indication

Indicated in combination with other antiretroviral agents for the treatment of HIV-infection.

pharmacology

Ritonavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Ritonavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs.

mechanism of action

Ritonavir inhibits the HIV viral proteinase enzyme which prevents cleavage of the gag-pol polyprotein, resulting in noninfectious, immature viral particles.

toxicity

Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir 1500 mg/day for two days. The patient reported paresthesias which resolved after the dose was decreased. A post-marketing case of renal failure with eosinophilia has been reported with ritonavir overdose. The approximate lethal dose was found to be greater than 20 times the related human dose in rats and 10 times the related human dose in mice.

biotransformation

Hepatic. Five metabolites have been identified. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of ritonavir, however, plasma concentrations are low. The cytochrome P450 enzymes CYP3A and CYP2D6 are primarily involved in the metabolism of ritonavir.

absorption

The absolute bioavailability of ritonavir has not been determined.

half life

3-5 hours

drug interactions

Abacavir: The serum concentration of Abacavir may be decreased by protease inhibitors such as Ritonavir. The antiviral response should be closely monitored.

Alfuzosin: Ritonavir increases the effect/toxicity of alfuzosin

Alprazolam: The protease inhibitor, ritonavir, may increase the effect of the benzodiazepine, alprazolam.

Aminophylline: Ritonavir decreases the effect of theophylline

Amiodarone: Ritonavir increases the effect and toxicity of amiodarone

Amitriptyline: Ritonavir may increase the effect and toxicity of the tricyclic antidepressant, amitriptyline, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of amitriptyline if ritonavir if initiated, discontinued or dose changed.

Amoxapine: Ritonavir may increase the effect and toxicity of the tricyclic antidepressant, amoxapine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of amoxapine if ritonavir if initiated, discontinued or dose changed.

Aprepitant: This CYP3A4 inhibitor increases the effect and toxicity of aprepitant

Astemizole: Increased risk of cardiotoxicity and arrhythmias

Atazanavir: Association with dose adjustment

Atomoxetine: The CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine

Atorvastatin: Ritonavir may increase the serum concentration of atorvastatin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of atorvastatin if ritonavir is initiated, discontinued or dose changed.

Bepridil: Ritonavir increases the effect and toxicity of bepridil

Bromazepam: Ritonavir, a strong CYP3A4 inhibitor, may increase the serum concentration of bromazepam by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of bromazepam if ritonavir is initiated, discontinued or dose changed. Dosage adjustments may be required.

Bupropion: Ritonavir increases the effect and toxicity of bupropion

Buspirone: Ritonavir increases the effect and toxicity of buspirone

Carbamazepine: Ritonavir increases the effect of carbamazepine

Chlordiazepoxide: The protease inhibitor, ritonavir, may increase the effect of the benzodiazepine, chlordiazepoxide.

Ciclesonide: Increased effects/toxicity of ciclesonide

Cisapride: Increased risk of cardiotoxicity and arrhythmias

Clomipramine: Ritonavir may increase the effect and toxicity of the tricyclic antidepressant, clomipramine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of clomipramine if ritonavir if initiated, discontinued or dose changed.

Clonazepam: The protease inhibitor, ritonavir, may increase the effect of the benzodiazepine, clonazepam.

Clorazepate: The protease inhibitor, ritonavir, may increase the effect of the benzodiazepine, clorazepate.

Clozapine: Ritonavir increases the effect and toxicity of clozapine

Cyclosporine: The protease inhibitor, ritonavir, may increase the effect of cyclosporine.

Dantrolene: Ritonavir may increase the serum concentration of dantrolene by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of dantrolene if ritonavir is initiated, discontinued or dose changed.

Darifenacin: This potent CYP3A4 inhibitor slows darifenacin/solifenacin metabolism

Delavirdine: Increases the effect of ritonavir

Desipramine: Ritonavir may increase the effect and toxicity of the tricyclic antidepressant, desipramine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of desipramine if ritonavir if initiated, discontinued or dose changed.

Diazepam: The protease inhibitor, ritonavir, may increase the effect of the benzodiazepine, diazepam.

Digoxin: Ritonavir increases levels/effect of digoxin

Dihydroergotamine: The protease inhibitor, ritonavir, may increase the effect and toxicity of the ergot derivative, dihydroergotamine.

Diltiazem: Ritonavir increases diltiazem levels

Doxepin: Ritonavir may increase the effect and toxicity of the tricyclic antidepressant, doxepin, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of doxepin if ritonavir if initiated, discontinued or dose changed.

Eletriptan: The protease inhibitor, ritonavir, may increase the effect and toxicity of eletriptan.

Eplerenone: This protease inhibitor, ritonavir, may increase the effect and toxicity of eplerenone.

Ergotamine: The protease inhibitor, ritonavir, may increase the effect and toxicity of the ergot derivative, ergotamine.

Erlotinib: This CYP3A4 inhibitor increases levels/toxicity of erlotinib

Erythromycin: Increased toxicity of both agents

Estazolam: The protease inhibitor, ritonavir, may increase the effect of the benzodiazepine, estazolam.

Ethinyl Estradiol: Ritonavir could decrease the contraceptive efficacy

Fentanyl: Ritonavir increases the effect and toxicity of fentanyl/alfentanyl

Flecainide: Ritonavir increases the toxicity of the anti-arrhythmic

Fluoxetine: Increased risk of serotonin syndrome

Flurazepam: The protease inhibitor, ritonavir, may increase the effect of the benzodiazepine, flurazepam.

Fusidic Acid: The protease inhibitor, ritonavir, may increase the effect and toxicity of fusidic acid.

Gefitinib: This CYP3A4 inhibitor increases levels/toxicity of gefitinib

Imipramine: Ritonavir may increase the effect and toxicity of the tricyclic antidepressant, imipramine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of imipramine if ritonavir if initiated, discontinued or dose changed.

Itraconazole: Itraconazole may increase the effect and toxicity of ritonavir.

Ketoconazole: Ketoconazole may increase the effect and toxicity of ritonavir.

Lovastatin: Ritonavir may increase the effect and toxicity of lovastatin. Concomitant therapy is contraindicated.

Mefloquine: Mefloquine decreases the effect of ritonavir

Meperidine: Ritonavir increases the levels of analgesic

Methadone: The protease inhibitor, ritonavir, may decrease the effect of methadone.

Midazolam: The protease inhibitor, ritonavir, may increase the effect of the benzodiazepine, midazolam.

Nortriptyline: Ritonavir may increase the effect and toxicity of the tricyclic antidepressant, nortriptyline, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of nortriptyline if ritonavir if initiated, discontinued or dose changed.

Olanzapine: Ritonavir decreases the effect of olanzapine

Oxtriphylline: Ritonavir decreases the effect of theophylline

Pimozide: The protease inhibitor, ritonavir, may increase the effect and toxicity of pimozide.

Piroxicam: Ritonavir increases the toxicity of piroxicam

Propafenone: Ritonavir increases the effect and toxicity of propafenone

Propoxyphene: Ritonavir increases the levels of analgesic

Quinidine: Ritonavir increases the effect and toxicity of quinidine

Quinupristin: This combination presents an increased risk of toxicity

Ranolazine: Increased levels of ranolazine - risk of toxicity

Rifabutin: Rifabutin decreases the effect of ritonavir

Rifampin: Rifampin decreases the effect of ritonavir

Rivaroxaban: Use of rivaroxaban with agents that are strong inhibitors of both CYP3A4 like ritonavir and P-glycoproteins are contraindicated.

Tacrolimus: The protease inhibitor, Ritonavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Ritonavir therapy is initiated, discontinued or altered.

Tadalafil: Ritonavir may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Tamoxifen: Ritonavir may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Concomitant therapy should be avoided.

Tamsulosin: Ritonavir, a CYP3A4/2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4/2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Ritonavir is initiated, discontinued, or dose changed.

Telithromycin: Ritonavir may increase the plasma concentration of Telithromycin. Consider alternate therapy or monitor therapeutic/adverse effects.

Temsirolimus: Ritonavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Teniposide: The strong CYP3A4 inhibitor, Ritonavir, may decrease the metabolism and clearance of Teniposide, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Teniposide if Ritonavir is initiated, discontinued or dose changed.

Terfenadine: Increased risk of cardiotoxicity and arrhythmias

Theophylline: Ritonavir decreases the effect of theophylline

Tiagabine: The strong CYP3A4 inhibitor, Ritonavir, may decrease the metabolism and clearance of Tiagabine, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Tiagabine if Ritonavir is initiated, discontinued or dose changed.

Tolterodine: Ritonavir may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.

Topotecan: The p-glycoprotein inhibitor, Ritonavir, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.

Tramadol: Ritonavir may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Ritonavir may decrease the effect of Tramadol by decreasing active metabolite production.

Trazodone: The protease inhibitor, Ritonavir, may increase the efficacy/toxicity of Trazodone by inhibiting Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Ritonavir is initiated, discontinued or dose changed.

Tretinoin: The strong CYP2C8 inhibitor, Ritonavir, may decrease the metabolism and clearance of oral Tretinoin. Consider alternate therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Ritonavir is initiated, discontinued to dose changed.

Triazolam: The protease inhibitor, ritonavir, may increase the effect of the benzodiazepine, triazolam.

Trimipramine: The strong CYP3A4/CYP2D6 inhibitor, Ritonavir, may decrease the metabolism and clearance of Trimipramine, a CYP3A4/CYP2D6 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimipramine if Ritonavir is initiated, discontinued or dose changed.

Vardenafil: Ritonavir, a potent CYP3A4 inhibitor, may decrease the metabolism and clearance of Vardenafil. Concomitant therapy is contraindicated.

Venlafaxine: Ritonavir, a CYP2D6 and CYP3A4 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP2D6 and CYP3A4 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Ritonavir is initiated, discontinued, or dose changed.

Verapamil: Ritonavir, a strong CYP3A4 inhibitor, may increase the serum concentration of Veramapil, a CYP3A4 substrate, by decreasing its metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Verapamil if Ritonavir is initiated, discontinued or dose changed.

Vinblastine: Ritonavir, a strong CYP3A4 inhibitor, may decrease the metabolism of Vinblastine. Consider alternate therapy to avoid Vinblastine toxicity. Monitor for changes in the therapeutic/adverse effects of Vinblastine if Ritonavir is initiated, discontinued or dose changed.

Vincristine: Ritonavir, a strong CYP3A4 and p-glycoprotein inhibitor, may increase the serum concentration of Vincristine by decreasing its metabolism and/or increasing efflux. Consider alternate therapy to avoid Vincristine toxicity. Monitor for changes in the therapeutic and adverse effects of Vincristine if Ritonavir is initiated, discontinued or dose changed.

Vinorelbine: Ritonavir, a strong CYP3A4 inhibitor, may increase the serum concentration of Vinorelbine by decreasing its metabolism. Consider alternate therapy to avoid Vinorelbine toxicity. Monitor for changes in the therapeutic and adverse effects of Vinorelbine if Ritonavir is initiated, discontinued or dose changed.

Voriconazole: Ritonavir may decrease the serum concentration of voriconazole by increasing its metabolism. Concomitant therapy with high dose ritonavir is contraindicated. Caution should be used with lower doses as decreased voriconazole efficacy may occur.

Zolpidem: Ritonavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zolpidem by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zolpidem if ritonavir is initiated, discontinued or dose changed.

Zonisamide: Ritonavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zonisamide by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zonisamide if ritonavir is initiated, discontinued or dose changed.

Zopiclone: Ritonavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if ritonavir is initiated, discontinued or dose changed.

Zuclopenthixol: Ritonavir, a strong CYP2D6 inhibitor, may increase the serum concentration of zuclopenthixol by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zuclopenthixol if ritonavir is initiated, discontinued or dose changed.