Zambian HIV Guidelines:: Tipranavir

	Zambia HIV National Guidelines
	Adverse Effects and Toxicity Antiretroviral Therapy Adherence ARV Therapy for Individuals with Tuberculosis Co-Infection Baseline evaluation and Monitoring Changing or Stopping ART Cotrimoxazole Prophylaxis General Principles of Antiretroviral Therapy for Chronic HIV Infection in Adults and Adolescents HIV Counseling and Testing Immune Reconstitution Inflammatory Syndrome (IRIS) Initial Regimen for ARV Therapy Introduction Sexually Transmitted Infections (STIs) Nutrition Care and Support Palliative Care in HIV and AIDS Post Exposure Prophylaxis Stopping ARV Therapy Treatment Failure When to Start ARV Therapy for Chronic HIV Infection in Adults and Adolescents WHO Staging in Adults and Adolescents Calculations: Ideal Body Weight, Body Mass Index and Creatinine Clearance
	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 and Jabbin Mulwanda MMed FCS

Drugs>Antiretrovirals>

Tipranavir

Paul A. Pham, Pharm.D. and John G. Bartlett, M.D.
04-24-2008

Zambia Specific Information

Currently not available in Zambia.
Active against many PI-resistant strains, but higher rates of side effects (e.g. GI intolerance, hepatitis, intracranial hemorrhage) compared to other boosted protease inhibitors.

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

INDICATIONS

FDA

Treatment of HIV+ pts with evidence of viral replication, who are highly treatment-experienced or have HIV resistant to multiple PIs.

FORMS

brand name	generic	Mfg	brand forms	cost*
Aptivus	Tipranavir	Boehringer Ingelheim	Oral capsule 250mg	$9.31

*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

TPV 500 mg + RTV 200 mg bid with food. A minimum of RTV 200 mg bid must be used with TPV in order to achieve desired serum level.
ETR, LPV/r, SQV, APV, FPV, and ATV: Co-administration not recommended due to potent inducing effects of TPV on Pgp and and glucuronidation.
EFV: Standard TPV dose, but PK study conducted with TPV 750mg + RTV 200?mg bid.
NVP: Consider standard dose.
DLV: no data.
IDV , NFV , DRV : no data, avoid co-administration
With maraviroc: TPV 500 mg + RTV 200 mg bid with food plus maraviroc 300 mg bid
With raltegravir: consider standard dose.

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

No data. Usual dose likely (dose post-HD)

DOSING IN PERITONEAL DIALYSIS

No data. Usual dose likely

DOSING IN HEMOFILTRATION

No data

ADVERSE DRUG REACTIONS

COMMON

Transaminase elevation: Grade 2-4 ALT and/or AST elevation reported in 17.5% of TPV/r-treated pts vs.10% in comparator group (LPV/r, IDV/r, SQV/r, and APV/r).
Elevated serum triglycerides: Grade 3-4 (TG >750 mg/dL) in 19% of TPV/r -treated pts vs. 9% in comparator group (LPV/r, IDV/r, SQV/r, and APV/r).
Elevated cholesterol: Grade 3-4 (chol >400 mg/dL) reported in 3% of TPV/r-treated pts vs. 0.3% in comparator group (LPV/r, IDV/r, SQV/r, and APV/r).
Incidence of diarrhea, nausea, vomiting, and abdominal pain comparable to other PIs.

OCCASIONAL

Other PI class adverse effects: insulin resistance, including hyperglycemia, and fat accumulation.
Headache
Rash reported in 8-14%. Appears to be higher in women.

RARE

Intracranial hemorrhage: avoid in pts with head trauma/surgery or bleeding diathesis

DRUG INTERACTIONS

In vitro, TPV/r inhibits CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A and induces phase II glucuronidation and the drug transporter P-glycoprotein (P-gp).

Drug-to-Drug Interactions

Drug-to-Drug Interaction

Drug	Effect of Interaction	Recommendations/Comments
Zidovudine	AZT AUC decreased by approx. 42% with TPV/r 250/200 mg BID co-administration	Clinical significance unknown. Intracellular AZT levels not measured.
Efavirenz	PK profile of TPV/r unchanged by EFV following single dose; EFV levels also unchanged. Increases in TPV AUC, Cmax, and C12h seen at steady-state with EFV.	Unclear from abstract if EFV levels were measured at steady-state (Roszko PJ, et al. 2nd IAS, Paris, abstract 865, 2003).?Phase III trials currently using TPV/r 500/200 mg with coadministration of EFV 600mg qhs.
Fluconazole	TPV AUC increased by 50%. No change in fluconazole levels.	Use standard dose TPV/r. Avoid fluconazole >200mg QD. Monitor liver function closely.
Lopinavir/ritonavir	LPV AUC decreased by 55%	Not recommended.
Rifampin	May significantly decrease serum level of TPV	Contraindicated. Consider use with rifabutin
Saquinavir	SQV AUC decreased 76%	Do not coadminister
Abacavir	ABC AUC decreased by approx 40%	Clinical significance unknown. ABC intracellular triphosphate levels not measured.
Clarithromycin	TPV AUC increased 66%. Clarithromycin AUC increased 19%.	Use standard dose TPV/r. Consider clarithromycin dose adjustment in renal failure. Cr CL 30-60 ml/min=50% of dose. Cr CL <30ml/min=25% of dose.
Metronidazole	May result in disulfiram like reaction.	Avoid co-administration due to the alcohol content in the TPV/r capsules
Fosamprenavir	May significantly decrease APV serum concentrations.	Avoid co-administration.
Atazanavir (ATV)	ATV AUC decreased by 39% and Cmin decreased by 70%. TPV AUC increased by 11% and Cmin increased by 59%.	Avoid co-administration.
Delavirdine (DLV)	May decrease DLV serum concentrations.	No data; avoid co-administration
Darunavir (DRV)	May significantly decrease DRV concentrations.	Avoid co-administration.
Darunavir (DRV)	May decrease DRV serum concentrations.	No data; avoid co-administration
Didanosine (EC)	ddI AUC decreased by 33% with TPV/r 250/200 mg BID co-admin.	Clinical significance unknown. Consider separating administration time by at least 2 hrs. ddI buffer may also decrease TPV serum level; separate administration time by at least 2 hrs.
Indinavir (IDV)	May decrease IDV serum concentrations.	No data; avoid co-administration
Nelfinavir (NFV)	Nelfinavir active metabolites may be decreased.	No data; avoid co-administration
Nevirapine (NVP)	NVP AUC not significantly decreased. TPV PK not reported.	Consider standard dose
Alprazolam	May increase serum level of alprazolam	Consider an alternative benzodiazepine (lorazepam, temazepam, oxazepam)
Amiodarone	May significantly increase amiodarone serum level	Contraindicated
Amlodipine	May increase serum level 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 level, which led to PR interval prolongation. All PIs and DLV have potential of prolonging PR interval with calcium channel blocker coadministration.
Amprenavir	APV AUC decreased 45%	Not recommended.
Antacid	TPV AUC decreased by 25-29%	Consider spacing antacid 2 hrs before or 2 hrs after TPV/r co-administration.
Antacids	TPV AUC decreased by approx 30%.	Avoid co-administration or separate administration time by 2 hrs.
Artemether (artemisinin)	May increase serum level of artemether	Data only available 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).
Aspirin	May increase risk of bleeding	Avoid co-administration or use with caution
Astemizole	May significantly increase astemizole serum level	Contraindicated
Atorvastatin	TPV/r increased atorvastatin AUC by 8-fold	Caution with coadministration. Consider alternative HMG CoA reductase inhibitor such as rosuvastatin or pravastatin.
Azathioprine	Interaction unlikely	Applies to all PIs and NNRTI: Use standard dose.
Bepridil	May significantly increase bepridil serum level	Contraindicated.
Carbamazepine	May decrease serum level of PIs and NNRTIs. PIs and NNRTIs may increase or decrease carbamazepine serum level	Applies to all PIs and NNRTIs: Consider alternative anticonvulsants (i.e valproic acid, lamotrigine, levetiracetam, or topiramate). Monitor carbamazepine levels and consider TDM of PIs and NNRTIs.
Chlordiazepoxide	May increase serum level of chlordiazepoxide	Applies to all PIs and DLV: Consider an alternative benzodiazepine (i.e lorazepam, oxazepam, or temazepam)
Cisapride	May significantly increase ergotamine serum level	Contraindicated
Clopidogrel	May increase risk of bleeding	Avoid co-administration or use with caution
Clorazepate	May increase serum level of clorazepate	Applies to all PIs and DLV: Consider an alternative benzodiazepine (lorazepam, oxazepam, temazepam)
Cyclophosphamide	May increase serum level of cyclophosphamide	Applies to all PIs and DLV: Data limited to an interaction study conducted with IDV resulting in 50% increase in cyclophosphamide levels. Since all PIs and DLV have the potential of increasing cyclophosphamide levels, close monitoring of cyclophosphamide-induced toxicity is recommended.
Cyclosporine	May significantly increase or decrease serum level of cyclosporine	Applies to All PIs: Monitor serum level of cyclosporine closely with coadministration.
Desipramine	Desipramine levels may be increased.	Use with caution. Consider dose reduction with close monitoring.
Tenofovir DF	17% decrease in TPV AUC at the 500/100 mg dose and an 11% decrease in TPV AUC with 750/200 mg.	Unlikely to be significant. Use standard dose.
Digoxin	May decrease digoxin concentrations secondary to Pgp induction.	No data. Monitor digoxin serum concentration with co-administration.
Diltiazem	May increase serum level of diltiazem	Applies to all PIs and DLV: Data limited to an interaction study conducted with ATV that resulted in doubling of diltiazem levels, which led to PR interval prolongation. All PIs and DLV have potential of prolonging PR interval with diltiazem coadministration.
Disopyramide	May increase disopyramide serum levels	Applies to all PIs and DLV: No data. Monitor disopyramide serum level (target: 2-7.5 mcg/mL).
Disulfiram	May result in disulfiram like reaction.	Avoid co-administration due to the alcohol content in the TPV/r capsules
Docetaxel	May increase serum level 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.
Ergotamine	May significantly increase ergotamine serum level	Contraindicated
Estazolam	May increase serum level of estazolam	Applies to all PIs and DLV: Consider an alternative benzodiazepine (lorazepam, oxazepam, or temazepam)
Ethinyl estradiol	EE AUC decreased by 50%	Alternative form of contraception should be used. 33% incidence of rash in healthy volunteer study.
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 level of etoposide	Applies to all PIs and DLV: No data. Close monitoring of chemotherapy-induced toxicity recommended.
Etravirine (ETR)	ETR AUC decreased by 76%	Avoid co-administration.
Etravirine (ETV)	Etravirine AUC decreased by 76%. TPV and RTV AUC increased by 18% and 23%, respectively	Avoid co-administration.
Felodipine	May increase serum level of felodipine	Applies to all PIs and DLV: Data limited to an interaction study conducted with ATV and diltiazem that resulted in doubling of diltiazem serum level, which led PR interval prolongation. All PIs and DLV have potential of prolonging PR interval with calcium channel blocker coadministration.
Flecainide	May increase antiarrhythmic serum levels	Contraindicated.
Flurazepam	May increase serum level of flurazepam	Applies to all PIs and DLV: Consider an alternative benzodiazepine (lorazepam, oxazepam, or temazepam)
Granisetron	May increase serum level of granisetron	Applies to all PIs and DLV: Due to large therapeutic index of granisetron, potential interaction 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.
Hypoglycemics	TPV/r may increase or decrease hypoglycemic agents (glimepiride, glipizide, glyburide, pioglitazone, repaglinide, and tolbutamide)	Careful glucose monitoring is recommended with co-administration.
Ifosphamide	May increase serum level of ifosphamide	Applies to all PIs and DLV: No data. Close monitoring of chemotherapy-induced toxicity recommended.
Irinotecan	May increase irinotecan serum level	Applies to all PIs and DLV: Coadministration of ATV contraindicated by manufacturer. All PIs and DLV also have potential for significant interaction with irinotecan; therefore, co-administer with extreme caution.
Itraconaozole	Itraconazole levels may be increased.	Doses higher than 200 mg not recommended.
Ketoconazole	Ketoconazole levels may be increased.	Doses higher than 200 mg not recommended.
Lidocaine	May increase antiarrhythmic serum levels	Applies to all PIs and DLV: No data. Use with caution, monitor lidocaine serum level (target: 1.5-6 mcg/mL) with co-administration.
Maraviroc	No significant interaction	Use standard dose.
Mefloquine	May increase serum levels of mefloquine	Applies to all PIs and DLV: If available consider mefloquine serum level monitoring. Monitor for mefloquine toxicity (i.e dizziness, LFTs, and periodic ophthalmic examination).
Meperidine	Increased normeperidine levels	Avoid co-administration.
Methadone	Methadone decreased by 50%	Monitor for withdrawal signs and symptoms. Methadone stereoisomer not specified but may require methadone dose increase.
Mexiletine	May increase serum levels of mexiletine	Applies to all PIs and DLV: No data. Use with caution. Monitor EKG and serum level. Serum levels exceeding 1.5-2 mcg/mL have been associated with an increased risk of toxicity.
Midazolam	May significantly increase midazolam serum level	Contraindicated. Consider alternative benzodiazepine (e.g lorazepam, oxazepam, or temazepam).
Mirtazapine	May increase serum level of mirtazapine	Applies to all PIs and DLV: Use with caution. Consider an alternative antidepressant (i.e SSRI: escitalopram, citalopram, sertraline, or fluoxetine.)
Mycophenolate	Interaction unlikely	Applies to all PIs and NNRTI.
Nefazodone	May increase serum level of nefazodone	Applies to all PIs and DLV: Use with caution. Consider 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 that resulted in doubling of diltiazem serum level, which led tp PR interval prolongation. All PIs and DLV have potential of prolonging PR interval with calcium channel blocker coadministration.
Nisoldipine	May increase serum level of nisoldipine	Applies to all PIs and DLV: Data limited to an interaction study conducted with ATV and diltiazem that resulted in doubling of diltiazem serum levels, which led to PR interval prolongation. All PIs and DLV have potential of prolonging PR interval with calcium channel blocker coadministration.
NSAIDs	May increase risk of bleeding	Avoid co-administration or use with caution
Paclitaxel	May increase paclitaxel serum level	Applies to all PIs and DLV: Data limited to case reports of severe toxicity associated with DLV and LPV/r coadministration with paclitaxel. Since all PIs have potential of significantly increasing paclitaxel serum level; close monitoring of paclitaxel-induced toxicity recommended.
PCP	May significantly increase serum level of PCP	Applies to all PIs and DLV: Avoid all illicit drug use with PIs and DLV.
Phenobarbital	May decrease serum level of PIs and NNRTIs. PIs and NNRTIs may increase or decrease phenobarbital serum levels	Applies to all PIs and NNRTIs: Consider alternative anticonvulsants (i.e valproic acid, lamotrigine, levetiracetam, or topiramate). With coadministration, monitor anticonvulsant levels and consider TDM of PIs and NNRTIs.
Phenytoin	May decrease serum level of PIs and NNRTIs. PIs and NNRTIs may increase or decrease phenytoin serum level	Applies to all PIs and NNRTIs: Consider alternative anticonvulsants (i.e valproic acid, lamotrigine, levetiracetam, or topiramate). With coadministration, monitor anticonvulsant levels and consider TDM of PIs and NNRTIs.
Pimozide	May significantly increase pimozide serum level	Contraindicated.
Propafenone	May increase antiarrhythmic serum levels	Contraindicated.
Quinidine	May increase antiarrhythmic serum levels	Contraindicated.
Raltegravir (RAL)	TPV/r decreased MK-0518 Cmin by 24%, but did not affect AUC.	Clinical significance unknown; standard dose likely. .
Rifabutin	Rifabutin AUC increased 190%. No change in TPV levels.	Dose rifabutin 150mg QOD with TPV/r co-administration.
Rifapentine	TPV serum levels may be significantly decreased.	Avoid coadministration. Consider using rifabutin.
Rosuvastatin	Other CYP3A4 inhibitor (i.e erythromycin) did not affect rosuvastatin serum level. In another study rosuvastatin AUC and Cmax increased 2.1 to 4.7-fold, respectively. LPV and RTV PK parameters not significantly affected.	Data available only for LPV . PK study evaluating the effects of TPV on rosuvastatin PK is underway . Close LFTs monitoring recommended due to limited clinical data.
Sildenafil	May increase sidenafil serum level.	Applies to all PIs and DLV: Use with close monitoring. Do not exceed 25 mg in a 48-hr period.
Sirolimus	May significantly increase or decrease serum level of sirolimus	Applies to all PIs: Dose sirolimus based on serum level.
Tacrolimus	May significantly increase or decrease serum level of tacrolimus	Applies to All PIs: Dose tacrolimus based on serum level.
Tadalafil	May increase serum level of tadalafil.	Applies to all PIs and DLV: Start with 5mg. Do not exceed 10mg in 72 hrs. Consider sildenafil due to more clinical data and shorter half-life allowing for easier titration.
Tamoxifen	May increase serum level of tamoxifen	Applies to all PIs and DLV: No data. Close monitoring fortamoxifen-induced toxicity recommended.
Teniposide	May increase serum level of teniposide	Applies to all PIs and DLV: No data. Close monitoring of teniposide-induced toxicity recommended.
Terfenadine	May significantly increase terfenadine serum level	Contraindicated
THC	Based on data with NFV and IDV, interactions unlikely	Applies to PIs and NNRTIs: Interactions are unlikely.
Ticlopidine	May increase risk of bleeding?	Avoid co-administration or use with caution
Trazadone	May increase serum level of trazadone	Applies to all PIs and DLV: Use with caution. Consider an alternative antidepressant (i.e SSRI:?escitalopram, citalopram, sertraline, or fluoxetine)
Triazolam	May significantly increase serum level of triazolam	Contraindicated. Consider alternative benzodizepine (e.g lorazepam, oxazepam, and temazepam).
Vardenafil	May significantly increase serum level of vardefnafil.	Applies to all PIs and DLV: Do not exceed vardenafil 2.5 mg in 72hrs (with RTV) or 2.5mg in 24 hrs (with other PIs and DLV). Consider sildenafil due to more clinical data and less pronounced interaction. Avoid coadministration with IDV.
Verapamil	May increase serum level of verapamil	Applies to all PIs and DLV: Data limited to an interaction study conducted with ATV and diltiazem that resulted in doubling of diltiazem serum level, which led PR interval prolongation. All PIs and DLV have potential for prolonging PR interval with calcium channel blocker coadministration.
Vinblastine	May increase serum level of vinblastine	Applies to all PIs and DLV: No data. Close monitoring of vinblastine-induced toxicity recommended.
Vincristine	May increase serum level of vincristine	Applies to all PIs and DLV: No data. Close monitoring of vincristine-induced toxicity recommended.
Voriconazole	May decrease voriconazole AUC. Voriconazole may increase TPV AUC.	Significant interaction with EFV and RTV (400mg bid) but not IDV; data with other PIs and NNRTIs not available and should be used with caution with close monitoring for therapeutic efficacy. Consider adding another antifungal for aspergillosis i.e Ambisome or caspofungin.
Warfarin	May increase risk of bleeding	Use with caution, with close monitoring of INR

RESISTANCE

In RESIST-1 & -2 trials, 50% response (VL reduction >0.5 log or wk 4 VL <50) with <12 PI mutations; 32% with >19. 41-44% response with up to 5 primary PI mutations.
Mutation score: the following mutations affect TPV susceptibility: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E, 69K, 74P, 82L/T, 83D, 84V. >2 mutations = reduced susceptibility; >7 mutations = resistance
30N, 48V, 50V/L, 82A, 90M do not contribute to TPV mutation score
Phenotypic resistance (PhenoSense assay): FC <1 = full susceptibility; FC 1-4 = partial susceptibility; FC >4 = resistance

PHARMACOLOGY

Pharmacology

COMMENTS

Pros: Active against many PI-resistant strains. More active than other boosted PIs in PI-experienced pts in RESIST trials.
Cons: Requires boosting with RTV 200 mg bid. More transaminase and lipid elevation than with comparator PIs. Can't be combined with other PIs because of potent Pgp induction. DRV often active in these pts (and in some with TPV resistance), and is generally better tolerated. Recent FDA black box warning of potential risk for fatal and nonfatal intracranial hemorrhage in patients treated with boosted TPV.

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Abbreviations