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Ritonavir (Norvir)
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Class
Background
U.S. Manufacturer
Approval
Formulation and Dosing
Clinical Use
Use in Initial vs Subsequent Therapy
Adverse Effects
Interactions with Other Drugs
Resistance
Implications of ritonavir resistance for treatment with other antiretrovirals
Implications of resistance to other antiretrovirals for ritonavir treatment
Special Uses
References
Related Resources
DHHS Guidelines
Characteristics of PIs
Drug Interactions with PIs
Interactions among PIs
Interactions between NNRTIs, Maraviroc, Raltegravir, and PIs
Drugs That Should Not Be Used with PIs, NNRTIs, or CCR5 Antagonists
Adverse Events of ARVs
Dosage Adjustments for ARV-ARV Drug Interactions (Adult Dosing)
Interactions Database
Stanford Resistance Figures/Notes
Drug Labeling (Package Insert)
Ritonavir (Norvir)
Class

Protease inhibitor

Background
U.S. Manufacturer

Abbvie, Inc.

Approval

Ritonavir received FDA approval in 1996 for use as an antiretroviral agent in adults with HIV infection. Pediatric approval followed in 1997. Initial approval was based on studies showing a substantial reduction in mortality and disease progression in subjects with advanced HIV disease who added ritonavir (vs placebo) to their existing nucleoside analogue regimen. Increases in CD4 T-lymphocyte counts and reductions in viral load were also found to be superior in antiretroviral-naive patients receiving ritonavir compared with zidovudine monotherapy.

Although ritonavir is a protease inhibitor, in current practice it is used almost exclusively at subtherapeutic dosages solely to achieve therapeutic serum levels of other protease inhibitors used in combination, ie, as a pharmacokinetic enhancer of other protease inhibitors.

Formulation and Dosing

Ritonavir is available in tablets, soft-gel capsules, and oral solution. When full-dose ritonavir is used (ie, without another protease inhibitor), initial escalation of the dose over 1-2 weeks may reduce side effects while maintaining therapeutic levels.

Ritonavir is also available in fixed-dose combination (Kaletra) with the protease inhibitor lopinavir.

Dosing of Ritonavir*
Adult

For dosing of ritonavir in combination with other protease inhibitors, see atazanavir, darunavir, fosamprenavir, indinavir, saquinavir, and tipranavir.

Pediatric

Ritonavir oral solution should not be given to neonates before a postmenstrual age of 44 weeks.

For dosing of ritonavir in combination with other protease inhibitors, see atazanavir, darunavir, fosamprenavir, indinavir, saquinavir, and tipranavir.

* Dosing information for ritonavir used as a single protease inhibitor can be found in the product labeling.

Ritonavir should be taken with food.
Ritonavir interacts with many other medications; dosage adjustment of certain interacting medications is recommended when they are combined with ritonavir. For further information, see the Database of Antiretroviral Drug Interactions.
No dosage adjustment is necessary in renal insufficiency.
For dosage information for patients with hepatic impairment, see the recommendations for the coadministered protease inhibitor.
Please consult product labeling for detailed dosing information.
FDA Pregnancy Category B.
Clinical Use
Use in Initial vs Subsequent Therapy

Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services include combinations of low-dose ritonavir with atazanavir or darunavir as "preferred" components of antiretroviral regimens for initial treatment of HIV infection, and include low-dose ritonavir in combination with lopinavir as a component of "alternative" regimens. Because of the persistent and long-term side effects of full-dose ritonavir, regimens containing ritonavir as the only protease inhibitor are not recommended.

Regimens consisting of 2 nucleoside analogues and full-dose ritonavir were found to provide potent suppression of viral load in previously untreated patients, but side effects were significant.(1) Use of low-dose ritonavir as a pharmacokinetic booster may achieve higher plasma concentrations of the coadministered protease inhibitor and sometimes less-frequent dosing, or fewer dietary restrictions compared with single-protease inhibitor use; and it avoids the more severe side effects of high-dose ritonavir.

A number of regimens containing low-dose ritonavir as a pharmacokinetic booster of another protease inhibitor have been found to be effective in initial therapy; these include ritonavir plus atazanavir,(2,3) darunavir,(4,5,6) fosamprenavir,(7) lopinavir,(8,2,6,9) and saquinavir.(9) Some protease inhibitors require administration with ritonavir in order to achieve therapeutic concentrations (darunavir, saquinavir tablets, tipranavir); lopinavir is available only in a coformulation with ritonavir.

The efficacy of ritonavir-boosted protease inhibitors in subsequent therapy has also been shown (10,11) (see profiles of other protease inhibitors for further information).

A Phase III study of initial therapy compared ritonavir (100 mg daily) with cobicistat (150 mg daily) as a pharmacokinetic enhancer of atazanavir. Each was given in combination with tenofovir and emtricitabine. At week 48, by snapshot analysis, rates of HIV suppression to <50 copies/mL were 87% in the atazanavir + ritonavir group and 85% in the atazanavir + cobicistat group; the difference was not statistically significant.(12) An earlier Phase II study also compared ritonavir with cobicistat in combination with atazanavir plus tenofovir/emtricitabine in treatment-naive patients. At 48 weeks, by intention-to-treat analysis, HIV RNA was suppressed to <50 copies/mL in 86% of the ritonavir group and 82% of the cobicistat group; CD4 cell increases were 206 cells/µL and 230 cells/µL, respectively.(4)

Failure of a regimen containing ritonavir may decrease the likelihood that subsequent protease inhibitor-containing regimens will succeed (see "Resistance," below).

Adverse Effects

Common symptomatic side effects of ritonavir include weakness, nausea, vomiting, diarrhea, and abdominal discomfort. Less-frequent effects include numbness around the mouth or in the extremities, and abnormal taste sensation; these typically occur at higher dosages. Laboratory abnormalities include abnormalities of liver function and hyperlipidemia. As with other protease inhibitors, ritonavir is associated with abnormalities of glucose metabolism and body fat distribution. Prolongation of the cardiac PR interval may occur.

Capsules require refrigeration. The oral solution should not be refrigerated, and it is usually characterized as unpleasant in taste.

Interactions with Other Drugs

Ritonavir is a potent inhibitor of cytochrome P450 3A (CYP3A) and CYP2D6, as well as an inducer of other hepatic enzyme systems. Coadministration with ritonavir may cause clinically significant alterations in serum levels of other antiretrovirals metabolized by these pathways, as well as in a great number of other drugs including certain antimicrobials, calcium channel blockers, HMG coenzyme A reductase inhibitors (statins), antiarrhythmics, sedative-hypnotics, oral contraceptives, erectile dysfunction agents, recreational substances, and others. Coadministration with rifampin decreases plasma ritonavir concentrations and should be avoided.

It is important to consult information on drug interactions before prescribing ritonavir, as dosage adjustments are frequently required, and some combinations are clearly contraindicated.

Resistance

Resistance to ritonavir may occur with exposure to full-dose ritonavir but generally does not arise when ritonavir is used at low dose as a pharmacokinetic enhancer.

Implications of ritonavir resistance for treatment with other antiretrovirals

Resistance mutations selected by ritonavir (eg, by previous treatment with full-dose ritonavir) frequently confer or contribute to resistance against other protease inhibitors. For example, M46I; V82A,F,T,S;and I84V are associated with cross-resistance to most available protease inhibitors. The presence of several mutations together can confer partial or full resistance.

Genotypic or phenotypic testing may be useful in predicting the likelihood of response to other protease inhibitors following failure of a regimen containing ritonavir.

Implications of resistance to other antiretrovirals for ritonavir treatment

As discussed above, treatment with full-dose ritonavir is not recommended. Resistance to other antiretrovirals does not affect the pharmacokinetic boosting effects of ritonavir.

Special Uses

Because of its strong inhibitory effect on CYP3A (see "Interactions with Other Drugs"), ritonavir at doses below the normal therapeutic dosage typically is combined with other protease inhibitors to achieve therapeutic levels of the second protease inhibitor while reducing the number of pills required, the dosing frequency, or both.

Coadministration of low-dose ritonavir may also be used to compensate for drug interactions that tend to decrease levels of a protease inhibitor metabolized by CYP3A (for example, in the case of fosamprenavir combined with efavirenz).

References
1.   Notermans DW, Jurriaans S, de Wolf F, et al. Decrease of HIV-1 RNA levels in lymphoid tissue and peripheral blood during treatment with ritonavir, lamivudine and zidovudine. Ritonavir/3TC/ZDV Study Group. AIDS 1998;12:167-73.
2.   Molina JM, Andrade-Villanueva J, Echevarria J, et al; CASTLE Study Team. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008 Aug 23;372(9639):646-55.
3.  Landovitz RJ, Ribaudo HJ, Ofotokun I, et al. Efficacy and tolerability of atazanavir, raltegravir, or darunavir with FTC/tenofovir: ACTG 5257. In: Program and abstracts of the 21st Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston. Abstract 85.
4.   Elion R, Cohen C, Gathe J, et al; GS-US-216–0105 Study Team. Phase 2 study of cobicistat versus ritonavir each with once-daily atazanavir and fixed-dose emtricitabine/tenofovir df in the initial treatment of HIV infection. AIDS. 2011 Sep 24;25(15):1881-6.
6.   Ortiz R, Dejesus E, Khanlou H, et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS. 2008 Jul 31;22(12):1389-97.
7.   Gathe JC Jr, Ive P, Wood R, et al. SOLO: 48-week efficacy and safety comparison of once-daily fosamprenavir/ritonavir versus twice-daily nelfinavir in naive HIV-1-infected patients. AIDS. 2004 Jul 23;18(11):1529-37.
9.   Walmsley S, Avihingsanon A, Slim J; et al. Gemini: a noninferiority study of saquinavir/ritonavir versus lopinavir/ritonavir as initial HIV-1 therapy in adults. J Acquir Immune Defic Syndr. 2009 Apr 1;50(4):367-74.
10.   Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection.N Engl J Med. 2002 Jun 27;346(26):2039-46.
11.   Clotet B, Bellos N, Molina JM, et al; POWER 1 and 2 study groups. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet. 2007 Apr 7;369(9568):1169-78.
12.  Gallant J, Koenig E, Andrade-Villanueva J, et al. Cobicistat versus ritonavir as pharmacoenhancers in combination with atazanavir plus tenofovir disoproxil fumarate/emtricitabine: phase 3 randomized, double blind, active-controlled trial, week 48 results. In: Program and abstracts of the XIX International AIDS Conference; July 22-27, 2012; Washington. Abstract TUAB0103.
13.   Zolopa AR, Shafer RW, Warford A, et al. HIV-1 genotypic resistance patterns predict response to saquinavir-ritonavir therapy in patients in whom previous protease inhibitor therapy had failed. Ann Intern Med 1999;131:813-21.
14.  Mathias A, Liu HC, Warren D, et al. Relative bioavailability and pharmacokinetics of darunavir when boosted with the pharmacoenhancer GS-9350 versus ritonavir. In: Programs and abstracts of the 11th International Workshop on Clinical Pharmacology of HIV Therapy; April 7–9, 2010; Sorrento. Abstract 28.