatitis	Avoid 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).
Lidocaine	May increase antiarrhythmic serum levels	Applies to all PIs and DLV: No data. Use with caution, monitor lidocaine serum level (target:1.5 to 6 mcg/mL) with co-administration.
Lovastatin	May significantly increase lovastatin levels	Contraindicated. 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.
Metoclopramide	May increase serum level of metoclopramide	No data. Start with a low dose and titrate to effect.
Metoprolol	May increase metoprolol serum level	Monitor 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.
Mexiletine	May increase antiarrhythmic serum levels	Applies to all PIs and DLV: 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 levels	Concurrent 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.
Mirtazapine	May increase serum levels of mirtazapine	Use with caution. Consider an alternative antidepressant (i.e. SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
MVC	Maraviroc AUC increased 161%	Dose: decrease maraviroc's dose to 150 mg BID
Mycophenolate	Interaction unlikely. No significant interaction observed with NVP.	Applies to all PIs and NNRT:No significant interaction observed with NVP. Use standard dose.
Nefazodone	May increase serum levels of nefazodone	Applies to all PIs and DLV: Use with caution. Consider an alternative antidepressant (i.e SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
Nifedipine	May increase serum level of nifedipine	Applies to all PIs and DLV: 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 and DLV 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.
Nisoldipine	May increase serum levels of nisoldipine	Applies to all PIs and DLV: 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 and DLV 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 nortriptyline	Use with caution. Consider an alternative antidepressant (i.e. SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
NVP		Dose: standard dose for both drugs.
Olanzapine	Olanzapine AUC decreased by 53%.	Olanzapine dose may need to be increased. Monitor and adjust as necessary.
Ondansetron	May increase serum levels of ondansetron	Due to the large therapeutic index of ondansetron, potential interaction is unlikely to be clinically significant.
Paclitaxel	May increase paclitaxel serum levels	Applies to all PIs and DLV: Data limited to case reports of severe toxicity associated with DLV and LPV/r co-administration with paclitaxel. Since all PIs have have the potential of significantly increasing paclitaxel serum level, close monitoring of paclitaxel-induced toxicity is recommended.
Paroxetine	May increase serum levels of paroxetine	Clinical significance unknown. Consider an alternative antidepressant (i.e SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
PCP	May significantly increase serum levels of PCP	Applies to all PIs and DLV. Illicit drug use should be avoided for the obvious reason.
Perphenazine	May increase serum levels of perphenazine	Consider an alternative neuroleptic: olanzapine.
Phenobarbital	May 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.
Phenytoin	May 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.
Pimozide	May significantly increase pimozide serum levels resulting in QTc prolongation	Contraindicated. 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 bid) co-administration.	Dose adjustment may be needed with long-term co-administration.
Propafenone	May significantly increase propafenone serum levels.	Contraindicated.
Propoxyphene	May significantly increase propoxyphene serum levels	Avoid concurrent administration.
Propranolol	May increase propranolol serum levels	Monitor 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 levels	Contraindicated.
RAL	No interactions	Dose: standard dose for both drugs
Rifabutin	RFB AUC increased by 400%.	Recommended dose: RFB 150 mg qod 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 bid.
Risperidone	Risperidone 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 NNRTIsClose monitoring recommended due to limited clinical data.
Sildenafil	Sildenafil 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 levels	Contraindicated. Alternatives that may be used include atorvastatin (start with10 mg/day), pravastatin, rosuvastatin, or fluvastatin. Monitor for adverse effect due to limited clinical data.
Sirolimus	May significantly increase serum levels of sirolimu	Applies 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 wort	May decrease RTV serum levels	Contraindicated. Studies done with IDV and NVP but St. John's wort likely to incresae the metabolism of other PIs and NNRTIs. Use an alternative (more effective) antidepressant.
Tacrolimus	May significantly increase serum levels of tacrolimu	Applies to all PIs: Dose tacrolimus based on serum levels. A significantly reduction of tacrolimus dose with all PIs co-administration is recommended.
Tadalafil	Tadalafil AUC increased by 124% (with RTV 200 mg bid).	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.
Tamoxifen	May increase serum levels of tamoxifen	Applies to all PIs and DLV: No data. Close monitoring of tamoxifen- induced toxicity recommended.
Teniposide	May increase serum levels of teniposide	Applies to all PIs and DLV: No data. Close monitoring of teniposide-induced toxicity recommended.
Terfenadine	May significantly increase terfenadine serum levels	Contraindicated due to the potential for cardiac arrhythmias. Recommended alternative antihistamine: loratadine, fexofenadine, desloratidine, or cetirizine.
THC	Based 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.
Theophylline	Theophylline AUC: decreased by 43%; Cmin: decreased by 57%.	Monitor theophylline levels; dose may need to be increased if sub therapeutic.
Thioridazine	May increase serum levels of thioridazine	Consider 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 triazolam	Applies to all PIs and DLV: Avoid co-administration. Consider alternative benzodiazepine (lorazepam, oxazepam, or temazepam).
Vardenafil	Vardenafil 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.
Venlafaxine	May increase serum levels of venlafaxine	Consider an alternative antidepressant (i.e SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
Verapamil	May increase serum levels of verapamil	Applies to all PIs and DLV: 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 and DLV 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.
Vinblastine	May increase serum levels of vinblastine	Applies to all PIs and DLV: No data. Close monitoring of vinblastine-induced toxicity recommended.
Vincristine	May increase serum levels of vincristine	Applies to all PIs and DLV: 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 bid) decreased steady-state voriconazole AUC by 82%. RTV levels was not affected by voriconazole. RTV (100 mg bid) decreased steady-state voriconazole AUC by 39%.	RTV (400 mg bid)contraindicated with voriconazole. . Avoid co-administration with boosted PI. Consider another antifungal for aspergillosis (i.e ambisome or caspofungin) or use with TDM.
Warfarin	Case 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" l: typically used to enhance pharmacokinetics of all PIs except NFV.
Cons: Costly; dose-dependent GI side effects, hepatitis, cholesterol and triglyceride elevation; many drug interactions.

REFERENCES

REFERENCED WITHIN THIS GUIDE

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Abbreviations