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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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Lopinavir/ritonavir

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

Zambia Specific Information

  • Available formulations in Zambia: 133.3 mg + 33.3 mg capsule; 400 mg + 100 mg/5 ml oral liquid.
  • LPV/r plus AZT/3TC or AZT/TDF/FTC or d4T/3TC is recommended second line regimen after TDF/FTC/EFV failure.
  • Refer to an HIV specialist if pt unable to tolerate LPV/r-based second line regimen.
  • PI-based regimen recommended for treatment of HIV-2 infection.
  • Store capsules and solution in the refrigerator at 2-8º C (36-46ºF) until expiration date or at room temperature for up to 2 months.
  • Avoid exposing capsules and solution to excessive heat.
Zambia Information Author: Paul A. Pham, Pharm.D.

INDICATIONS

FDA

  • Treatment of HIV infection in combination with other antiretrovirals.

FORMS

brand 
name
 
generic 
Mfg 
brand 
forms
 
cost* 
Kaletra (U.S); Aluvia (developing countries)Lopinavir/ritonavir (LPV/r) Abbott Laboratoriesoral
solution
LPV/r 400/100 mg per 5 mL (160 mL bottle)
$420.95 160 mL; $13.15 per 5 mL
      oral
tablet
LPV/r 200/50 mg; 100/25 mg
$7.02 per 200/50 mg tab; $3.51 per 100/25 mg tab

*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

  • 400/100 mg 2 tabs twice-daily with or without food OR 5 ml twice-daily with food.
  • PI-naive or treatment-experienced patients with <3 LPV resistant mutations: Consider 800/200 mg (4 tabs or 10 mL liquid) once-daily (tabs with or without food, liquid with food).
  • With EFV: Consider LPV/r 500/125 mg twice-daily + EFV 600 mg qhs, especially in PI-experienced pts. Standard doses acceptable for PI naive pts.
  • With NVP: Consider LPV/r 500/125 mg twice-daily + NVP 200 mg twice-daily, especially in PI-experienced pts. Standard doses acceptable for PI naive pts.
  • With IDV: LPV/r 400/100 mg (2tabs) twice-daily. + IDV 600 or 666 mg twice-daily.
  • With SQV: LPV/r 400/100 mg (2tabs) twice-daily. + SQV 1000 mg twice-daily.
  • With FPV: Not recommended by some. Consider LPV/r 600/150 mg (3 tabs) with FPV 1400 mg twice-daily. (high rate of GI intolerance).
  • With NFV: avoid co-administration.
  • With ATV: LPV/r 400/100 mg (2 tabs) twice-daily. + ATV 300 mg once-daily .Use with caution due to prolong PR interval.
  • With TPV/r: co-administration not recommended.
  • With DRV/r: co-administration not recommended.
  • With ETR: usual dose.
  • With RAL: usual dose.
  • With MVC: usual dose + MVC 150 mg twice-daily.

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

Usual dose

DOSING FOR GLOMERULAR FILTRATION OF 10-50

No data; usual dose likely.

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

No data; usual dose likely.

DOSING IN HEMODIALYSIS

Usual dose (not removed with HD).

DOSING IN PERITONEAL DIALYSIS

No data; usual dose likely.

DOSING IN HEMOFILTRATION

No data

ADVERSE DRUG REACTIONS

COMMON

  • Diarrhea (any grade) 50% and 39% with LPV/r tabs administered once-daily and twice-daily, respectively. Moderate or severe drug diarrhea occurred in 14% and 11% in patients taking LPV/r once- and twice-daily, respectively.
OCCASIONAL

  • Nausea, vomiting, abdominal pain, asthenia, and headache
  • Elevated triglycerides (12-22%) and cholesterol (14-22%). Significant triglyceride elevation more common when LPV/r is combined with EFV.
  • Insulin resistance, hyperglycemia, and diabetes
  • Hepatitis (10-12%)
RARE

  • Pancreatitis (unclear association)
  • Rash. Toxic epidermal necrolysis (TEN) has been reported.
  • Nephrolithiasis (unclear association)
  • QTc prolongation (5.3 msec [95% CI 8.1]). Use with caution with other drugs that can prolong QTc.
  • PR interval prolongation (24.9 msec [95% CI 21.5, 28.3]). 2nd and 3rd degree AV block reported. Use with caution in pts with baseline cardiac conduction abnormalities.

DRUG INTERACTIONS

Substrate, inhibitor, and likely an inducer of CYP3A4 and glucuronyl transferase. May also weakly induce CYP2C9 and CYP2C19 and weakly inhibit CYP2D6 (clinical significance unknown). LPV/r generally increases serum levels of drugs that are substrates of CYP3A4 (but reduction in serum levels have also occurred). Drugs that are inducers of CYP3A4 may decrease serum levels of LPV. Drugs that are inhibitors of CYP3A4 may increase serum levels of LPV.

Drug-to-Drug Interactions

Drug-to-Drug Interaction

DrugEffect of InteractionRecommendations/Comments
Abacavir (ABC) May increase serum levels of alprazolam.Applies to all PIs: Consider alternative benzodiazepine (i.e lorazepam, temazepam, or oxazepam).
Efavirenz (EFV) LPV/r AUC decreased by 19% and Cmin decreased by 39%; EFV levels unaffected.Dose: LPV/r 500/125 mg twice-daily + EFV 600 mg qhs, especially in pts with PI resistance. Standard doses may be acceptable in PI-naive pts.
Indinavir (IDV) IDV AUC increased by 20% and Cmin increased by 46%; IDV Cmin increased by 247%. Dose: IDV 600 mg or 666 mg twice-daily + LPV/r 400/100 mg twice-daily.
Metronidazole Disulfiram-like reaction.Applies to LPV liquid formulation. Warn pts of LPV alcohol content (liquid). Use LPV/r caps.
NFV LPV AUC decreased by 27% and Cmin decreased by 33% NFV Cmin increased by 113%.Do not co-administer or consider LPV/r 600/150 mg (3 tabs) + NFV 1250 mg twice-daily with TDM
Nevirapine (NVP) LPV AUC decreased by 22%. NVP levels unaffected.Dose: LPV/r 500/125 mg twice-daily + NVP standard dose, especially in pts. with PI resistance. Standard doses may be acceptable for PI-naive pts. 
Rifampin LPV/r AUC decreased by 75% and Cmin decreased by 99%.Generally not recommended. With co-administration consider LPV/r 400/100 mg (3 caps) +RTV 300 mg twice-daily (note: monitor LFTs, GI intolerance, and lipids). A more recent study of LPV/r 3 to 4 tabs twice-daily + rifampin found high incidence of nausea, vomiting, and grade 4 LFTs elevation. Rifabutin preferred w/ LPV/r co-administration.
Saquinavir (SQV) SQV AUC increased by 836% and Cmin increased by 1700%.Dose: SQV 1000 mg twice-daily + LPV/r 400/100 mg twice-daily.
Fluconazole Interaction unlikely. Use standard doses for both drugs.
Atazanavir (ATV) ATV geometric mean Cmin increased by 45% with LPV/r 400/100 mg twice-daily co-administration (compared to ATV-r 300/100 mg once-daily). LPV PK comparable to historical data. Dose: ATV 300 mg once-daily + LPV/r 400/100 mg twice-daily. May increase risk of PR interval prolongation.
Fosamprenavir (FPV) Decreased APV and LPV levels Not recommended by some. Consider FPV 1400 mg twice-daily + LPV/r 600/150 mg (3 tabs) twice-daily (and consider TDM).
TPV (tipranavir) LPV AUC decreased by 49% (studied dose TPV 500 mg + LPV/r 400/100 mg twice-daily.) Not generally recommended. LPV/r 400/100 mg twice-daily with TPV/r 500/200 mg twice-daily (additional RTV 200 mg ) resulted in "adequate" LPV Cmin, but significant interpatient variability and small sample size suggest confirmation of these findings before this dosing regimen can be recommended.
Darunavir DRV AUC and Cmin decreased 53% and 65%, respectively. LPV AUC and Cmin increased 37% and 72%, respectively.Avoid co-administration.
Etravirine LPV AUC decreased 18%. ETR Cmin decreased by 45%. Usual dose recommended.. ETR Cmin reduction with LPV/r was comparable to observed reduction with DRV/r co-administration.
Maraviroc MVC AUC increased 283%Dose: MVC 150 mg twice-daily + LPV/r 400/100 mg twice-daily .
Clarithromycin Clarithromycin and LPV serum concentrations may increased. Current recommendation is to use standard clarithromycin dose in pts with normal renal function, but pts at risk for QTc or PR interval prolongation should be closely monitored. For creatinine clearance 30-60 mL/min, administer clarithromycin 500 mg PO once daily. For creatine clearance < 30 mL/min administer clarithromycin 250 mg PO once daily. Consider using azithromycin.
Erythromycin Erythromycin and LPV serum concentrations may increased. May increase risk for QTc and PR interval prolongation. Avoid co-administration and consider using azithromycin.
Alfuzosin May significantly increase alfuzosin levels. Contraindicated. Consider doxazosin and terazosin for BPH (with close monitoring).
AmiodaroneMay significantly increase amiodarone serum level.Applies to all PIs: Data limited to case report of increased amiodarone levels with IDV co-administration. RTV, APV, and ATV manufacturers recommend against use of amiodarone, but all PIs have the same potential of significantly increasing amiodarone serum levels. If co-administration can not be avoided, monitor for amiodarone ADR (PFTs and TSH). Consider monitoring serum levels of amiodarone, but its long half-life may make titration difficult.
AmlodipineMay increase serum levels of amlodipine.Applies 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.
Artemether (artemisinin)May increase serum levels of artemether.Data available only for EFV. Co-administration of EFV with artesunate + amodiaquine resulted in significant LFT elevations. Close monitoring for artemether toxicity (bone marrow suppression, bradycardia and seizure).
AstemizoleMay significantly increase astemizole serum levels.Contraindicated due to the potential for cardiac arrhythmias. Recommended alternative antihistamine: loratadine, fexofenadine, desloratadine, or cetirizine.
Atorvastatin Atorvastatin AUC increased by 488%.Use with caution at lower end of dosing range (10-40 mg/d). Monitor for Sx of atorvastatin toxicity (rhabdomyolysis and myopathy). Consider alternative agents: pravastatin, fluvastatin, or rosuvastatin.
AzathioprineInteraction unlikely.Applies to all PIs and NNRTIs: Use standard dose.
BepridilMay significantly increase bepridil serum levels.Applies to all PIs: No data. The manufacturer of ATV, RTV, and APV does not recommend bepridil co-administration, this contraindication should extend to all PIs since a significant increase in bepridil serum level can result in pro-arrhythmic events such as VT, PVC, and VFib.
Bisoprolol
May increase risk of PR interval prolongation. Co-administer with close clinical monitoring.
Bosentan 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 patients already on bosentan: discontinue bosentan for >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).
Buprenorphine No significant change in buprenorphine AUC. Use standard dose.
bupropion Bupropion AUC decreased by 46%. Titrate bupropion dose to therapeutic effect.
Bupropion Bupropion AUC decreased 57%. Titrate bupropion based on clinical response.
CarbamazepineLPV serum levels may be significantly decreased.Consider alternative anticonvulsants (e.g.  levetiracetam). With coadministration, monitor anticonvulsants level and consider TDM of LPV.
ChlordiazepoxideMay increase serum levels of chlordiazepoxide.Applies to all PIs: Consider an alternative benzodiazepine (lorazepam, temazepam, or oxazepam).
CisaprideMay significantly increase cisapride serum levels.Contraindicated due to potential for cardiac arrhythmias. Recommended alternative: metoclopramide.
Clorazepate May increase serum levels of clorazepate.Applies to all PIs: Consider an alternative benzodiazepine (lorazepam, temazepam, or oxazepam).
CyclophosphamideMay increase serum level of cyclophosphamide.Applies to all PIs: Data limited to an interaction study conducted with IDV resulting in a 50% increase in cyclophosphamide serum levels. Since all PIs have the potential of increasing cyclophosphamide levels, close monitoring of cyclophosphamide-induced toxicity is recommended.
CyclosporineMay significantly increase serum levels of cyclosporine.Applies to all PIs: Monitor serum levels of cyclosporine closely with co-administration. Cyclosporine dose may need to be decreased.
Dasatinib
Serum concentrations of dasatinib may be increased. Lower doses of dasatinib may be needed.
Desipramine Desipramine AUC may be increased. LPV not affected.Clinical significance unknown. Monitor for desipramine adverse drug reaction and serum level (if available). Consider alternative antidepressant: escitalopram, citalopram, sertraline, or fluoxetine.
Digoxin Digoxin AUC increased 81% with LPV/r co-administration. Monitor digoxin plasma concentration closely with co-administration.May increase risk of PR interval prolongation.
DiltiazemMay increase serum levels of diltiazem.Applies to all PIs: 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 have the potential of prolonging 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 levels.Applies to all PIs: No data. Monitor disopyramide serum levels (target: 2 to 7.5 mcg/mL).
DocetaxelMay increase serum levels of docetaxel.Applies to all PIs: No data. Close monitoring of chemotherapy-induced toxicity recommended.
DofetilideMay significantly increase serum levels of dofetilide.Applies 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.
Echinacea May decrease LPV/r serum levels. Echinacea (400 mg 4xd) decreased CYP3A4 substrate (midazolam) by 23%.Clinical significance unknown but should avoided until the safety of this combination is further evaluated.
Echinacea No interaction. LPV and RTV serum concentrations not affected with Echinacea purpurea 500 mg 3 times daily.
Ergot AlkaloidMay significantly increase serum levels of ergotamine resulting in acute ergot toxicity.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).
Estazolam May increase serum levels of estazolam.Applies to all PIs: Consider an alternative benzodiazepine (i.e lorazepam, temazepam, or oxazepam).
Ethinyl estradiolEthinyl estradiol AUC decreased by 42%.Recommend an alternative or additional form of contraception.
EthosuximideMay increase serum levels of ethosuximide.Applies to all PIs: Consider switching to valproic acid for the treatment of absence seizure.
EtoposideMay increase serum levels of etoposide.Applies to all PIs: No data. Close monitoring of chemotherapy-induced toxicity recommended.
Ezetimibe No significant change in lopinavir/ritonavir trough measurements after the addition of ezetimibe. Separate administration time if possible. Observation pharmacokinetic substudy that needs confirmation
FelodipineMay increase serum levels of felodipine.Applies to all PIs: Data limited to an interaction study conducted with ATV and diltiazem which resulted in doubling of diltiazem serum level (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.
Fentanyl May significantly increase fentanyl serum levels.Use with caution. Consider morphine.
FlecainideMay significantly increase serum levels of flecainide.Contraindicated.
Flurazepam May increase serum levels of flurazepam.Applies to all PIs: Consider an alternative benzodiazepine (i.e lorazepam, temazepam, or oxazepam).
Fluticasone With RTV co-administration fluticasone AUC and Cmax increased by 350-fold and 25-fold, respectively. Data limited to RTV co-administration. With chronic RTV co-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.
FoodIncreases LPV AUC.LPV/r tabs can be taken with or without food.
Garlic supplement 49% and 51% reduction of SQV Cmin and AUC, respectively when co-administered with garlic supplement (3.5 mg twice-daily).
Studies only done with SQV but garlic may affect the serum levels of other PIs or NNRTIs. Co-administration of garlic supplements should be avoided with PIs and NNRTIs.
GranisetronMay increase serum levels of granisetron.Applies to all PIs: Due to the large therapeutic index of granisetron, potential interaction is unlikely to be clinically significant.
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 ifosphamide.Applies to all PIs: No data. Close monitoring of chemotherapy-induced toxicity recommended.
IrinotecanMay increase irinotecan serum levels.Applies 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.

Use standard dose with itraconazole and LPV/r co-administration. Consider monitoring itraconazole levels.
Ketoconazole LPV increased 13%. Ketoconazole increased by 3-fold.Do not exceed ketoconazole 200 mg once-daily with LPV/r co-administration.
Lamotrigine Lamotrigine Cmin and AUC decreased 56% and 50%, respectively. LPV not affected. Increase lamotrigine dose to 200 mg twice-daily when coadministering with LPV/r.
Lamotrigine LPV not affected. Lamotrigine AUC decreased by 50%. Titrate lamotrigine dose to therapeutic effect.
LidocaineMay increase antiarrhythmic serum levels.Applies to all PIs: No data. Use with caution, monitor lidocaine serum levels (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 at 10 mg once-daily). Monitor for adverse effect due to limited clinical data.
Mefloquine May increase serum levels of mefloquine.Applies to all PIs: Monitor mefloquine serum levels. Monitor for mefloquine toxicity (i.e dizziness, LFTs, and periodic ophthalmic examination).
Methadone Methadone AUC decreased by 26-36%.No withdrawal Sx observed in 2 of 3 studies. Standard methadone dose recommended, but may need to increase methadone dose in a small subset of pts. Monitor QTc with high dose methadone; co-administration may increase risk of QTc prolongation.
Metoprolol May increase risk of PR interval prolongation. Co-administer with close clinical monitoring.
MexiletineMay increase antiarrhythmic serum levels.Applies 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 levels.Concurrent administration of oral midazolam is contraindicated. Consider alternative benzodiazepines(temazepam, oxazepam, or lorazepam). If LPV/r is coadministered with IV midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation and dosage adjustment should be considered.
Milk thistle Data limited to an interaction study with milk thistle and IDV. IDV AUC: unchanged and IDV Cmin decreased by 47%.
Unknown effect on LPV serum levels. Avoid co-administration with PIs and NNRTIs until it can be further evaluated.
MirtazapineMay increase serum levels of mirtazapine.Applies to all PIs: Use 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 NNRTI: No significant interaction observed with NVP. Use standard dose.
Nadolol May increase risk of PR interval prolongation. Co-administer with close clinical monitoring.
NefazodoneMay increase serum levels of nefazodone.Applies to all PIs: Use with caution. Consider an alternative antidepressant (i.e SSRI: escitalopram, citalopram, sertraline, or fluoxetine).
NifedipineMay increase serum levels of nifedipine.Applies 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.
Nilotinib Serum concentrations of Nilotinib may be increased. Lower doses of nilotinib may be needed.
NisoldipineMay increase serum levels of nisoldipine.Applies 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.
OmeprazoleNo change in lopinavir/ritonavir pharmacokinetics.Use standard dose LPV/r tablet with omeprazole co-administration.
Paclitaxel May increase serum levels of paclitaxel. Reports of toxicity associated with LPV/r and paclitaxel co-administration.Monitor closely for paclitaxel-induced toxicity.
PCPMay significantly increase serum levels of PCPApplies to all PIs: Avoid all illicit drug use for obvious reasons.
PhenobarbitalLPV levels may be significantly decreased.Consider alternative anticonvulsants (e.g. levetiracetam). Monitor anticonvulsants level when applicable and consider TDM of LPV.
PhenytoinLPV AUC decreased by 33%. Phenytoin AUC decreased by 31%.Avoid co-administration. Monitor anticonvulsants levels. Consider alternative anticonvulsants (e.g. levetiracetam). Consider empirically increasing LPV/r to 600/150 mg (3 tabs) twice-daily (with TDM).
PimozideMay significantly increase pimozide serum levels resulting in QTc prolongation.Contraindicated. Consider alternative: Olanzapine.
Pravastatin Pravastatin AUC increased 33%. Use standard dose.
Prednisone May increase prednisone serum concentration. May require dose adjustment with long-term co-administration.
PropafenoneMay significantly increase serum levels of propafenone.Contraindicated.
Propranolol May increase risk of PR interval prolongation. Co-administer with close clinical monitoring.
Quinidine May increase antiarrhythmic serum levels.Applies to all PIs: No data. Contraindicated with RTV. With all PIs and NNRTI co-administration, monitor EKG (QTc) and serum levels: Target: 2 to 5 mcg/mL.
Raltegravir Interaction unlikely. No data with LPV/r. RTV (100 mg twice-daily ) did not affect RAL PK parameters. Consider usual dose with close monitoring of virologic efficacy.
RanitidineNo interactionUse standard dose LPV/r tablet with ranitidine co-administration.
Ranolazine May significantly increase ranolazine serum concentrations. Avoid co-administration. May increase risk of QTc prolongation.
Rifabutin Rifabutin AUC increased by 203%. LPV serum level increased 20% (NS).Dose: LPV/r 2 tabs twice-daily +rifabutin 150 mg every other day. In an observational study, rifabutin serum concentrations lower compared to historical controls. Rifabutin TDM recommended with co-administration.
Rifapentine LPV serum levels may be significantly decreased.Avoid co-administration. Consider using rifabutin.
RosiglitazoneLPV AUC increased by 20% and Cmin increased by 21%. Use standard dose. Limited sample size (NS) (n=4).
Rosuvastatin Rosuvastatin AUC and Cmax increased 2.1 to 4.7-fold, respectively. LPV and RTV PK parameters not significantly affected.Use with close monitoring due to limited clinical data. Use low dose rosuvastatin and titrate slowly.
Salmeterol May increase salmeterol serum concentrations. Avoid co-administration. Consider formoterol
SildenafilMay increase sildenafil serum levels.Applies to all PIs: Use with close monitoring. Do not exceed 25 mg in 48-hrs.
Simvastatin May significantly increase simvastatin levels.Contraindicated. Alternative HMG-CoA reductase inhibitor that may be used include pravastatin, cerivastatin, fluvastatin. Monitor for adverse effects due to limited clinical data.
SirolimusMay significantly increase serum levels of sirolimus.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 wortMay significantly decrease LPV serum levels.Contraindicated. Studies only done with IDV but St. John's wort likely to increase metabolism of other PIs and NNRTIs. Use an alternative (more effective) antidepressant.
TacrolimusTacrolimus increased 10-fold with co-administration. Several case reports of toxic serum levels of tacrolimus upon initiation of LPV/r.Dose tacrolimus based on serum levels. A much lower dose (0.5-1 mg/week or 1/20-1/10 of standard dose) may be sufficient with LPV/r co-administration.
TadalafilMay increase serum level of tadalafil.Applies to all PIs: 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 level of tamoxifen.Applies to all PIs: No data. Close monitoring of tamoxifen- induced toxicity recommended.
TeniposideMay increase serum level of teniposide.Applies to all PIs: No data. Close monitoring of teniposide induced toxicity recommended.
TerfenadineMay significantly increase terfenadine serum levels.Contraindicated 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.
TrazadoneMay increase serum levels of trazadone.Applies to all PIs: Use with caution. Consider an alternative antidepressant (SSRI:escitalopram, citalopram, sertraline, or fluoxetine).
Trazodone Trazodone AUC increased by 2.4 fold with RTV co-administration. Data limited to RTV co-administration. 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 triazolam serum levels.Contraindicated. Consider alternative benzodiazepines(temazepam, oxazepam, or lorazepam).
Valproic Acid May decrease valproic serum concentrations. LPV AUC increased by 75%. Monitor for LPV associated ADR and valproic serum concentrations with co-administration.
VardenafilMay significantly increase serum levels of vardenafil.Applies to all PIs: Do not exceed vardenafil 2.5 mg in 72 hrs (with RTV) or 2.5 mg in 24 hrs (with other PIs). Consider sildenafil due to more clinical data and less pronounced interaction. Avoid co-administration with IDV.
VerapamilMay increase serum levels of verapamil.Applies 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.
VinblastineMay increase serum levels of vinblastine.Applies to all PIs: No data. Close monitoring of vinblastine- induced toxicity recommended.
VincristineMay increase serum levels of vincristine.Applies 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 PI and NNRTI serum levels may be affected when co-administered with similar dose of vitamin C.
Voriconazole May significantly decrease voriconazole AUC. Voriconazole may increase LPV. Significant interaction with EFV and RTV (400mg twice-daily); contraindicated. Voriconazole AUC decreased 39% with RTV 200 mg/d co-administration; avoid co-administration with boosted PI. Consider another antifungal for aspergillosis (i.e ambisome or caspofungin) or use with TDM. Voriconazole dose may need to be increased.
Warfarin A case report of increased warfarin requirement after RTV initiation.
Other PIs and NNRTIs may also affect warfarin requirements. Monitor INR closely with co-administration.

RESISTANCE

  • Resistance develop from multiple PI mutations.
  • Primary PI mutations (32I, 82A/F/T/S, 47V/A ) and secondary PI mutations (10, 20, 24, 33, 46, 47, 50, 53, 54, 63, 71, 73, 76, 84, 90): >4 mutations: decrease potency of LPV/r.
  • I50V: selected by APV; reduces susceptibility to LPV.
  • 63P: reduced susceptibility to LPV when combined with other PI mutations.

PHARMACOLOGY

Pharmacology

COMMENTS

  • Pros: Coformulation with RTV may improve adherence in some pts. Preferred PI in pregnancy. Long-term efficacy as initial therapy; good PK profile that exceed IC50 by >25-fold throughout dosing interval,enabling LPV/r to have activity against some PI resistant strains, though DRV/r or sometimes TPV/r now preferred for pts with PI resistance based on TITAN, POWER and RESIST studies. Better CD4 response compared to EFV-containing regimens, and less resistance with failure.
  • Cons: GI intolerance, hyperlipidemia, and/or insulin resistance in some pts. More GI toxicity than with some other boosted PIs. Virologically inferior to EFV-containing regimens in PI-naive patients. DRV/r and TPV/r preferred for highly experienced pts, and DRV/r may have advantage even in LPV-susceptible, PI-experienced pts. For PI-naive pts, other once-daily boosted PIs with lower RTV dose (e.g. ATV/r, DRV/r, and possibly FPV/r) have comparable or superior efficacy with better tolerability and less toxicity. May have lower potency in pts with baseline CD4 <50 compared to CD4>200.

REFERENCES

REFERENCED WITHIN THIS GUIDE


 
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