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Ritonavir (Norvir)
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Class
Background
U.S. Manufacturer
Approval
Formulation and Dosing
Clinical Use
Combinations
Use in Initial vs Subsequent Therapy
Factors Affecting Adherence
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
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Drug Labeling (Package Insert)
Ritonavir (Norvir)
Class

Protease inhibitor

Background
U.S. Manufacturer

Abbott Laboratories

Approval

Ritonavir received FDA approval in 1996 for use 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.

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*
Adult600 mg BID
PediatricAge <1 monthNot FDA approved
Age 1 month - 12 years350-400 mg/m2 BID; maximum 600 mg BID**
AdolescentAdult dosing

Key to abbreviations: BID, twice daily.

* Dosing information is for ritonavir used as a single protease inhibitor. For dosing of ritonavir in combination with other protease inhibitors, see atazanavir, darunavir, fosamprenavir, indinavir, saquinavir, tipranavir.

** For pediatric patients, start ritonavir at 250 mg/m2 BID, increase by 50 mg/m2 every 2-3 days until full dosage is reached.

Ritonavir should be taken with food.
Ritonavir interacts with many other medications; dose adjustment of certain interacting medications is recommended when they are combined with ritonavir. For further information, see ritonavir/other medications interaction table.
No dosage adjustment is necessary in renal insufficiency.
Please consult product labeling for detailed dosing information.
FDA Pregnancy Category B.
Clinical Use
Combinations

Regimens consisting of 2 nucleoside analogues and ritonavir have been found to provide potent suppression of viral load in previously untreated patients, but side effects are significant.(1) A number of regimens containing ritonavir in combination with another protease inhibitor have also been found to be effective, and allow lower doses of both of the protease inhibitors than when either is used alone. For example, the efficacy of saquinavir + ritonavir or lopinavir + ritonavir in combination with nucleoside analogues compares favorably with that of other potent combination regimens.(2,3) In some cases, combination with ritonavir also allows less frequent dosing or fewer dietary restrictions than single-protease inhibitor use. In current practice, ritonavir is used almost exclusively at subtherapeutic doses solely to maintain therapeutic serum levels of other protease inhibitors used in combination, ie, as a pharmacokinetic enhancer of other protease inhibitors.

Ritonavir may be combined with any of the other protease inhibitors, although optimal dosing information for combination with certain protease inhibitors has not been fully determined. Lopinavir is available only as a coformulation with low-dose ritonavir and both tipranavir and darunavir must be used in combination with ritonavir. The addition of low-dose ritonavir may boost amprenavir,(4) atazanavir,(5) fosamprenavir,(6) or saquinavir (7) to therapeutic levels when any of these protease inhibitors is used in combination with efavirenz.

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 therefore causes clinically significant alterations in serum levels not only of other antiretrovirals, but also of a variety of drugs including certain calcium channel blockers, cholesterol-lowering agents, antiarrhythmics, sedative-hypnotics, erectile dysfunction agents, oral contraceptives, recreational substances, and others.

Information on drug interactions should be consulted, as dose adjustments are frequently required, and some combinations are clearly contraindicated.

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 several other protease inhibitors as "alternative" components. Because of the persistent and long-term side effects of full-dose ritonavir, regimens containing ritonavir as the only protease inhibitor are not recommended.

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

Regimens incorporating combinations of ritonavir with other protease inhibitors may be effective subsequent to virologic recurrence on initial treatment regimens.(8,9)

Factors Affecting Adherence

Common symptomatic side effects of ritonavir include weakness, diarrhea, abdominal discomfort, and nausea. Less-frequent effects include numbness around the mouth or in the extremities, and abnormal taste sensation. Abnormalities of liver function are common, as is hyperlipidemia. As with other protease inhibitors, ritonavir is associated with abnormalities of glucose metabolism and body fat distribution. Capsules require refrigeration. The oral solution should not be refrigerated, and it is usually characterized as unpleasant in taste.

Resistance

Resistance to ritonavir is associated with the selection of 1 or more of several resistance mutations.

Implications of ritonavir resistance for treatment with other antiretrovirals

Resistance mutations selected by ritonavir frequently confer or contribute to resistance against other protease inhibitors. Different mutations are associated with cross-resistance to different drugs. For example, M46I is associated with cross-resistance to indinavir, nelfinavir, and fosamprenavir (but not to saquinavir); V82A,F,T,S alone is associated with cross-resistance to indinavir, but in combination with other mutations also confers resistance to nelfinavir, fosamprenavir, and saquinavir; and I84V contributes to resistance against all available protease inhibitors. Although no single one of these mutations is associated with full resistance to lopinavir, each contributes partial resistance, and the presence of several mutations together can confer resistance.

Response to indinavir is unlikely in the setting of resistance to ritonavir.

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

Response to ritonavir is unlikely in the setting of resistance to indinavir.

Following failure of a regimen containing a single protease inhibitor or NNRTI, patients may respond to regimens containing the combination of low-dose ritonavir and another protease inhibitor (a "boosted" protease inhibitor).

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

Special Uses

Because of its strong inhibitory effect on CYP3A (see "Combinations") ritonavir at doses below the normal therapeutic dosage is frequently 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, Foudraine NA, de Jong JJ, Cavert W, Schuwirth CM, Kauffmann RH, Meenhorst PL, McDade H, Goodwin C, Leonard JM, Goudsmit J, Danner SA. 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.   Kirk O, Katzenstein TL, Gerstoft J, Mathiesen L, Nielsen H, Pedersen C, Lundgren JD. Combination therapy containing ritonavir plus saquinavir has superior short-term antiretroviral efficacy: a randomized trial. AIDS 1999;13:F9-16.
3.   Walmsley S, Bernstein B, King M, Arribas J, Beall G, Ruane P, Johnson M, Johnson D, Lalonde R, Japour A, Brun S, Sun E. Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection.N Engl J Med. 2002 Jun 27;346(26):2039-46.
4.  Piscitelli S, Bechtel C, Sadler B, Falloon J. The Addition of a Second Protease Inhibitor Eliminates Amprenavir-Efavirenz Drug Interactions and Increases Plasma Amprenavir Concentrations. Abstract 78. 7th Conference on Retroviruses and Opportunistic Infections. January 30 - February 2, 2000; San Francisco.
5.  Tackett D, Child M, Agarwala S, Geiger M, Geraldes M, Laura B, O'Mara E. Atazanavir: A Summary of Two Pharmacokinetic Drug Interaction Studies in Healthy Subjects 10th Conference on Retroviruses and Opportunistic Infections, Boston, February 10-14, 2003. Abstract 543
6.   Wire MB, Ballow C, Preston SL, Hendrix CW, Piliero PJ, Lou Y, Stein DS. Pharmacokinetics and safety of GW433908 and ritonavir, with and without efavirenz, in healthy volunteers. AIDS. 2004 Apr 9;18(6):897-907.
7.  Hendrix CW, Fiske WD, Fuchs EJ, Redpath EC, Stevenson DL, Benedek IH, Kornhauser DM. Pharmacokinetics of the Triple Combination of Saquinavir, Ritonavir, and Efavirenz in HIV-Positive Patients. Abstract 79. 7th Conference on Retroviruses and Opportunistic Infections. January 30 - February 2, 2000; San Francisco.
8.   Tebas P, Patick AK, Kane EM, Klebert MK, Simpson JH, Erice A, Powderly WG, Henry K. Virologic responses to a ritonavir--saquinavir-containing regimen in patients who had previously failed nelfinavir. AIDS 1999;13:F23-8.
9.   Zolopa AR, Shafer RW, Warford A, Montoya JG, Hsu P, Katzenstein D, Merigan TC, Efron B. 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.