ritonavir 100 mg tablet generic norvir

Uses

Treatment of HIV Infection

Ritonavir is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults, adolescents, and pediatric patients older than 1 month of age.

Concomitant use of low-dose ritonavir and certain other HIV protease inhibitors (PIs) results in increased plasma concentrations of the other PI and is used to therapeutic advantage (ritonavir-boosted PIs) in PI-based regimens used in antiretroviral-naive (have not previously received antiretroviral therapy) and antiretroviral-experienced patients (received prior antiretroviral therapy). Regimens that contain full-dose ritonavir or ritonavir as the sole HIV protease inhibitor (PI) are not recommended for initial treatment because of a high pill burden, GI intolerance, and metabolic toxicity.

The most appropriate antiretroviral regimen cannot be defined for each clinical scenario, and selection of specific antiretroviral agents for use in such regimens should be individualized based on current knowledge regarding antiretroviral potency, potential rate of development of resistance, known toxicities, and potential for pharmacokinetic interactions as well as virologic, immunologic, and clinical characteristics of the patient. For information on the general principles and guidelines for use of antiretroviral therapy, including specific recommendations for initial therapy in antiretroviral-naive patients and recommendations for changing antiretroviral regimens, see .

Ritonavir-boosted Therapy

Low-dose ritonavir is used in conjunction with other PIs to decrease metabolism of and increase plasma concentrations of the other PI. Use of low-dose ritonavir in conjunction with another PI has been referred to as ritonavir pharmacokinetic enhancement or ritonavir-boosted therapy. The antiretroviral activity of these regimens is due to the other PI since a therapeutic dosage of ritonavir is not administered. A fixed-combination preparation of lopinavir and low-dose ritonavir is commercially available (lopinavir/ritonavir); other ritonavir-boosted regimens involve administration of a specific dosage of ritonavir and the other PI recommended for the combined regimen.

Regimens that include low-dose ritonavir in conjunction with another PI have been recommended for use in antiretroviral-naive and antiretroviral-experienced patients.

Antiretroviral-naive Adults and Adolescents

The US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents states that several PI-based regimens that include a ritonavir-boosted PI and 2 HIV nucleoside reverse transcriptase inhibitors (dual NRTIs) are recommended or alternative regimens for initial treatment in antiretroviral-naive adults and adolescents.

PI-based regimens that are recommended by these experts for initial treatment in antiretroviral-naive adults and adolescents regardless of pretreatment viral load or CD4 T-cell count are ritonavir-boosted atazanavir or ritonavir-boosted darunavir in conjunction with tenofovir disoproxil fumarate (tenofovir DF) and emtricitabine (or lamivudine).Ritonavir-boosted atazanavir in conjunction with abacavir and lamivudine (or emtricitabine) is another recommended regimen for initial treatment in antiretroviral-naive adults and adolescents, but should be used only in those with pretreatment plasma HIV RNA levels less than 100,000 copies/mL who are human leukocyte antigen (HLA)-B*5701 negative.

Alternative PI-based regimens recommended by these experts for initial treatment in antiretroviral-naive adults and adolescents include ritonavir-boosted darunavir or lopinavir/ritonavir in conjunction with certain dual NRTIs.

Ritonavir-boosted fosamprenavir, ritonavir-boosted indinavir, ritonavir-boosted saquinavir, and ritonavir-boosted tipranavir are not recommended for initial treatment regimens in antiretroviral naive adults and adolescents.

Clinical Experience

Safety and efficacy of ritonavir for antiretroviral therapy in antiretroviral-naive adults was initially evaluated in a randomized, double-blind study (study 245) that used regimens that are no longer considered standard of care (monotherapy, 2-drug regimens). Patients in this study had mild to moderate HIV infection (mean baseline CD4 T-cell counts 364/mm) and were randomized to receive monotherapy with oral ritonavir (600 mg twice daily), monotherapy with oral zidovudine (200 mg 3 times daily), or a 2-drug regimen of oral ritonavir (600 mg twice daily) and oral zidovudine (200 mg 3 times daily). During the double-blind phase of the study, ritonavir monotherapy was associated with greater mean increases in CD4 T-cell count from baseline to week 12 compared with the zidovudine arms; mean CD4 T-cell count then appeared to plateau through week 24 in those receiving ritonavir monotherapy, but gradually diminished through week 24 in those receiving zidovudine monotherapy or the regimen that included both drugs. From baseline to week 2, greater mean decreases in plasma HIV-1 RNA levels were observed in those receiving ritonavir or the 2-drug regimen containing ritonavir compared with those receiving zidovudine monotherapy. After week 2 and through week 24, mean plasma HIV-1 RNA levels remained stable in those receiving ritonavir or zidovudine monotherapy or gradually rebounded toward baseline in those receiving both drugs.

Antiretroviral-experienced Adults and Adolescents

Clinical Experience

Safety and efficacy of ritonavir for use in previously treated HIV-infected patients was initially evaluated in a randomized, double-blind study with open-label follow-up (study 247) that used regimens that are no longer considered standard of care (monotherapy, 2-drug regimens). The study involved 1090 patients with advanced HIV infection (baseline CD4 T-cell count 100/mm or less; mean baseline count 32/mm) who had received at least 9 months of NRTI therapy. Oral ritonavir (600 mg twice daily) or placebo was added to the patient's existing regimen (i.e., no antiretroviral therapy, monotherapy with zidovudine, zalcitabine (no longer commercially available in the US), didanosine, or stavudine, or therapy with zidovudine and zalcitabine, didanosine, or stavudine) and efficacy was assessed by disease progression or death over the following 6 months.

At week 24, patients who received ritonavir in conjunction with their existing regimen had clinically important increases in CD4 T-cell counts and decreases in plasma HIV-1 RNA levels; there were no improvements in these surrogate markers in patients randomized to receive placebo in addition to their existing regimen. The cumulative incidence of clinical disease progression or death during the double-blind phase (median duration 6 months) was 26% in patients randomized to receive ritonavir in conjunction with their existing regimen and 42% in those randomized to receive placebo with the existing regimen. The cumulative mortality through the end of the open-label follow-up phase (median duration 13.5 or 14 months) was 18 or 26% in patients randomized to receive ritonavir or placebo, respectively, in conjunction with their existing regimen. Results of this study indicated that, in patients with advanced HIV infection who have received long-term NRTI therapy, addition of ritonavir to the regimen increased the probability of survival and was associated with certain clinical benefits such as decreased incidence and severity of opportunistic infections (e.g., esophageal candidiasis, Kaposi's sarcoma, cytomegalovirus retinitis or other cytomegalovirus infections, Pneumocystis carinii pneumonia, Mycobacterium avium complex infections, HIV-associated wasting syndrome). During the double-blind phase of the study, increases in CD4 T-cell counts were observed at week 2 and 4 in those receiving ritonavir, and mean CD4 T-cell count then appeared to plateau from week 4 through week 24. In contrast, there was no apparent change in mean CD4 T-cell count at any visit between baseline and week 24 in patients randomized to placebo.

Pediatric Patients

Ritonavir is used in conjunction with other antiretroviral agents for the treatment of HIV-1 infection in children older than 1 month of age.

For initial treatment in antiretroviral-naive pediatric patients, the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children recommends a PI or HIV nonnucleoside reverse transcriptase inhibitor (NNRTI) in conjunction with 2 NRTIs. These experts state that the preferred PI-based regimens for initial treatment in antiretroviral-naive pediatric patients are lopinavir/ritonavir and 2 NRTIs (used only in those 14 days of age or older and postmenstrual age at least 42 weeks [i.e., time elapsed since first day of the mother's last menstrual period to birth plus time elapsed after birth]) or ritonavir-boosted atazanavir and 2 NRTIs (used only in those 6 years of age or older). Alternative PI-based regimens recommended by these experts for initial treatment are ritonavir-boosted darunavir (twice-daily) and 2 NRTIs (used only in those 3 years to less than 12 years of age) and ritonavir-boosted darunavir (once daily) and 2 NRTIs (used only in those 12 years of age or older without darunavir-associated resistance substitutions). These experts state that regimens that contain full-dose ritonavir or ritonavir as the sole PI are not recommended for initial therapy in pediatric patients because of GI intolerance and metabolic toxicity.

Clinical Experience

Safety and efficacy of ritonavir in children 2-17 years of age was evaluated in a randomized, phase 2 study (PACTG 338) that used regimens that are no longer considered standard of care (monotherapy, 2-drug regimens). In this study, HIV-infected children who had received prior antiretroviral therapy (86% had previously received zidovudine alone or in conjunction with didanosine) were randomized to receive a 2-drug regimen of zidovudine and lamivudine, a 2-drug regimen of ritonavir and stavudine, or a 3-drug regimen of zidovudine, lamivudine, and ritonavir (350 mg/m twice daily). At week 12, interim analysis indicated that only 14% of those receiving zidovudine and lamivudine had undetectable levels of plasma HIV-1 RNA (i.e., less than 400 copies/mL) whereas 57 or 61% of those receiving the 2- or 3-drug regimen containing ritonavir, respectively, had undetectable levels. In the subgroup of children who had undetectable plasma HIV-1 RNA levels at study entry, 27% of those receiving the 2-drug ritonavir regimen and 42% of those receiving the 3-drug ritonavir regimen had undetectable levels at 48 weeks. The virologic response to the ritonavir-containing regimens was lower in those with a higher viral load at study entry. In the subgroups of children who had baseline plasma HIV-1 RNA levels of 2.6-3, 3-4, 4-5, or 5-6 log₁₀ copies/mL, plasma HIV-1 RNA levels were undetectable at 48 weeks in 69, 44, 32, or 19%, respectively, in those receiving the 2- or 3-drug ritonavir regimens.

Efficacy of ritonavir in conjunction with zidovudine and lamivudine was evaluated in an open-label, phase 1 and 2 study in HIV-infected infants 1-24 months of age who had not previously received therapy with a PI. At week 16, 36 of 43 children who continued study treatment (as-treated analysis) had plasma HIV-1 RNA levels less than 400 copies/mL. At week 104, durable viral suppression was maintained in 46% of children (as-treated analysis).

The efficacy, safety, and pharmacokinetics of ritonavir have been evaluated in a multicenter phase 1 and 2 study in HIV-infected children 6 months to 18 years of age who were treatment-naive or who had become refractory or intolerant to previous antiretroviral therapy. These children received ritonavir monotherapy (250-400 mg/m twice daily) for the first 12 weeks, then zidovudine (90 mg/m every 6 hours) and/or didanosine (90 mg/m twice daily) was added to the regimen. Interim analysis at 24 weeks of data from children 2 years of age or older (younger children were excluded from this analysis) indicate that regimens that included ritonavir in a dosage of 300 mg/m twice daily in conjunction with zidovudine and/or didanosine were associated with a mean increase in CD4 T-cell counts of 263/mm from baseline counts and a mean decrease in plasma HIV-1 RNA levels of 0.4 logs/mL from baseline levels. Ritonavir was well tolerated, and additional studies have been initiated and are ongoing to further evaluate safety and efficacy of the drug in pediatric patients.

Dosage and Administration

Administration

Ritonavir is administered orally as soft gelatin capsules, film-coated tablets, or oral solution.

Capsules

Ritonavir capsules should be taken with meals, if possible. Food may help maintain relatively consistent GI absorption and decrease adverse GI effects.

Tablets

Ritonavir tablets should be taken with meals.

The tablets should be swallowed whole, and should not be chewed, broken, or crushed.

Ritonavir tablets are not bioequivalent to ritonavir capsules. Because of higher peak ritonavir plasma concentrations following administration of ritonavir tablets compared to the capsules, patients who were previously receiving 600 mg of ritonavir twice daily as capsules may experience more adverse GI effects (e.g., nausea, vomiting, abdominal pain, diarrhea) when switched to the tablet formulation. Adverse effects (e.g., GI effects, paresthesias) may lessen with continued ritonavir therapy.

Oral Solution

Ritonavir oral solution should be taken with meals.

Ritonavir oral solution contains 43.2% (v/v) alcohol and 26.57% (w/v) propylene glycol and should not be used in neonates with postmenstrual age less than 44 weeks (i.e., time elapsed since first day of the mother's last menstrual period to birth plus time elapsed after birth).(See Cautions: Pediatric Precautions.)

Doses of ritonavir oral solution should be administered using a calibrated oral dosing syringe whenever possible. The oral solution should be agitated well prior to administration of each dose.

The oral solution has an unpleasant taste even though the formulation contains flavorings. The manufacturer states that the taste of the oral solution may be improved by mixing with up to 240 mL of chocolate milk, Ensure, or Advera; these diluted oral solutions should be used within 1 hour of preparation.

Dosage

Adult Dosage

Treatment of HIV Infection

When low-dose ritonavir is used with another human immunodeficiency virus (HIV) protease inhibitor (PI) as a pharmacokinetic enhancer (ritonavir-boosted PI) in adults and adolescents, it usually is given in a dosage ranging from 100-400 mg daily. The specific ritonavir dosage for ritonavir-boosted regimens varies depending on which PI is used (e.g., atazanavir, darunavir, fosamprenavir, indinavir, saquinavir, tipranavir). (For further information regarding dosage of ritonavir-boosted PIs, see the individual HIV protease inhibitor monographs in 8:18.08.08.)

If ritonavir is used as the sole HIV PI in multiple-drug regimens for the treatment of HIV type 1 (HIV-1) infection (full-dose ritonavir) in adults and adolescents, the manufacturer recommends a dosage of 600 mg twice daily. Because nausea may occur when full-dose ritonavir therapy is initiated, use of a dose escalation schedule is recommended to minimize adverse GI effects. If such a schedule is followed, the manufacturer recommends that ritonavir therapy be initiated with a minimum dosage of 300 mg twice daily and dosage increased at 2- to 3-day intervals by 100 mg twice daily up to a maximum dosage of 600 mg twice daily. If adverse effects likely to be caused by ritonavir occur during the first few weeks of ritonavir therapy, these effects are likely to be transient and therapy with the drug usually can be continued. Vomiting persists for an average of 1 week, nausea for 2-3 weeks, peripheral paresthesia for 3-4 weeks, circumoral paresthesia and asthenia for 3-5 weeks, and diarrhea for 5 weeks in patients experiencing such adverse effects while receiving ritonavir. If ritonavir therapy is discontinued temporarily, the drug may be reinitiated using the manufacturer recommended dose escalation schedule.

Pediatric Dosage

When low-dose ritonavir is used with another HIV PI as a pharmacokinetic enhancer (ritonavir-boosted PI) in pediatric patients, it usually is given in a dosage ranging from 4-6 mg/kg daily (80-400 mg daily). The specific ritonavir dosage for ritonavir-boosted regimens varies depending on which PI is used (e.g., atazanavir, darunavir, fosamprenavir, tipranavir). (For further information regarding dosage of ritonavir-boosted PIs, see the individual HIV protease inhibitor monographs in 8:18.08.08.)

If ritonavir is used as the sole PI in multiple-drug regimens for the treatment of HIV-1 infection (full-dose ritonavir) in pediatric patients older than 1 month of age, the manufacturer recommends a dosage of 350-400 mg/m twice daily (not to exceed 600 mg twice daily). To minimize nausea that may occur when full-dose ritonavir is initiated, use of a dose escalation schedule is recommended. The manufacturer recommends that full-dose ritonavir therapy in pediatric patients older than 1 month of age be initiated with a dosage of 250 mg/m twice daily and then increased at 2- to 3-day intervals by 50 mg/m every 12 hours.

The manufacturer's product information should be consulted for recommendations regarding the volume of ritonavir oral solution to use for each dosage level when the dose escalation schedule is used in pediatric patients 1 month of age or older.

If a child is unable to tolerate a dosage of 400 mg/m twice daily because of adverse effects, the highest dose that is tolerated may be used for maintenance therapy in conjunction with other antiretroviral agents; however, alternative therapy should be considered.

Dosage in Renal and Hepatic Impairment

Although the pharmacokinetics of ritonavir have not been studied in patients with renal impairment, renal clearance of the drug is negligible and the manufacturer states that clinically important decreases in ritonavir clearance are not anticipated if the drug is administered to patients with renal impairment. Some experts state that dosage adjustments are not necessary if ritonavir is used in patients with impaired renal function.

Ritonavir dosage adjustments are not necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B). However, patients with moderate hepatic impairment should be carefully monitored since lower plasma concentrations of ritonavir have been reported in these patients compared with those with normal hepatic function. Ritonavir is not recommended in patients with severe hepatic impairment (Child-Pugh class C).

Cautions

Information on safety and efficacy of ritonavir has been obtained principally from phase 1 and 2 and phase 2 and 3 clinical studies in adults 19 years of age or older with advanced human immunodeficiency virus (HIV) infection who received the drug in the recommended full-dose ritonavir dosage (i.e., 600 mg every 12 hours) alone or in conjunction with HIV nucleoside reverse transcriptase inhibitors (NRTIs). Information also has been obtained from a study in HIV-infected adults who received ritonavir in conjunction with saquinavir. Safety data reported by the manufacturer regarding the adverse effect profile of ritonavir was compiled from randomized, double-blind studies in HIV-infected patients who had received ritonavir for a median duration of 9.1-9.4 months (studies 245 and 247), from a study in HIV-infected patients who received ritonavir and saquinavir for 48 weeks (study 462), and from postmarketing experience.

The principal adverse effects reported with ritonavir are GI effects such as nausea, diarrhea, vomiting, anorexia, abdominal pain, and taste perversion and nervous system effects such as asthenia and circumoral and peripheral paresthesia. Many of these effects are transient, generally occurring within the first few weeks of ritonavir therapy and lasting 1-5 weeks. Addition of full-dose ritonavir to NRTI therapy at recommended dosages has resulted in an increased incidence of certain adverse effects (e.g., asthenia, nausea, vomiting) compared with monotherapy with either drug.

GI Effects

The most frequent adverse effects associated with ritonavir therapy involve the GI tract. In one clinical study in HIV-infected patients (study 245), nausea occurred in 25.6%, vomiting in 13.7%, diarrhea in 15.4%, taste perversion in 11.1%, abdominal pain in 6%, local throat irritation in 1.7%, anorexia in 1.7%, and flatulence in 0.9% of patients who received full-dose ritonavir monotherapy. In clinical studies in patients with HIV infection who received ritonavir in conjunction with NRTI therapy (studies 245 and 247) or ritonavir in conjunction with saquinavir (study 462), nausea occurred in 18.4-46.6%, vomiting in 7.1-23.3%, diarrhea in 22.7-25%, taste perversion in 5-17.2%, anorexia in 4.3-8.6%, abdominal pain in 2.1-8.3%, local throat irritation in 0.9-2.8%, and flatulence in 1.7-3.5% of patients. Constipation, dyspepsia, or fecal incontinence occurred in 0.2-3.4, 0.7-5.9, or 0-2.8%, respectively, of patients receiving ritonavir with other antiretroviral agents; these effects were not reported in patients receiving ritonavir monotherapy. Many adverse GI effects reported with ritonavir are transient; vomiting persists for an average of 1 week, nausea for 2-3 weeks, and diarrhea for 5 weeks.

Adverse GI effects reported in less than 2% of patients receiving ritonavir alone or in conjunction with other antiretroviral agents include abnormal stools, bloody diarrhea, cheilitis, cholestatic jaundice, colitis, dry mouth, dysphagia, enlarged abdomen, eructation, esophageal ulcer, esophagitis, gastritis, gastroenteritis, GI disorder, GI hemorrhage, gingivitis, ileus, melena, mouth ulcer, pseudomembranous colitis, rectal disorder, rectal hemorrhage, sialadenitis, stomatitis, taste loss, tenesmus, thirst, tongue edema, and ulcerative colitis.

Nervous System Effects

Peripheral paresthesia occurred in 6% and paresthesia or circumoral paresthesia occurred in 2.6-3.4% of patients with HIV infection receiving full-dose ritonavir monotherapy in one clinical study (study 245). In clinical studies in patients receiving ritonavir in conjunction with NRTI therapy (studies 245 and 247) or in conjunction with saquinavir (study 462), peripheral paresthesia was reported in 0-5.7%, paresthesia in 2.1-5.2%, and circumoral paresthesia in 5.2-6.7% of patients. Asthenia occurred in 10.3% of patients receiving ritonavir monotherapy and in 15.3-28.4% of patients receiving ritonavir with other antiretroviral agents. Many of these adverse effects are transient; peripheral paresthesia persists for an average of 3-4 weeks and circumoral paresthesia and asthenia persist for 3-5 weeks.

Dizziness, insomnia, or somnolence have been reported in 2.6% of patients receiving ritonavir monotherapy and in 3.9-8.5, 2-3.4, or 0-2.6%, respectively, of patients receiving ritonavir with other antiretroviral agents. Headache, depression, or abnormal thinking were reported in 4.3-7.8, 1.7-7.1, or 0.7-2.6%, respectively, of patients receiving ritonavir in conjunction with other antiretroviral agents. Anxiety or confusion were reported in up to 2.1% of patients receiving ritonavir with other antiretroviral agents.

Adverse nervous system effects reported in less than 2% of patients receiving ritonavir alone or with other antiretroviral agents include abnormal dreams, abnormal gait, agitation, amnesia, aphasia, ataxia, coma, dementia, depersonalization, emotional lability, euphoria, hallucinations, hyperesthesia, hyperkinesia, hypesthesia, incoordination, manic reaction, migraine, nervousness, neuralgia, neuropathy, paralysis, peripheral neuropathic pain, peripheral neuropathy, peripheral sensory neuropathy, personality disorder, seizures (including tonic-clonic [grand mal] seizures), sleep disorder, speech disorder, stupor, subdural hematoma, tremor, vertigo, and vestibular disorder.

Dermatologic and Sensitivity Reactions

In clinical studies, rash occurred in 0.7-3.5% of patients receiving full-dose ritonavir in conjunction with other antiretroviral agents. Allergic reactions, including urticaria, mild skin eruptions, bronchospasm, and angioedema, have been reported in patients receiving ritonavir. Anaphylaxis, toxic epidermal necrolysis, and Stevens-Johnson syndrome have been reported.

Sweating was reported in 1.7-3.4% of patients receiving ritonavir with other antiretroviral agents. Other sensitivity and dermatologic effects that have been reported in less than 2% of patients receiving ritonavir alone or with other antiretroviral agents include acne, contact dermatitis, dry skin, eczema, erythema multiforme, exfoliative dermatitis, folliculitis, fungal dermatitis, furunculosis, maculopapular rash, molluscum contagiosum, onychomycosis, photosensitivity reaction, pruritus, psoriasis, seborrhea, skin disorder (discoloration, hypertrophy), skin melanoma, urticaria, and vesiculobullous or pustular rash.

Musculoskeletal Effects

Arthralgia or myalgia occurred in 0-2.4% of patients receiving full-dose ritonavir in conjunction with other antiretroviral agents. Adverse musculoskeletal effects reported in less than 2% of patients receiving ritonavir include arthritis, arthrosis, back pain, bone pain, extraocular palsy, joint disorder, leg cramps, neck pain, neck rigidity, muscle cramps, muscle weakness, myositis, and twitching.

Hepatic Effects

Hepatic aminotransferase elevations exceeding 5 times the upper limit of normal, clinical hepatitis, and jaundice have occurred in patients receiving full-dose ritonavir alone or in conjunction with other antiretroviral agents. In clinical studies in HIV-infected individuals, increased serum concentrations of AST (SGOT) (exceeding 180 IU/L) or ALT (SGPT) (exceeding 215 IU/L) occurred in 5.3-9.5 or 5.3-9.2%, respectively, and increased serum concentrations of γ-glutamyltransferase (GGT, GGTP) (exceeding 300 IU/L) occurred in 1.8-19.6% of patients receiving ritonavir. Some data indicate that the risk of severe hepatotoxicity is substantially higher in patients receiving a ritonavir-containing regimen than in patients receiving regimens that include a different HIV protease inhibitor (PI) (e.g., indinavir, nelfinavir, saquinavir) or regimens that consist of 2 NRTIs. The manufacturer suggests that there may be an increased risk for transaminase elevations during ritonavir therapy in patients with underlying hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.

Hepatic coma, hepatitis, hepatomegaly, hepatosplenomegaly, or liver damage have been reported in less than 2% of patients receiving ritonavir in clinical studies. There have been postmarketing reports of hepatic dysfunction, including some fatalities, in patients receiving ritonavir. These generally occurred in patients receiving multiple drugs and/or with advanced acquired immunodeficiency syndrome (AIDS).

Hematologic Effects

While laboratory test results consistent with hematologic toxicity have been reported in a substantial number of previously treated patients with advanced HIV infection who received full-dose ritonavir in conjunction with NRTIs (study 247), marked alterations in hematologic test results occurred infrequently when ritonavir was used in antiretroviral-naive patients with mild to moderate HIV infection either alone or in conjunction with zidovudine (study 245) or in conjunction with saquinavir (study 462). In study 247 in previously treated adults with advanced HIV infection who received ritonavir with NRTIs, hemoglobin concentrations less than 8 g/dL were reported in 3.8%, hematocrit values less than 30% in 17.3%, erythrocyte counts less than 3 x 10/L in 18.6%, leukocyte counts less than 2.5 x 10/L in 36.9%, and neutrophil counts less than 0.5 x 10/L in 6% of patients. In study 245 in antiretroviral-naive patients with mild to moderate HIV infection who received ritonavir and zidovudine, hemoglobin concentrations less than 8 g/dL were reported in 0.9%, hematocrit less than 30% in 2.6%, and erythrocyte counts less than 3 x 10/L in 1.8% of patients.

Adverse hematologic effects reported in less than 2% of patients receiving ritonavir alone or with other antiretroviral agents include acute myeloblastic leukemia, anemia, ecchymosis, leukopenia, lymphadenopathy, lymphocytosis, myeloproliferative disorder, and thrombocytopenia.

Spontaneous bleeding episodes have been reported occasionally in patients with hemophilia A or hemophilia B receiving various PIs (e.g., amprenavir [commercially available as fosamprenavir], indinavir, ritonavir, saquinavir). Of the 15 initial cases of spontaneous bleeding, 11 presented as hematomas and 5 presented as hemarthroses (in one case, both effects were present). There also has been a report of at least one patient who presented with an intracerebral hemorrhage (considered remotely related to PI therapy). While additional doses of antihemophilic factor were necessary to control bleeding episodes in some patients, PI therapy was continued or reintroduced in more than half of reported cases. A causal relationship to PI therapy has not been established. In clinical studies reported to date evaluating PIs, there has been no evidence of an increased incidence of bleeding or coagulation abnormalities in patients with or without hemophilia. Pending further accumulation of data, clinicians should monitor patients with hemophilia for spontaneous bleeding episodes whenever any PI is used. In addition, such patients should be advised not to independently discontinue PI therapy as a result of these reports, but instead should consult with their clinician about any concerns. At this time, there is no evidence to suggest that PI therapy should be avoided in HIV-infected patients with hemophilia, although caution is warranted pending additional experience.

Hyperglycemic and Diabetogenic Effects

Hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus in HIV-infected individuals receiving a PI (i.e., amprenavir [commercially available as fosamprenavir], nelfinavir, indinavir, ritonavir, saquinavir) has been reported during postmarketing experience. Of the 83 initial reports of diabetes mellitus or hyperglycemic episodes occurring in patients receiving PI therapy, 14 had a known history of diabetes and experienced loss of glucose control while receiving one of these antiretroviral agents. There have been 5 cases of diabetic ketoacidosis and, while some of these occurred in patients with no known history of diabetes, baseline status was not well characterized for all these individuals. While these hyperglycemic and diabetic episodes occurred on an average of 76 days after initiation of PI therapy, some occurred as early as 4 days after initiation of the antiretroviral agent. Of the 83 initial cases reported, 27 were severe enough to require hospitalization and 6 were considered life-threatening events. In some patients, insulin or oral hypoglycemic agent therapy had to be initiated or dosage adjusted; however, PI therapy was continued in approximately 50% of reported cases. In most patients who discontinued PI therapy, the hyperglycemic or diabetic episode resolved; however, hyperglycemia persisted in some patients, including a few without a known history of diabetes at baseline. Many of these hyperglycemic or diabetic episodes occurred in patients with confounding medical conditions that required therapy with agents that have been associated with the development of diabetes mellitus or hyperglycemia. A causal relationship between these episodes and PI therapy has not been established and patients should be advised not to independently discontinue PI therapy as a result of these reports, but instead to consult with their clinicians about any concerns. There is no evidence at this time that PI therapy should be avoided in patients with diabetes mellitus, although caution is warranted pending additional experience. Patients receiving a PI should be advised about the warning signs of hyperglycemia and diabetes (e.g., increased thirst and hunger, unexplained weight loss, increased urination, fatigue, dry or itchy skin).

Adipogenic Effects

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and general cushingoid appearance, has been reported in patients receiving PIs, including ritonavir. The mechanisms responsible for these adipogenic effects and the long-term consequences of these effects are unknown. A causal relationship has not been established.

Effects on Lipoproteins

Hypertriglyceridemia (serum triglyceride concentration exceeding 1500 mg/dL) has been reported in 1.8-12.6% of patients receiving full-dose ritonavir alone or in conjunction with other antiretroviral agents; fasting triglyceride concentrations exceeding 1500 mg/dL occurred in 1.3-9.9% of patients receiving the drug. Hypercholesterolemia (total serum cholesterol exceeding 240 mg/dL) has been reported in 30.7-44.8% of patients receiving ritonavir alone or with NRTIs and in 65.2% of patients receiving ritonavir with saquinavir.

Cardiovascular Effects

Prolongation of the PR interval has occurred in individuals receiving ritonavir. Second- or third-degree AV block has been reported in patients receiving ritonavir during postmarketing experience.

Dose-dependent prolongation of QT and PR intervals has been reported in individuals receiving ritonavir-boosted saquinavir. Torsades de pointes and second- or third-degree (complete) atrioventricular (AV) heart block have been reported rarely. In healthy individuals, a twice-daily regimen of saquinavir 1g (as Invirase) and ritonavir 100 mg or a twice-daily regimen of saquinavir 1.5 g (as Invirase) and ritonavir 100 mg produced a maximum mean increase from adjusted baseline values in study-specific QT_c interval of approximately 19 and 30 msec, respectively. Maximum QT_c intervals were observed approximately 12-20 hours after a dose. In the same study, the maximum mean increase in PR interval for these 2 regimens was approximately 25 or 34 msec greater than baseline, respectively. PR interval prolongation exceeded 200 msec in 40-47% of individuals receiving ritonavir-boosted saquinavir compared with 3-5% of individuals receiving placebo or active control (moxifloxacin).(See Cautions: Precautions and Contraindications.)

Vasodilation or syncope occurred in 1.7-3.5 or 0.6-2.1%, respectively, of patients receiving ritonavir in conjunction with other antiretroviral agents. Cardiovascular disorder, cerebral ischemia, cerebral venous thrombosis, chest pain (including substernal chest pain), hypertension, hypotension, myocardial infarct, palpitation, peripheral vascular disorder, phlebitis, postural hypotension, tachycardia, and vasospasm have occurred in less than 2% of patients receiving ritonavir.

Respiratory Effects

Pharyngitis has been reported in 0.4-1.4% of patients receiving full-dose ritonavir in conjunction with other antiretroviral agents. Adverse respiratory effects reported in less than 2% of patients receiving ritonavir include asthma, bronchitis, dyspnea, epistaxis, hiccup, hypoventilation, increased cough, interstitial pneumonia, larynx edema, lung disorder, rhinitis, and sinusitis.

Ocular and Otic Effects

Abnormal electro-oculogram, abnormal electroretinogram, abnormal vision, amblyopia/blurred vision, blepharitis, conjunctivitis, diplopia, ocular disorder, ocular pain, iritis, photophobia, uveitis, visual field defect, and vitreous disorder have been reported in less than 2% of patients receiving full-dose ritonavir in clinical studies. Otic pain, hearing impairment, increased cerumen, and tinnitus have been reported in less than 2% of patients receiving the drug.

Genitourinary Effects

Nocturia has occurred in up to 2.8% of patients receiving full-dose ritonavir. Adverse renal effects reported in less than 2% of patients receiving ritonavir alone or in conjunction with other antiretroviral agents include abnormal renal function, albuminuria, increased BUN, cystitis, dysuria, glycosuria, hematuria, kidney calculus, kidney pain, renal failure, polyuria, urethritis, urinary frequency, urinary retention, and urinary tract infection.

Decreased libido, penis disorder, impotence, breast pain, pelvic pain, menorrhagia, and vaginitis have been reported in less than 2% of patients receiving ritonavir.

Pancreatitis

Pancreatitis, including some fatalities, has been reported in patients receiving ritonavir, including some patients who developed hypertriglyceridemia. Pancreatitis has been reported in less than 2% of patients receiving ritonavir in clinical studies. Pancreatorenal syndrome consisting of acute pancreatitis in conjunction with acute renal failure has been reported in at least one patient receiving a multiple-drug regimen that included ritonavir; this syndrome also has been reported rarely in patients receiving regimens that did not include ritonavir.

Immune Reconstitution Syndrome

Patients receiving potent antiretroviral therapy may experience an immune reconstitution syndrome during the initial phase of therapy. Patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii]); this may necessitate further evaluation and treatment.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome) have been reported in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of antiretroviral therapy.

Other Adverse Effects

Fever, weight loss, unspecified pain, or malaise occurred in 0.7-5, 0-2.4, 0.9-4.3, or 0.7-5.2%, respectively, of patients receiving full-dose ritonavir with other antiretroviral agents. Adrenal cortex insufficiency, alcohol intolerance, altered hormone concentrations, avitaminosis, cachexia, chills, dehydration, edema (including facial edema or peripheral edema), enzymatic abnormality, facial pain, flu-like syndrome, gout, xanthomatosis, hypothermia, parosmia, as well as accidental injury have been reported in less than 2% of patients receiving ritonavir in clinical studies. There have been postmarketing reports of dehydration, usually associated with GI symptoms, and sometimes resulting in hypotension, syncope, or renal insufficiency. Syncope, orthostatic hypotension, and renal insufficiency also have been reported without known dehydration.

Serum uric acid concentrations exceeding 12 mg/dL have occurred in up to 3.8% of ritonavir-treated patients. Increases in plasma creatine kinase (CK, creatine phosphokinase, CPK) concentrations to greater than 1000 IU/L have occurred in 9.1-12.1% of patients receiving ritonavir alone or with other antiretroviral agents.

Precautions and Contraindications

Ritonavir is contraindicated in patients with known hypersensitivity (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome) to the drug or any ingredient in the formulation. Ritonavir should be discontinued if a severe reaction occurs.

Ritonavir should always be administered in conjunction with other antiretroviral agents and should not be used alone in the treatment of HIV infection. Patients should be monitored closely for adverse effects. When ritonavir-boosted regimens are used, the usual cautions, precautions, and contraindications associated with the other PI should be considered.

If adverse effects likely to be caused by ritonavir occur during the first few weeks of therapy, these effects are likely to be transient and therapy with the drug usually can be continued. If ritonavir therapy is temporarily interrupted, the drug may be reinitiated using the manufacturer recommended dose escalation schedule. (See Dosage and Administration: Dosage.) Patients receiving ritonavir should be advised of the importance of taking the drug exactly as prescribed and that adverse effects such as mild to moderate GI effects, peripheral paresthesia, circumoral paresthesia, and asthenia may diminish as therapy is continued.

Interactions

Concomitant use of ritonavir with a wide variety of drugs may result in clinically important drug interactions that, in some cases, contraindicate such use because of potentially serious and/or life-threatening adverse effects or, in other cases, necessitate dosage adjustment of ritonavir and/or the other drug. Because there is a high probability of drug interactions when ritonavir is used concomitantly with other drugs, patients should be instructed to inform their clinicians of their use of other drugs, including prescription and nonprescription drugs, or dietary or herbal supplements such as St. John's wort (Hypericum perforatum).

The manufacturer cautions that therapeutic drug concentration monitoring and/or increased monitoring of therapeutic and adverse effects is necessary when ritonavir is used with certain other drugs, especially those with a narrow therapeutic margin (e.g., oral anticoagulants, anticonvulsants, antiarrhythmics). Concomitant use of ritonavir with alfuzosin, amiodarone, bepridil (no longer commercially available in the US), cisapride, ergot alkaloids (dihydroergotamine, ergonovine, ergotamine, methylergonovine), flecainide, lovastatin, oral midazolam, pimozide, propafenone, quinidine, sildenafil used for the treatment of pulmonary arterial hypertension (PAH), simvastatin, or triazolam is contraindicated because such use is likely to produce substantially increased plasma concentrations of these drugs and possibly precipitate serious and/or life-threatening arrhythmogenic, hematologic, neurologic, or other toxicities. Concomitant use of ritonavir (400 mg twice daily or greater) with voriconazole is contraindicated; concomitant use of ritonavir (100 mg) with voriconazole is not recommended unless potential benefits outweigh risks. Because St. John's wort may cause decreased ritonavir concentrations with possible loss of virologic response and development of drug resistance, concomitant use of St. John's wort and ritonavir is contraindicated. For further information on drug interactions with ritonavir, see Drug Interactions.

Precautions Related To Cardiovascular Effects

Prolongation of the PR interval has occurred in individuals receiving ritonavir.(See Cautions: Cardiovascular Effects.) Ritonavir should be used with caution in patients with structural heart disease, cardiac conduction abnormalities, ischemic heart disease, or cardiomyopathies; these individuals may be at increased risk for cardiac conduction abnormalities. Caution is advised if ritonavir is used with other drugs that prolong the PR interval (e.g., some β-adrenergic blocking agents, digoxin, calcium-channel blockers, atazanavir), especially drugs metabolized by the cytochrome P-450 (CYP) isoenzyme 3A. Patients should be advised to consult their clinician if they experience dizziness, lightheadedness, heart rhythm changes, or loss of consciousness.

Precautions Related to Hepatic Effects and Pancreatitis

Because there have been reports of hepatic dysfunction, including some fatalities, in patients receiving ritonavir, the drug should be used with caution in patients with preexisting liver disease, liver enzyme abnormalities, or HBV or HCV infection and consideration should be given to more frequent testing of serum AST and ALT concentrations in these patients, especially during the first 3 months of therapy.

Potentially fatal pancreatitis has been reported in patients receiving ritonavir, including those with hypertriglyceridemia. Patients who develop clinical signs or symptoms suggestive of pancreatitis (nausea, vomiting, abdominal pain, increased serum lipase or amylase concentrations) should be evaluated and ritonavir therapy should be discontinued if a diagnosis of pancreatitis is made.

Precautions Associated with Alcohol and Propylene Glycol in the Oral Solution

Ritonavir oral solution contains 43.2% (v/v) alcohol and 26.57% (w/v) propylene glycol. When administered concomitantly with propylene glycol, ethanol competitively inhibits metabolism of propylene glycol, which may lead to elevated propylene glycol concentrations. Preterm neonates may be at increased risk of propylene glycol-associated adverse effects due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events.

Life-threatening cardiac toxicity (including complete AV block, bradycardia, cardiomyopathy), lactic acidosis, acute renal failure, CNS depression, and respiratory complications leading to death have been reported, predominately in preterm neonates receiving lopinavir/ritonavir oral solution, which also contains alcohol and propylene glycol.(See Cautions: Pediatric Precautions.)

Other Precautions

Because ritonavir has been associated with alterations in certain laboratory test results (e.g., serum AST, ALT, GGT, CK, uric acid), appropriate clinical chemistry tests should be performed prior to and periodically after initiation of ritonavir therapy or whenever symptoms occur during therapy with the drug.

Because substantial increases in serum triglyceride and serum cholesterol concentrations have been reported in patients receiving ritonavir alone or in conjunction with other antiretroviral agents, serum triglyceride and cholesterol concentrations should be evaluated prior to and at periodic intervals during ritonavir therapy. (See Cautions: Effects on Lipoproteins.) Lipid disorders should be managed by appropriate interventions; the fact that concomitant use of ritonavir and some antilipemic agents (e.g., lovastatin, simvastatin) is contraindicated or not recommended should be considered. (See Antilipemic Agents under Drug Interactions: Cardiovascular Agents.)

The possibility that the risk of spontaneous bleeding may be increased in patients with hemophilia A or B receiving a PI should be considered. (See Cautions: Hematologic Effects.)

The possibility that hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus may occur in patients receiving a PI should be considered. (See Cautions: Hyperglycemic and Diabetogenic Effects.)

Patients receiving ritonavir should be informed that redistribution or accumulation of body fat may occur in patients receiving a PI and that the cause and long-term consequences of these adipogenic effects are not known. (See Cautions: Adipogenic Effects.)

Strains of HIV-1 with in vitro resistance to ritonavir have emerged during therapy with the drug. Varying degrees of cross-resistance can occur among the various PIs. Continued use of full-dose ritonavir therapy (600 mg twice daily) after loss of viral suppression may increase the likelihood of cross-resistance to other PIs. (See Resistance.)

Patients should be informed that ritonavir in conjunction with other antiretroviral agents is not a cure for HIV infection and that opportunistic infections and other complications associated with HIV disease may still occur. Patients receiving ritonavir should be under close clinical observation by clinicians experienced in treatment of diseases associated with HIV infection and patients should be advised to seek medical care if any clinically important change in their health status occurs.

Patients should be advised that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others. Patients should continue to practice safer sex (e.g., use latex or polyurethane condoms to minimize sexual contact with body fluids), never share personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reuse or share needles.

Pediatric Precautions

Safety and efficacy of ritonavir have been established in pediatric patients older than 1 month of age.

Adverse effects reported to date in pediatric patients older than 1 month of age receiving ritonavir are similar to those reported in adults and have included GI disturbance (vomiting, diarrhea), rash/allergy, anemia, thrombocytopenia, hyperamylasemia, increased serum triglyceride concentrations, neutropenia, increased bilirubin, increased serum potassium concentrations, and increased AST and ALT concentrations.

Ritonavir oral solution contains 43.2% (v/v) alcohol and 26.57% (w/v) propylene glycol. Inadvertent ingestion of the oral solution or overdosage in an infant or young child may result in substantial toxicity and is potentially lethal.(See Precautions Associated with Alcohol and Propylene Glycol in the Oral Solution under Cautions: Precautions and Contraindications.)

Preterm neonates may be at increased risk of propylene glycol-associated adverse effects due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events. There have been postmarketing reports of life-threatening cardiac toxicity (including complete AV block, bradycardia, cardiomyopathy), lactic acidosis, acute renal failure, CNS depression, and respiratory complications leading to death, predominately in preterm neonates receiving lopinavir/ritonavir oral solution, which also contains alcohol and propylene glycol.

Because of possible toxicities, ritonavir oral solution should not be used in preterm neonates in the immediate postnatal period. However, if the benefits of using ritonavir oral solution for treatment of HIV infection in an infant immediately after birth outweigh potential risks, the infant should be monitored closely for increases in serum osmolality and serum creatinine and other signs of toxicity related to the oral solution. These toxicities include hyperosmolality with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, apnea), seizures, hypotonia, cardiac arrhythmias, ECG changes, and hemolysis.

If ritonavir oral solution is used in preterm neonates or infants 1-6 months of age, the total amounts of alcohol and propylene glycol from all drugs that the child is receiving should be taken into account to avoid toxicity associated with these excipients.

Geriatric Precautions

Clinical studies of ritonavir to date have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric patients respond differently than younger adults. In general, dosage for geriatric patients should be selected carefully since these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Mutagenicity and Carcinogenicity

Ritonavir was not mutagenic or clastogenic in vitro and in vivo studies, including bacterial reverse mutation (Ames) assays using Salmonella typhimurium and Escherichia coli, the mouse lymphoma cell test, and the mouse micronucleus assay. In addition, no chromosome aberrations were detected in human lymphocyte assays.

Carcinogenicity studies in mice using ritonavir dosages of 50, 100, or 200 mg/kg daily indicated that there was a dose-dependent increase in the incidence of adenomas and combined adenomas and carcinomas in the liver in males but not in females. Systemic exposure (based on AUC) of the high dosage in the males was approximately 0.3-fold that in humans receiving the recommended ritonavir dosage (600 mg twice daily) and systemic exposure in the females was approximately 0.6-fold that in humans. There were no carcinogenic effects in rats using ritonavir dosages of 7, 15, or 30 mg/kg daily (systemic exposure of the high dose was approximately 6% that of human exposure with the recommended ritonavir dosage). The relevance to humans of these results in rodents is unknown.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats or rabbits at ritonavir exposure levels calculated to be equivalent to or twice the usual human dosage, respectively, did not reveal evidence of embryotoxicity or teratogenicity. In rats, developmental toxicity (i.e., early resorptions, decreased fetal body weight, ossification delays, developmental variations) occurred at a maternally toxic dosage (i.e., ritonavir exposure level equivalent to 30% of that attained with the usual human dosage); a slight increase in the incidence of cryptorchidism was observed in rats at a ritonavir exposure level equivalent to 22% of that achieved with the usual human dosage. In rabbits, developmental toxicity (i.e., resorptions, decreased litter size, decreased fetal body weight) occurred at a maternally toxic dosage (i.e., ritonavir exposure level equivalent to 1.8 times that attained with the usual human dosage based on a body surface area conversion factor).

There are no adequate and controlled studies to date using ritonavir in pregnant women, and the drugs should be used during pregnancy only when clearly needed. Ritonavir has been used in pregnant women either as full-dose ritonavir in conjunction with 2 NRTIs or as low-dose ritonavir given concomitantly with another PI (ritonavir-boosted regimes). In at least 2 women, neonates were born prematurely and had transient hypoglycemia. Low ritonavir concentrations have been reported in pregnant women when full-dose ritonavir was used alone.

The US Department of Health and Human Services (HHS) Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that ritonavir should only be given as low-dose ritonavir in conjunction with another PI (ritonavir-boosted PI regimens) in pregnant women.

To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including ritonavir, an antiretroviral pregnancy registry was established through the collaboration of antiretroviral manufacturers and an advisory committee of practitioners. Clinicians are encouraged to contact the pregnancy registry at 800-258-4263 or http://www.APRegistry.com to report cases of prenatal exposure to antiretroviral agents. As of January 2012, the registry had received reports of 3860 cases of exposure to ritonavir-containing regimens (1567 first trimester exposures, 2293 second and third trimester exposures). Data indicate that birth defects occurred in 2.2% of live births following first trimester exposures and in 2.6% of live births following second/third trimester exposures; the birth defect rate among pregnant women in the US reference population is 2.7%.

Fertility

There was no evidence that ritonavir affected fertility when the drug was given to male or female rats at exposure levels equivalent to 40 or 60%, respectively, of those expected with the usual human dosage. Higher ritonavir doses were not studied in these animals due to hepatic toxicity.

Lactation

Ritonavir is distributed into milk in rats; it is not known whether ritonavir is distributed into human milk. Because of the risk of transmission of HIV to an uninfected infant, the US Centers for Disease Control and Prevention (CDC) and other experts recommend that HIV-infected women not breast-feed infants, regardless of antiretroviral therapy. Therefore, because of the potential for HIV transmission and the potential for serious adverse effects from ritonavir if the drug were distributed into milk, women should be instructed not to breast-feed while they are receiving ritonavir.

Drug Interactions

Clinically important drug interactions may occur when ritonavir is used concomitantly with a wide variety of drugs, principally because of pharmacokinetic interactions. Ritonavir is an inhibitor of cytochrome P-450 (CYP) enzymes 3A and, to a lesser extent, 2D6. Ritonavir appears to induce CYP3A, 1A2, 2C9, 2C19, and 2B6. Therefore, if ritonavir is used concomitantly with drugs that are extensively metabolized by these isoenzymes, plasma concentrations of the drugs may be substantially altered because of decreased or increased metabolism. There also is some evidence that ritonavir may increase the activity of glucuronosyl transferase, and concomitant use with drugs that are directly glucuronidated could result in a loss of therapeutic effect of these drugs. In addition, concomitant use with some drugs may affect plasma concentrations of ritonavir. Metabolism of ritonavir is mediated by CYP3A and CYP2D6, and concomitant use with drugs that induce these isoenzymes may result in clinically important decreases in ritonavir plasma concentrations. Conversely, concomitant use of ritonavir with drugs that inhibit CYP3A and CYP2D6 isoenzymes may result in increased plasma ritonavir concentrations.

Over 200 drugs used in individuals with human immunodeficiency virus (HIV) infection have been reviewed systematically by the manufacturer to identify potential drug interactions with ritonavir. While pharmacokinetic drug interaction studies evaluating concomitant use of ritonavir and some drugs are available, the manufacturer's information on and recommendations for concomitant use with many other drugs is based on theoretical interactions. With some drugs, concomitant use with ritonavir is contraindicated because of potentially serious and/or life-threatening adverse effects, including serious arrhythmogenic, hematologic, neurologic, or other toxicities, that could occur as the result of increased plasma concentrations of the drugs. With other drugs, concomitant use is possible as long as appropriate dosage adjustment of ritonavir and/or the other drug(s) is made. Large dosage adjustments (e.g., 50% or more) may be necessary when ritonavir is used concomitantly with drugs extensively metabolized by the CYP3A isoenzyme. While the need for dosage modification depends on whether substantial changes in the pharmacokinetics of the drugs are anticipated, only limited information is available on many of these interactions and additional clinical data are necessary to assess the clinical significance and appropriate intervention for these interactions. The manufacturer cautions that therapeutic drug concentration monitoring and/or increased monitoring of therapeutic and adverse effects are necessary when the possibility of a drug interaction exists, especially when ritonavir is used with drugs with a narrow therapeutic margin (e.g., anticoagulants, anticonvulsants, antiarrhythmics). The fact that dosage adjustments of ritonavir and/or the other drug may be necessary in patients receiving concomitant therapy with drugs that are extensively metabolized by, or that induce or inhibit, CYP isoenzymes should be considered. The manufacturer's labeling and/or specialized references should be consulted for additional information and specific recommendations concerning therapeutic drug monitoring and dosage adjustments.

Alfuzosin

Concomitant use of ritonavir and alfuzosin is contraindicated. Concomitant use of the drugs may result in increased plasma concentrations of alfuzosin and hypotension.

Anticoagulants

Rivaroxaban

Concomitant use of rivaroxaban (single 10-mg dose on days 0 and 7) and full-dose ritonavir (600 mg twice daily on days 2-7) resulted in a 60% increase in peak plasma concentrations of rivaroxaban and a 150% increase in the area under the concentration-time curve (AUC) of the drug. Increased rivaroxaban concentrations may lead to increased risk of bleeding.

Concomitant use of rivaroxaban and ritonavir should be avoided.

Warfarin

Concomitant use of ritonavir and warfarin may result in decreased plasma concentrations of R-warfarin and increased or decreased plasma concentrations of S-warfarin. If ritonavir and warfarin are used concomitantly, frequent monitoring of INR is recommended, particularly during initiation or discontinuance of ritonavir.

Antifungal Agents

Fluconazole

In a multiple-dose cross-over study in a limited number of healthy adults, concomitant use of fluconazole (400 mg on day 1, then 200 mg daily for 4 days) and ritonavir (200 mg every 6 hours for 4 days) increased the mean peak plasma concentration and AUC of ritonavir by 15% or less. This effect on the pharmacokinetics of ritonavir was considered minor and it has been suggested that adjustment of ritonavir dosage probably is unnecessary in patients receiving concomitant fluconazole. It is not known whether ritonavir affects the pharmacokinetics of fluconazole.

Itraconazole

Concomitant use of ritonavir and itraconazole may increase plasma concentrations of both drugs. Itraconazole dosage should not exceed 200 mg daily in patients receiving ritonavir. Some experts state that consideration should be given to monitoring plasma itraconazole concentrations in patients receiving ritonavir-boosted HIV protease inhibitors (PIs).

Ketoconazole

Concomitant use of ketoconazole (200 mg daily for 7 days) and full-dose ritonavir (500 mg every 12 hours for 10 days) increased the peak plasma concentration and AUC of ritonavir by 10 or 18%, respectively, and increased the peak plasma concentration and AUC of ketoconazole by 55 and about 300%, respectively. Ketoconazole dosage should not exceed 200 mg daily in patients receiving ritonavir.

Voriconazole

Concomitant use of ritonavir (400 mg twice daily) and voriconazole decreases the AUC and peak plasma concentration of voriconazole by 82 and 66%, respectively. Concomitant use of low-dose ritonavir (100 mg twice daily) and voriconazole decreases the AUC and peak plasma concentration of voriconazole by 39 and 24%, respectively. Concomitant use of ritonavir at dosages of 400 mg every 12 hours or greater with voriconazole is contraindicated. Concomitant use of ritonavir 100 mg and voriconazole is not recommended unless benefits outweigh risks. Some experts state that consideration should be given to monitoring plasma voriconazole concentrations in patients receiving ritonavir-boosted PIs.

Antimalarial and Antiprotozoal Agents

Concomitant use of ritonavir and quinine is predicted to result in increased plasma concentrations of quinine; dosage reduction of the antimalarial agent may be necessary.

The manufacturer of ritonavir states that concomitant use of commercially available ritonavir capsules or oral solution and metronidazole may result in a disulfiram-like reaction since these ritonavir formulations contain alcohol.

Concomitant use of atovaquone and ritonavir is predicted to result in decreased plasma concentrations of the antiprotozoal agent. Although the clinical importance of the interaction is unknown, atovaquone dosage may need to be increased.

Antimycobacterial Agents

Pharmacokinetic interactions between some antimycobacterial agents (e.g., bedaquiline, rifabutin, rifampin) and ritonavir or other PIs (e.g., indinavir, lopinavir, nelfinavir, saquinavir) have been reported or are expected to occur. The fact that concomitant use of a PI with some antimycobacterial agents can affect plasma concentrations of the antimycobacterial agent(s) and/or the PI must be considered when antimycobacterial therapy is indicated for the treatment of active tuberculosis or latent tuberculosis infection or for the prophylaxis or treatment of Mycobacterium avium complex infections in HIV-infected patients who are receiving or are being considered for PI therapy. Because the management of these patients is complex and must be individualized, experts in the management of mycobacterial infections in HIV-infected patients should be consulted.

Bedaquiline

Concomitant use of bedaquiline and ritonavir-boosted PIs may result in increased bedaquiline concentrations, but the clinical importance of the interaction is unknown. If potential benefits outweigh risks, some experts state that bedaquiline and ritonavir-boosted PIs may be used concomitantly with caution; patients should be monitored for corrected QT (QT_c) interval prolongation and liver dysfunction.

Ethambutol

Ethambutol has been used in a limited number of patients receiving ritonavir; however, concomitant use of the drugs has not been specifically evaluated in drug interaction studies.

Rifabutin

Concomitant use of ritonavir and rifabutin results in substantially increased plasma concentrations of rifabutin and its 25-O-desacetyl metabolite and also may result in decreased plasma concentrations of ritonavir. In a limited number of healthy individuals, concomitant use of rifabutin (150 mg once daily for 14 days) and full-dose ritonavir (500 mg every 12 hours for 10 days) increased peak concentrations of rifabutin and its 25-O-desacetyl metabolite by 2.5- and 16-fold, respectively, and increased their AUCs by 4- and 35-fold, respectively. In a phase 3 study in patients with advanced HIV infection, the incidence of leukopenia, arthralgia, joint stiffness, and uveitis was higher in patients receiving ritonavir concomitantly with rifabutin than in those receiving rifabutin alone.

If ritonavir is used concomitantly with rifabutin, the rifabutin dosage should be decreased to 150 mg every other day or 3 times weekly (further dosage reduction may be needed). However, because a rifabutin dosage of 150 mg 3 times weekly in patients receiving the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) has resulted in inadequate rifabutin concentrations and acquired rifamycin resistance, some experts recommend a rifabutin dosage of 150 mg daily or 300 mg 3 times weekly in patients receiving ritonavir-boosted PIs and suggest that rifabutin plasma concentrations and antimycobacterial activity be monitored.

Rifampin

Rifampin increases the activity of CYP3A isoenzymes and increases clearance of ritonavir resulting in decreased plasma concentrations of the PI. Preliminary data from a study evaluating concomitant use of rifampin (300 or 600 mg daily for 10 days) and full-dose ritonavir (500 mg every 12 hours for 20 days) in healthy adults indicate that the peak plasma concentrations of ritonavir are decreased by 25% and the AUC of the drug is decreased by 35%. The use of additional ritonavir does not overcome this interaction and increases the risk of hepatotoxicity.

Because of the possibility of loss of virologic response, concomitant use of rifampin and full-dose ritonavir or ritonavir-boosted PIs is not recommended; use of other antimycobacterial agents (e.g., rifabutin) should be considered.

Rifapentine

Concomitant use of rifapentine and ritonavir may result in decreased ritonavir concentrations. Concomitant use of ritonavir and rifapentine is not recommended. HIV-infected tuberculosis patients treated with rifapentine have a higher rate of tuberculosis relapse than those treated with other rifamycin-based tuberculosis regimens; an alternative antimycobacterial agent is recommended in HIV patients.

Antineoplastic Agents

Dasatinib

Concomitant use of dasatinib and ritonavir may result in increased dasatinib concentrations; dosage of the antineoplastic agent may need to be decreased.

Nilotinib

Concomitant use of nilotinib and ritonavir may result in increased nilotinib concentrations; dosage of the antineoplastic agent may need to be decreased.

Vinca Alkaloids

Concomitant use of vincristine or vinblastine and ritonavir may result in increased concentrations of the vinca alkaloid. The manufacturer of ritonavir states that temporarily withholding ritonavir-containing antiretroviral regimens should be considered in patients who develop substantial hematologic or GI toxicity from the vinca alkaloid. Alternatively, use of a regimen that does not include agents that inhibit CYP3A or the P-glycoprotein transport system should be considered.

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

Enfuvirtide

Concomitant use of enfuvirtide (90 mg twice daily) and ritonavir (200 mg every 12 hours for 4 days) increased peak plasma concentrations and AUC of enfuvirtide by 24 and 22%, respectively. This interaction is not considered clinically important.

Maraviroc

Concomitant use of maraviroc (100 mg twice daily) with low-dose ritonavir (ritonavir 100 mg twice daily) results in increased maraviroc plasma concentrations and AUC. If maraviroc is used in a regimen that includes low-dose ritonavir (except ritonavir-boosted tipranavir), the recommended dosage of maraviroc is 150 mg twice daily. If maraviroc is used with ritonavir-boosted tipranavir, the recommended dosage of maraviroc is 300 mg twice daily.

There is no in vitro evidence of antagonistic antiretroviral effects between maraviroc and ritonavir.

HIV Integrase Inhibitors (INSTIs)

Elvitegravir and Cobicistat

Concomitant use of ritonavir and the fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/COBI/TDF/FTC) may alter concentrations of elvitegravir or cobicistat. Ritonavir and cobicistat have similar effects on CYP3A4.

EVG/COBI/TDF/FTC should not be used concomitantly with ritonavir.

Raltegravir

Concomitant use of raltegravir (single 400-mg dose) and low-dose ritonavir (100 mg twice daily) decreases the peak plasma concentration and AUC of raltegravir by 24 and 16%, respectively. Dosage adjustments are not necessary if raltegravir is used concomitantly with low-dose ritonavir; however, when low-dose ritonavir is used to boost concentrations of other PIs, the possibility of drug interactions between raltegravir and the other PIs in the regimen should be considered.

Although data are not available regarding concomitant use of raltegravir and ritonavir dosage exceeding 100 mg twice daily, decreased raltegravir concentrations may occur.

There is in vitro evidence of additive to synergistic antiretroviral effects between raltegravir and ritonavir.

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Delavirdine

Concomitant use of delavirdine (400 or 600 mg twice daily) and ritonavir (300 mg twice daily) did not appear to affect the pharmacokinetics of either drug, but other data in HIV-infected patients suggest that usual dosage of delavirdine used concomitantly with ritonavir (600 mg twice daily) results in a 70% increase in trough ritonavir concentrations and systemic exposure. Appropriate dosages for concomitant use of delavirdine and ritonavir with respect to safety and efficacy have not been established.

Efavirenz

Concomitant use of efavirenz (600 mg once daily for 10 days) and full-dose ritonavir (500 mg every 12 hours for 8 days) increased the AUC of each drug by about 20%. Concomitant use of efavirenz and full-dose ritonavir (500 mg twice daily) has been associated with a higher incidence of adverse effects (e.g., dizziness, nausea, paresthesia) and alterations in laboratory values (i.e., elevated serum concentrations of hepatic enzymes) than regimens that did not include both drugs. Serum hepatic enzymes should be monitored in patients receiving concomitant efavirenz and ritonavir.

Etravirine

Concomitant use of etravirine with full-dose ritonavir (600 mg twice daily) results in a substantial decrease in plasma concentrations of etravirine and possible decreased antiretroviral efficacy. Etravirine and full-dose ritonavir should not be used concomitantly.

Nevirapine

Concomitant use of full-dose ritonavir (600 mg twice daily) and nevirapine in a limited number of HIV-infected patients did not result in clinically important changes in peak plasma concentration or AUC of ritonavir.

Rilpivirine

Concomitant use of ritonavir-boosted PIs and rilpivirine may result in increased rilpivirine concentrations, but is not expected to affect concentrations of the boosted PI.

The antiretroviral effects of ritonavir and rilpivirine are not antagonistic against HIV-1 in vitro.

HIV Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Concomitant use of full-dose oral ritonavir (600 mg every 12 hours or 300 mg every 6 hours) with oral didanosine (200 mg every 12 hours) or oral zidovudine (200 mg every 8 hours) for 4 days decreased peak plasma concentrations and AUC of didanosine or zidovudine by 13-16% or 25-27%, respectively. Concomitant use of ritonavir and didanosine or zidovudine does not appear to result in a clinically important effect on the pharmacokinetics of ritonavir. Modification of the usual dose of didanosine or zidovudine generally is not necessary in ritonavir-treated patients; however, the manufacturer of ritonavir recommends that doses of didanosine and ritonavir be administered 2.5 hours apart to avoid formulation incompatibility.

The antiretroviral effects of ritonavir and some HIV nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., didanosine, emtricitabine, zidovudine) are additive or synergistic against HIV-1 in vitro. In vitro tests in MT-4 cells (a human lymphoblastoid T-cell line) indicate that ritonavir may potentiate the antiretroviral activity of zidovudine and didanosine against HIV-1. It has been suggested that the additive or synergistic effects of these drugs occur because NRTIs (e.g., didanosine, zidovudine) act at early stages of the HIV replicative cycle whereas PIs (e.g., indinavir, lopinavir, ritonavir, saquinavir) act at a later stage. In addition, PIs are active in a subset of chronically infected cells (e.g., monocytes and macrophages) that generally are not affected by NRTIs.

HIV Protease Inhibitors (PIs)

Atazanavir

Concomitant use of ritonavir and atazanavir may result in substantially increased plasma concentrations of atazanavir. Low-dose ritonavir is used concomitantly with atazanavir for therapeutic advantage (ritonavir-boosted atazanavir).

If ritonavir-boosted atazanavir is used, some experts and the manufacturer of atazanavir recommend a dosage of atazanavir 300 mg once daily with ritonavir 100 mg once daily with food. Safety and efficacy of atazanavir used concomitantly with ritonavir given in a dosage exceeding 100 mg once daily have not been established.

Because prolonged PR interval has been reported with both ritonavir and atazanavir, the drugs should be used concomitantly with caution and clinical monitoring.

The antiretroviral effects of ritonavir and atazanavir are not antagonistic against HIV-1 in vitro.

Darunavir

Concomitant use of ritonavir and darunavir results in substantially increased plasma concentrations of darunavir. Low-dose ritonavir is used concomitantly with darunavir for therapeutic advantage (ritonavir-boosted darunavir).

Fosamprenavir

Concomitant use of ritonavir and fosamprenavir may result in substantially increased plasma concentrations of amprenavir. Low-dose ritonavir is used concomitantly with fosamprenavir for therapeutic advantage (ritonavir-boosted fosamprenavir).

If ritonavir-boosted fosamprenavir is used, the recommended dosage is fosamprenavir 1.4 g once daily with ritonavir 100 or 200 mg once daily or, alternatively, fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily.

Indinavir

Concomitant use of indinavir and ritonavir may increase plasma concentrations of both drugs and may increase the risk of nephrolithiasis. The manufacturers state that dosages of ritonavir and indinavir for concomitant use with respect to safety and efficacy have not been established.

Some experts suggest that if low-dose ritonavir is used with indinavir (ritonavir-boosted indinavir), an indinavir dosage of 800 mg twice daily with ritonavir 100 or 200 mg twice daily is recommended.

Lopinavir

Concomitant use of ritonavir and lopinavir results in increased peak plasma concentration and AUC of lopinavir. Low-dose ritonavir is used concomitantly with lopinavir for therapeutic advantage (ritonavir-boosted lopinavir). Lopinavir is commercially available only in a fixed combination containing low-dose ritonavir (lopinavir/ritonavir). In patients receiving lopinavir/ritonavir, appropriate dosage of additional ritonavir with respect to safety and efficacy have not been established.

Nelfinavir

Concomitant use of ritonavir and nelfinavir increases plasma concentrations of nelfinavir but does not appear to affect plasma concentrations of ritonavir. While administration of ritonavir (a single 500-mg dose) in individuals receiving nelfinavir (750 mg 3 times daily for 5 doses) did not affect the AUC or peak plasma concentration of ritonavir, administration of ritonavir (500 mg twice daily for 3 doses) and a single 750-mg dose of nelfinavir increased the AUC and peak plasma concentration of nelfinavir by 152 and 44%, respectively.

The manufacturer of nelfinavir states that appropriate dosages of nelfinavir and ritonavir for concomitant therapy with respect to safety and efficacy have not been established.

Saquinavir

Concomitant use of ritonavir and saquinavir results in substantially increased saquinavir plasma concentrations. Low-dose ritonavir is used concomitantly with saquinavir for therapeutic advantage (ritonavir-boosted saquinavir).

If ritonavir-boosted saquinavir is used, the recommended dosage is saquinavir 1 g twice daily with ritonavir 100 mg twice daily.

Ritonavir-boosted saquinavir causes dose-dependent prolongation of QT and PR intervals, and torsades de pointes and complete heart block have been reported. (See Cautions: Cardiovascular Effects.) Electrolytes and ECG should be monitored prior to and during therapy with ritonavir-boosted saquinavir

Concomitant use of ritonavir-boosted saquinavir and rifampin is not recommended because of the risk of severe hepatotoxicity.

Tipranavir

Concomitant use of ritonavir and tipranavir results in substantially increased plasma concentrations of tipranavir. Low-dose ritonavir is used concomitantly with tipranavir for therapeutic advantage (ritonavir-boosted tipranavir).

If ritonavir-boosted tipranavir is used in antiretroviral-experienced adults and adolescents, the recommended dosage is tipranavir 500 mg twice daily with ritonavir 200 mg twice daily.

There have been reports of clinical hepatitis and hepatic decompensation, including fatalities, with ritonavir-boosted tipranavir. Close clinical and laboratory monitoring are recommended, particularly in patients with increased risk of hepatotoxicity (e.g., coinfection with chronic hepatitis B virus [HBV] or hepatitis C virus [HCV]). Liver function tests should be assessed prior to initiating ritonavir-boosted tipranavir and frequently during therapy. (

Bosentan

Concomitant use of bosentan and ritonavir may result in increased bosentan concentrations.

In patients who have been receiving ritonavir (including low-dose ritonavir) for at least 10 days, bosentan should be initiated using a dosage of 62.5 mg once daily or every other day based on individual tolerability.

In patients who have been receiving bosentan, bosentan should be discontinued for at least 36 hours prior to initiating ritonavir (including low-dose ritonavir); after at least 10 days of PI therapy, bosentan can be resumed using a dosage of 62.5 mg once daily or every other day based on individual tolerability.

Cardiovascular Agents

Cardiac Drugs and Hypotensive Agents

Concomitant use of ritonavir and amiodarone, bepridil, flecainide, propafenone, or quinidine is contraindicated since ritonavir is expected to produce substantially increased plasma concentrations of these cardiac drugs and increase the potential for serious and/or life-threatening adverse effects associated with the drugs such as cardiac arrhythmias.

Concomitant use of ritonavir and calcium-channel blocking agents such as diltiazem, nifedipine, or verapamil is predicted to result in an increase in plasma concentrations of these agents. Caution is advised if ritonavir is administered with these agents; dosage reduction of the calcium-channel blocking agent may be necessary. Careful monitoring of the patient is recommended.

Concomitant use of ritonavir and disopyramide, mexiletine, or systemic lidocaine is predicted to result in an increase in plasma concentrations of these agents. Caution is advised if ritonavir is administered with these agents; plasma concentrations of the cardiovascular agent should be monitored. There have been postmarketing reports of cardiac and neurologic events when ritonavir was used concomitantly with disopyramide or mexiletine, and the possibility of a drug interaction cannot be excluded.

Concomitant use of ritonavir and metoprolol or timolol is predicted to result in an increase in plasma concentrations of the β-adrenergic blocking agent. Caution is advised if ritonavir is administered with these agents; dosage reduction of the β-adrenergic blocking agent may be necessary. Careful monitoring of the patient is recommended. There have been postmarketing reports of cardiac and neurologic events when ritonavir was used concomitantly with β-adrenergic blocking agents, and the possibility of a drug interaction cannot be excluded.

Concomitant use of ritonavir 200 mg twice daily and digoxin increased the digoxin AUC by 29% and prolonged the digoxin half-life by 43%. Caution is advised if ritonavir and digoxin are used concomitantly. Serum digoxin concentrations should be monitored as appropriate; digoxin dosage reductions may be required.

Antilipemic Agents

Concomitant use of some hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) (e.g., atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) and PIs, including ritonavir, may increase plasma concentrations of these antilipemic agents resulting in increased effects and increased risk of statin-associated adverse effects, including myopathy and rhabdomyolysis.

Atorvastatin

If atorvastatin is used concomitantly with certain ritonavir-boosted PI regimens (e.g., ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, ritonavir-boosted saquinavir), the lowest necessary dosage of atorvastatin should be used and dosage of the statin should not exceed 20 mg daily. Concomitant use of atorvastatin and some other ritonavir-boosted PI regimens (e.g., ritonavir-boosted tipranavir) should be avoided.

Lovastatin

Concomitant use of lovastatin and ritonavir (including low-dose ritonavir) is contraindicated.

Pitavastatin

Dosage adjustments are not necessary if pitavastatin is used concomitantly with ritonavir-boosted PI regimens.

Pravastatin

If pravastatin is used concomitantly with certain ritonavir-boosted PI regimens (e.g., ritonavir-boosted darunavir), pravastatin dosage should be titrated using the lowest possible starting dosage and patients closely monitored for adverse effects.

Rosuvastatin

If rosuvastatin is used concomitantly with certain ritonavir-boosted PI regimens (e.g., ritonavir-boosted atazanavir, lopinavir/ritonavir), the lowest necessary rosuvastatin dosage should be used and should not exceed 10 mg once daily.

Simvastatin

Concomitant use of simvastatin and ritonavir (including low-dose ritonavir) is contraindicated.

CNS Agents

Opiate Agonists

Administration of a single 50-mg oral dose of meperidine and full-dose ritonavir (500 mg every 12 hours for 10 days) decreased the AUC of meperidine by 67% and increased the AUC of its metabolite, normeperidine, by 47%. The manufacturer of ritonavir does not recommend increasing meperidine dosage or long-term concomitant use of meperidine and ritonavir since such dosage adjustments or use may result in increased concentrations of normeperidine, which has analgesic and CNS-stimulant activity (e.g., seizures).

Administration of a single 5-mg dose of methadone and full-dose ritonavir (500 mg every 12 hours for 15 days) decreased the AUC of methadone by 36%. There has been at least one report of opiate withdrawal and subtherapeutic or decreased serum methadone concentrations following initiation of ritonavir therapy in an HIV-infected patient who was receiving long-term methadone treatment for opiate addiction. Individuals receiving concomitant ritonavir, including low-dose ritonavir, and methadone therapy should be informed of this potential interaction, and should be closely monitored for manifestations of opiate withdrawal when ritonavir therapy is initiated; an increase in the maintenance dosage of methadone may be necessary. If methadone dosage is increased during ritonavir therapy, patients should be monitored for methadone overdosage when the antiretroviral agent is discontinued.

Concomitant use of fentanyl and ritonavir is expected to increase fentanyl plasma concentrations. If fentanyl and ritonavir are used concomitantly, patients should be carefully monitored for therapeutic and adverse effects, including potentially fatal respiratory depression.

Caution is advised if ritonavir is administered with tramadol or propoxyphene; dosage reduction of the analgesic may be necessary.

Anticonvulsants

Because anticonvulsants have a narrow therapeutic margin, drug concentrations should be monitored and/or monitoring for therapeutic and adverse effects should be increased in patients receiving ritonavir concomitantly.

Concomitant use of ritonavir and carbamazepine, clonazepam, or ethosuximide is predicted to increase plasma concentrations of the anticonvulsant. Caution is advised if ritonavir is administered with these agents; dosage reduction of the anticonvulsant may be necessary. Clinicians should consider monitoring concentrations of the anticonvulsant.

Concomitant use of ritonavir and divalproex, lamotrigine, or phenytoin is predicted to result in a decrease in plasma concentrations of the anticonvulsant. Caution is advised if ritonavir is administered with these agents; dosage increase of the anticonvulsant may be necessary. Clinicians should consider monitoring concentrations of the anticonvulsant.

Concomitant use of phenobarbital and a PI, including ritonavir, may result in substantial decreases in plasma concentrations of the active PI. Some experts state that an alternative anticonvulsant should be considered; alternatively, virologic response and plasma concentrations of both drugs (phenobarbital and the active PI) should be monitored.

Anorexigenic Agents and Respiratory and Cerebral Stimulants

Concomitant use with ritonavir is predicted to result in an increase in plasma concentrations of methamphetamine. Caution is advised if ritonavir is administered with methamphetamine; dosage reduction of methamphetamine may be necessary.

Life-threatening reactions and at least one fatality have been reported secondary to interactions between methylenedioxymethamphetamine (MDMA, ecstasy) or γ-hydroxybutyrate (GHB, liquid ecstasy) and ritonavir. One HIV-infected adult receiving an antiretroviral regimen that included ritonavir (400 mg twice daily) and saquinavir (400 mg twice daily) experienced a prolonged reaction to MDMA and then a life-threatening reaction after ingesting GHB about a day later (in an attempt to counteract the effects of MDMA); the patient reportedly had previously taken similar doses of MDMA and GHB without incident prior to initiating ritonavir and saquinavir therapy. A fatality occurred in an HIV-infected adult within a few hours of ingesting 180 mg of MDMA; full-dose ritonavir (600 mg twice daily) had recently been added to his antiretroviral regimen and MDMA serum concentrations at autopsy were approximately 10 times greater than expected based on the amount of MDMA ingested. MDMA undergoes demethylenation principally by CYP2D6 but also is metabolized by CYP1A2, CYP2B6, and CYP3A4; concomitant use with inhibitors of these enzymes (e.g., ritonavir) can result in substantial increases in MDMA exposure. Although metabolism of GHB has not been identified, the drug may undergo first-pass metabolism mediated by the CYP450 isoenzyme system. Because the margin of safety for many illicit drugs is narrow or poorly defined and the known or potential interactions between some of these drugs and antiretroviral agents is complex and potentially life-threatening, patients should be advised of the risk of serious consequences if they use these drugs while receiving antiretroviral therapy.

Psychotherapeutic Agents

Concomitant use of ritonavir and pimozide is contraindicated since ritonavir is expected to produce substantially increased plasma concentrations of pimozide and increase the potential for serious and/or life-threatening adverse effects associated with the drug such as cardiac arrhythmias.

Concomitant use of ritonavir with nefazodone, trazodone, antipsychotic agents (e.g., perphenazine, risperidone, thioridazine), or buspirone increases or is predicted to increase plasma concentrations of these agents. Caution is advised if ritonavir is administered with these agents; dosage reduction of the psychotherapeutic agent may be necessary. Nausea, dizziness, hypotension, and syncope were observed when ritonavir and trazodone were used concomitantly. If trazodone is used in patients receiving ritonavir, use with caution and consider decreased trazodone dosage. There have been postmarketing reports of cardiac and neurologic events when ritonavir was used concomitantly with nefazodone, and the possibility of a drug interaction cannot be excluded.

Concomitant use of ritonavir with bupropion may reduce plasma concentrations of bupropion and hydroxybupropion (active metabolite); patients should be monitored for response to bupropion.

Quetiapine

Concomitant use of quetiapine and ritonavir is expected to result in increased quetiapine concentrations. In patients receiving ritonavir, quetiapine should be initiated at the lowest dosage and titrated as needed. If ritonavir is initiated in a patient receiving a stable dosage of quetiapine, dosage of quetiapine should be reduced to one-sixth of the original dosage and the patient should be monitored for efficacy and adverse effects of the antipsychotic.

Selective Serotonin-reuptake Inhibitors

Concomitant use of ritonavir with some selective serotonin uptake inhibitors (SSRIs) (e.g., fluoxetine, paroxetine) may increase plasma concentrations of the SSRI. Caution is advised if ritonavir is administered with SSRIs; dosage of the SSRI may need to be reduced.

In one study in healthy individuals receiving fluoxetine (30 mg every 12 hours for 8 days), administration of a single dose of ritonavir (600 mg) resulted in a 19% increase in the AUC of ritonavir but had no effect on the peak plasma concentration of the drug. Adverse cardiac and neurologic effects have been reported in patients receiving ritonavir and fluoxetine concomitantly, and the possibility of a drug interaction cannot be excluded.

Concomitant administration of escitalopram (20 mg as a single dose) and ritonavir (600 mg as a single dose) had no effect on the pharmacokinetics of either drug.

Tricyclic Antidepressants

Concomitant use of ritonavir with some tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine, nortriptyline) is expected to increase plasma concentrations of the antidepressant. Caution is advised if ritonavir is administered with tricyclic antidepressants; reduction of the antidepressant dosage may be required. Some experts state that the lowest possible dosage of the tricyclic antidepressant should be used in patients receiving ritonavir-boosted PIs; dosage should be titrated based on clinical assessment and/or plasma concentrations of the antidepressant.

Clinically important increases in plasma desipramine concentrations may occur in patients receiving ritonavir, and the manufacturer of ritonavir recommends that reduction of the usual desipramine dosage be considered and plasma desipramine concentrations be monitored if the drugs are used concomitantly. Administration of a single 100-mg dose of desipramine in a limited number of healthy individuals receiving full-dose ritonavir (500 mg every 12 hours for 12 days) resulted in a 22% increase in peak desipramine plasma concentrations and a 145% increase in the AUC of the drug; plasma concentrations and AUC of 2-OH desipramine were decreased 67 and 15%, respectively.

Sedatives and Hypnotics

Concomitant use of ritonavir and oral midazolam or triazolam is contraindicated since ritonavir is expected to produce substantially increased plasma concentrations of these sedative-hypnotics and increase the potential for serious and/or life-threatening adverse effects associated with the drugs (e.g., prolonged or increased sedation or respiratory depression).

Although specific studies are not available regarding concomitant administration of parenteral midazolam and ritonavir, the effect is expected to be less substantial than that reported with oral midazolam. Some experts state that a single parenteral dose of midazolam can be given with caution in a monitored situation for procedural sedation in patients receiving ritonavir. If ritonavir is used concomitantly with parenteral midazolam, the manufacturer of ritonavir states that patients should be monitored closely for respiratory depression and/or prolonged sedation and reduced dosage of midazolam should be considered, particularly if multiple parenteral doses are administered.

In one study, concomitant use of full-dose ritonavir (500 mg every 12 hours for 10 days) with a single 1-mg oral dose of alprazolam decreased the peak plasma concentration and AUC of alprazolam by 16 and 12%, respectively. In another study, concomitant use of ritonavir (200-mg doses given every 9-15 hours for 4 doses) and alprazolam (a single 1-mg dose given 1 hour after the second ritonavir dose) in healthy adults resulted in a 59% decrease in clearance of alprazolam and an increase in the plasma half-life and AUC of alprazolam; however, there was no significant effect on peak plasma concentrations or the time to peak plasma concentrations of the drug. Although the clinical importance of this pharmacokinetic interaction is unclear, use of ritonavir in patients receiving alprazolam may increase the risk of sedative effects associated with the benzodiazepine.

Concomitant use of ritonavir with clorazepate, diazepam, estazolam, flurazepam, or zolpidem is predicted to increase plasma concentrations of the sedative-hypnotic. Caution is advised if ritonavir is administered with these agents; dosage reduction of the sedative-hypnotic may be necessary. Alternatively, although data regarding concomitant use are not available, some experts suggest that use of a benzodiazepine not metabolized by CYP isoenzymes (e.g., lorazepam, oxazepam, temazepam) should be considered.

Colchicine

Concomitant use of PIs, including ritonavir, and colchicine may result in increased plasma concentrations of colchicine. Concomitant use of colchicine and ritonavir is not recommended in patients with renal or hepatic impairment. If used concurrently in patients with normal renal and hepatic function, colchicine dosage adjustments are recommended.

When colchicine is used for treatment of gout flares in patients receiving ritonavir, the manufacturer of ritonavir and some experts recommend that an initial colchicine dose of 0.6 mg be followed by 0.3 mg 1 hour later and that the dose be repeated no earlier than 3 days later.

When colchicine is used for prophylaxis of gout flares in patients receiving ritonavir, the manufacturer of ritonavir and some experts recommend that the colchicine dosage be reduced to 0.3 mg once daily in those originally receiving 0.6 mg twice daily or decreased to 0.3 mg once every other day in those originally receiving 0.6 mg once daily.

When colchicine is used for treatment of familial Mediterranean fever (FMF) in patients receiving ritonavir, the manufacturer of ritonavir and some experts recommend that a maximum colchicine dosage of 0.6 mg daily (may be given as 0.3 mg twice daily) be used.

Corticosteroids

Orally Inhaled or Intranasal Corticosteroids

Concomitant use of budesonide (orally inhaled or intranasal) or fluticasone (orally inhaled or intranasal) with ritonavir-boosted PIs may result in increased concentrations of the corticosteroid and reduced serum cortisol concentrations which may result in adrenal insufficiency or Cushing's syndrome. Cushing's syndrome and adrenal suppression have been reported when ritonavir (including low-dose ritonavir) was used concomitantly with fluticasone propionate (intranasal inhalation in a dosage of 200-800 mcg daily or oral inhalation in a dosage of 500-2000 mcg daily) or with budesonide.

Budesonide (orally inhaled or intranasal) and fluticasone (orally inhaled or intranasal) should not be used concomitantly with ritonavir-boosted PIs unless potential benefits of the inhaled or intranasal corticosteroid outweigh risks of systemic corticosteroid adverse effects. An alternative corticosteroid (e.g., beclomethasone) should be considered.

Some experts state that concomitant use of beclomethasone (inhaled or intranasal) and a ritonavir-boosted PI is not expected to result in clinically important pharmacokinetic interactions.

Local Injections of Corticosteroids

Concomitant use of intra-articular or other local injections of methylprednisolone, prednisolone, or triamcinolone with ritonavir-boosted PIs may result in increased concentrations of the inhaled or intranasal corticosteroid and may result in adrenal insufficiency or Cushing's syndrome.

Ritonavir-boosted PIs should not be used concomitantly with local injections of methylprednisolone, prednisolone, or triamcinolone; other nonsteroidal therapies should be considered. If intra-articular corticosteroid therapy is required, an alternative antiretroviral that does not alter CYP3A4 activity (e.g., dolutegravir, raltegravir) should be considered.

Systemic Corticosteroids

Concomitant use of systemic budesonide, dexamethasone, or prednisone with ritonavir may increase corticosteroid concentrations and may result in adrenal insufficiency or Cushing's syndrome. Concomitant use of systemic budesonide or dexamethasone with ritonavir may result in decreased ritonavir concentrations.

Systemic budesonide, dexamethasone, or prednisone should be used concomitantly with ritonavir with caution and only when potential benefits outweigh risks of systemic corticosteroid adverse effects. An alternative to dexamethasone should be considered for long-term corticosteroid use.

Co-trimoxazole

Administration of a single dose of co-trimoxazole (sulfamethoxazole 800 mg and trimethoprim 160 mg) in healthy individuals receiving full-dose ritonavir (500 mg every 12 hours for 12 days) decreased the AUC of sulfamethoxazole by 20% and increased the AUC of trimethoprim by 20%. The manufacturer of ritonavir states that dosage adjustments based on these changes generally are unnecessary.

Disulfiram

Commercially available ritonavir capsules and oral solution contain alcohol, and concomitant use with disulfiram may result in disulfiram-like reactions.

Ergot Alkaloids

Concomitant use of ritonavir and ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine) is contraindicated since ritonavir is expected to produce substantially increased plasma concentrations of these ergot alkaloids and increase the potential for serious and/or life-threatening adverse effects associated with the drugs such as ergot toxicity. There have been postmarketing reports of acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities in patients who received ritonavir concomitantly with ergotamine or dihydroergotamine.

If a woman receiving ritonavir or any other PI as part of an antiretroviral regimen experiences uterine atony and excessive postpartum bleeding, methylergonovine maleate (Methergine) should be used for treatment of the hemorrhage only if alternative treatments (e.g., carboprost, misoprostol, oxytocin, dinoprostone) cannot be used and the potential benefits of the ergot alkaloid outweigh the risks. In this situation, methylergonovine maleate should be used in the lowest dosage and shortest duration possible.

Estrogens

Concomitant use of ethinyl estradiol (oral or transdermal preparations) and ritonavir may result in substantially decreased plasma concentrations of ethinyl estradiol. In a study evaluating administration of a single dose of an oral contraceptive containing ethinyl estradiol (50-mcg of ethinyl estradiol) in healthy women receiving full-dose ritonavir (500 mg every 12 hours for 16 days), peak plasma concentrations and AUC of the estrogen were decreased 32% and 40%, respectively.

The manufacturer of ritonavir and some experts recommend use of alternative nonhormonal or additional methods of contraception in patients receiving ritonavir, including low-dose ritonavir.

GI Drugs

Concomitant use of ritonavir and cisapride is contraindicated since ritonavir is expected to produce substantially increased plasma concentrations of unchanged cisapride and increase the potential for serious and/or life-threatening adverse effects associated with the drug such as cardiac arrhythmias.

Concomitant use of ritonavir and dronabinol is predicted to result in increased plasma concentrations of the antiemetic. Caution is advised and a reduction in the dronabinol dosage may be necessary if ritonavir and dronabinol are used concomitantly.

Grapefruit Juice

While specific studies have not been performed, the manufacturer of ritonavir states that concomitant administration with grapefruit juice is not expected to effect bioavailability of the drug.

HCV Antivirals

HCV Protease Inhibitors

Boceprevir

Concomitant use of boceprevir (400 mg 3 times daily for 15 days) and low-dose ritonavir (100 mg once daily for 12 days) decreased boceprevir peak plasma concentrations and AUC. Concomitant use of boceprevir and ritonavir-boosted PIs (e.g., ritonavir-boosted atazanavir, ritonavir-boosted darunavir, lopinavir/ritonavir) has decreased boceprevir plasma concentrations and AUC. Although specific studies are not available regarding concomitant use of boceprevir and ritonavir-boosted fosamprenavir, ritonavir-boosted saquinavir, or ritonavir-boosted tipranavir, similar pharmacokinetic interactions may occur since low-dose ritonavir alone decreases boceprevir peak plasma concentrations and AUC.

Concomitant use of boceprevir and ritonavir-boosted PIs is not recommended. If boceprevir was initiated for treatment of chronic HCV infection in a patient coinfected with HIV who is receiving a suppressive antiretroviral regimen containing a ritonavir-boosted PI, the patient should be informed of the possible drug interactions and closely monitored for HCV treatment response and potential HCV and HIV virologic rebound.

Simeprevir

Concomitant use of simeprevir and low-dose ritonavir (100 mg twice daily) increased the AUC of simeprevir by 618%. Concomitant use of simeprevir and ritonavir is not recommended.

Telaprevir

Concomitant use of telaprevir (750 mg every 12 hours for 14 days) and low-dose ritonavir (100 mg every 12 hours for 14 days) decreased the peak plasma concentrations and AUC of telaprevir. Concomitant use of telaprevir and ritonavir-boosted PIs (e.g., ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, lopinavir/ritonavir) has decreased telaprevir plasma concentrations and AUC. Although specific studies are not available regarding concomitant use of telaprevir and ritonavir-boosted saquinavir or ritonavir-boosted tipranavir, similar pharmacokinetic interactions may occur since low-dose ritonavir alone decreases telaprevir plasma concentrations and AUC.

Concomitant use of telaprevir and ritonavir-boosted PIs (e.g., ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, lopinavir/ritonavir) is not recommended.

Immunosuppressive Agents

Concomitant use of ritonavir with cyclosporine, sirolimus, or tacrolimus is predicted to result in increased plasma concentrations of the immunosuppressive agent. Clinicians should monitor plasma concentrations of the immunosuppressive agent.

Macrolides

Concomitant use of ritonavir and clarithromycin may affect plasma concentrations of both drugs. In one study in healthy individuals, concomitant use of ritonavir (200 mg every 8 hours) with clarithromycin (500 mg every 12 hours) for 4 days increased the peak plasma concentration and AUC of clarithromycin by 31 and 77%, respectively, and decreased the peak plasma concentration and AUC of 14-hydroxyclarithromycin by 99 and 100%, respectively. In this study, the peak plasma concentration and AUC of ritonavir were increased 15 and 12%, respectively. Because 14-hydroxyclarithromycin appears to enhance the antimicrobial activity of the parent drug against some pathogens (e.g., Haemophilus influenzae), it has been suggested that the decreased plasma concentrations of the metabolite reported with concomitant ritonavir theoretically could adversely affect clarithromycin's efficacy in the treatment of certain infections.

The manufacturer of ritonavir and some experts state that when clarithromycin is used in patients receiving ritonavir, modification of the usual clarithromycin dosage generally is not necessary in those with normal renal function; however, the clarithromycin dose should be reduced by 50% in patients with creatinine clearances of 30-60 mL/minute and reduced by 75% in patients with creatinine clearances less than 30 mL/minute.

Phosphodiesterase Type 5 Inhibitors

Concomitant use of ritonavir and selective phosphodiesterase type 5 (PDE5) inhibitors (e.g., avanafil, sildenafil, tadalafil, vardenafil) is contraindicated or should be used with particular caution since ritonavir is expected to result in substantially increased plasma concentrations of the PDE5 inhibitor and increase the risk of adverse effects (e.g., hypotension, visual disturbances, priapism, syncope) associated with these agents.

Avanafil

Concomitant use of full-dose ritonavir (600 mg twice daily) and avanafil (single 50-mg dose) results in an approximately 13-fold increase in the AUC of avanafil. Avanafil should not be used in patients receiving ritonavir; a safe and effective dosage of avanafil has not been established for such patients.

Sildenafil

Concomitant use of full-dose ritonavir (500 mg twice daily) and sildenafil (single 100-mg dose) results in an approximately 11-fold increase in the AUC of sildenafil.

If sildenafil is used for the treatment of pulmonary arterial hypertension (PAH), concomitant use of ritonavir (including low-dose ritonavir) is contraindicated. The manufacturer of ritonavir states that a safe and effective dosage for such concomitant use has not been established.

If sildenafil is used for the treatment of erectile dysfunction in a patient receiving ritonavir, sildenafil should be initiated with a reduced dose of 25 mg and the dosage should not exceed 25 mg in 48 hours; the patient should be monitored for sildenafil-related adverse effects.

Tadalafil

Concomitant use of ritonavir with tadalafil results in a 124% increase in the AUC of tadalafil.

If tadalafil (Adcirca) is initiated for the treatment of PAH in patients who have been receiving ritonavir for at least 1 week, an initial tadalafil dosage of 20 mg once daily is recommended; dosage may be increased to 40 mg once daily based on individual tolerability. Use of tadalafil (Adcirca) for the treatment of PAH should be avoided during initiation of PI therapy. If ritonavir is indicated in a patient already receiving tadalafil (Adcirca) for the treatment of PAH, tadalafil should be discontinued for at least 24 hours before starting ritonavir; tadalafil can be restarted after at least 1 week of ritonavir therapy using an initial tadalafil dosage of 20 mg once daily and increasing the dosage to 40 mg once daily based on individual tolerability.

If tadalafil is used for the treatment of erectile dysfunction in a patient receiving ritonavir, tadalafil should be initiated with a dose of 5 mg and the dosage should not exceed 10 mg once every 72 hours.

If tadalafil is used for the treatment of benign prostatic hyperplasia in patients receiving ritonavir, tadalafil dosage should not exceed 2.5 mg once daily.

Vardenafil

Concomitant use of ritonavir with vardenafil results in a 49-fold increase in the AUC of vardenafil.

If vardenafil is used for the treatment of erectile dysfunction in a patient receiving ritonavir, initiate vardenafil with a dose of 2.5 mg and do not exceed a vardenafil dosage of 2.5 mg in 72 hours.

Quinupristin and Dalfopristin

Although specific studies are not available, it is possible that concomitant use of ritonavir and quinupristin and dalfopristin may result in increased ritonavir plasma concentrations since quinupristin and dalfopristin is a potent inhibitor of CYP3A4.

Respiratory Smooth Muscle Relaxants

Concomitant use of theophylline and ritonavir may result in decreased concentrations of theophylline, and the manufacturer of ritonavir states that theophylline dosage may need to be increased and therapeutic monitoring should be considered if ritonavir is initiated in patients receiving theophylline therapy. In a limited number of individuals receiving theophylline (3 mg/kg every 8 hours for 15 days), concomitant use of full-dose ritonavir (500 mg every 12 hours for 10 days) decreased theophylline peak plasma concentrations and AUC by 32 and 43%, respectively.

Salmeterol

Concomitant use of salmeterol and ritonavir results in increased salmeterol concentrations and may result in an increased risk of salmeterol-associated adverse cardiovascular effects, including QT interval prolongation, palpitations, and sinus tachycardia. The manufacturer of ritonavir and some experts state that concomitant use of ritonavir (including low-dose ritonavir) and salmeterol is not recommended.

Dietary and Herbal Supplements

St. John's Wort (Hypericum perforatum)

Concomitant use of St. John's wort (Hypericum perforatum) and ritonavir is contraindicated since such use is expected to result in suboptimal antiretroviral concentrations and may be associated with loss of virologic response and development of resistance. Although specific studies with ritonavir have not been performed, there is evidence that concomitant use of indinavir and St. John's wort results in substantial decreases in the AUC and plasma concentrations of the PI. Preliminary data suggest that this drug interaction occurs because St. John's wort is a potent inducer of CYP isoenzymes responsible for metabolism of indinavir. St. John's wort is an extract of hypericum and contains at least 7 different components that may contribute to its pharmacologic effects, including hypericin, pseudohypericin, and hyperforin. There is evidence that hypericum extracts can induce several different CYP isoenzymes, including CYP3A4 and CYP1A2, and also may induce the P-glycoprotein transport system. Therefore, it has been recommended that concomitant use of St. John's wort and PIs or NNRTIs metabolized by CYP isoenzymes be avoided. For further information on drug interactions between St. John's wort and drugs metabolized by CYP isoenzymes, see .

Garlic (Allium sativumor A. ampeloprasum)

In a limited study in 10 healthy adults, concomitant use of garlic supplements did not appear to affect the pharmacokinetics of ritonavir. Individuals received a garlic supplement (10 mg of garlic extract given as capsules twice daily) for 3 days and then received the garlic supplement and a single 400-mg dose of ritonavir on the following day. Although there was a trend toward a lower AUC of ritonavir and higher ritonavir clearance with concomitant garlic supplements, these changes were not statistically significant. Additional study involving a longer duration of concomitant use is needed before a conclusion can be made regarding the effect of garlic supplements on ritonavir pharmacokinetics. There is evidence from a multiple-dose study that concomitant use of garlic supplements may result in substantial decreases in the AUC and plasma concentrations of saquinavir, and it has been suggested that garlic supplements may affect the bioavailability of this PI by inducing CYP450 isoenzymes. This theory is supported by an in vitro study evaluating the effects of various garlic products (e.g., fresh garlic bulbs, aged garlic, odorless garlic, garlic oil, freeze-dried garlic) on human CYP450 isoenzymes. Results of this in vitro study indicate that, although there are some differences among the various products, garlic generally inhibits the activity of CYP2C9, CYP2C19, CYP3A4, CYP3A5, and CYP3A7 but has little or no effect on the activity of CYP2D6. In addition, results of this in vitro study indicate that extracts of fresh garlic can induce CYP2C9*2.

Pharmacokinetics

The pharmacokinetics of ritonavir have been studied in healthy adults and in adults with human immunodeficiency virus (HIV) infection. Results to date indicate that pharmacokinetic parameters of the drug in healthy individuals are similar to those in HIV-infected individuals. Pharmacokinetic studies have not revealed gender-related or race-related differences in the pharmacokinetics of ritonavir. In addition, there has been no evidence of age-related differences in the pharmacokinetics of the drug in adults 18-63 years of age. Pharmacokinetics of the drug have been evaluated in a limited number of HIV-infected children 1 month of age or older. The pharmacokinetics of ritonavir in adults older than 63 years of age and in individuals with renal impairment have not been determined to date.

Absorption

Ritonavir is well absorbed following oral administration, and peak plasma concentrations of the drug generally are attained within 2-4 hours. Oral administration of ritonavir 600 mg every 12 hours in adults with HIV infection results in a steady-state area under the plasma concentration-time curve (AUC) averaging 60.8 mcg&bul;h/mL, peak plasma concentrations averaging 11.2 mcg/mL, and trough concentrations averaging 3-3.7 mcg/mL. Following oral administration of a single 600-mg dose of radiolabeled ritonavir given as the oral solution, essentially all of the dose in systemic circulation represented unchanged ritonavir.

Presence of food in the GI tract may affect the rate and/or extent of absorption of oral ritonavir; however, the effect that food has on GI absorption of ritonavir varies depending on the dosage form of the drug administered. While administration of ritonavir oral solution or tablets with food generally decreases the rate and extent of absorption of the drug, administration of ritonavir capsules with a meal may increase the extent of absorption.

In fasting adults who received a single 600-mg dose of ritonavir as the oral solution, peak plasma ritonavir concentrations were attained 2 hours after the dose; when the same dose was administered with food (12% protein, 79% carbohydrate, 9% fat; 514 kcal), peak plasma concentrations were attained 4 hours after the dose. Compared with administration on an empty stomach, administration of ritonavir oral solution with a meal decreases peak plasma ritonavir concentrations by 23% and decreases the extent of absorption by 7%.

The extent of absorption of ritonavir administered as liquid-filled (soft gelatin) capsules was increased 13% in patients receiving the capsules with a meal (615 kcal, 9% protein, 76% carbohydrate, 14.5% fat) compared with administration on an empty stomach. Administration of a single 100-mg ritonavir tablet with a high-fat (907 kcal, 15% protein, 33% carbohydrate, 52% fat) or moderate-fat meal results in a 21-23% decrease in ritonavir AUC and peak plasma concentration.

While specific studies have not been done, the manufacturer of ritonavir states that concomitant administration with grapefruit juice is not expected to affect bioavailability of the drug.

Ritonavir tablets are not bioequivalent to ritonavir capsules. Following administration of a single dose with a moderate-fat meal, the AUC of the tablet is similar to that of the capsule, but the peak plasma concentration is approximately 26% higher in patients receiving the tablet. Results of a crossover study in healthy, nonfasting adults indicate that the bioavailability of a single 600-mg dose of ritonavir administered as the oral solution is not affected by diluting the dose in 240 mL of chocolate milk, Ensure, or Advera within 1 hour of administration.

Results of a limited study in HIV-infected children 2-14 years of age indicate that a ritonavir dosage of 350-400 mg/m twice daily results in plasma concentrations that approximate those reported in adults receiving a ritonavir dosage of 600 mg (approximately 330 mg/m) twice daily. In HIV-infected infants 1-24 months of age receiving a ritonavir dosage of 350-450 mg/m twice daily, trough concentrations of ritonavir were lower than those reported in adults receiving a ritonavir dosage of 600 mg twice daily. Higher ritonavir exposures were not observed in infants receiving a ritonavir dosage of 450 mg/m twice daily compared with those receiving a dosage of 350 mg/m twice daily.

Results of a study in a limited number of HIV-infected adults indicate that use of a ritonavir dosage of 400 mg twice daily in patients with mild hepatic impairment results in similar ritonavir exposures as those reported in control individuals receiving 500 mg twice daily. In a limited number of adults with moderate hepatic impairment, administration of ritonavir 400 mg twice daily resulted in dose-normalized steady-state ritonavir exposures approximately 40% lower than that reported in adults with normal hepatic function receiving ritonavir 500 mg twice daily.

Distribution

Distribution of ritonavir into body tissues and fluids has not been fully characterized. The volume of distribution following oral administration of a single 600-mg oral dose averages 0.41 L/kg. Although the clinical importance has not been established, the erythrocyte/plasma distribution ratio averages 0.14. In 11 HIV-infected patients receiving ritonavir concomitantly with saquinavir, ritonavir concentrations in CSF ranged from 1.9-23 ng/mL, and these concentrations were 0.1-0.5% of concurrent plasma concentrations.

Ritonavir is 98-99% bound to plasma proteins, principally serum albumin and alpha-1 acid glycoprotein, over a concentration range of 0.01-30 mcg/mL. Mild or moderate hepatic impairment does not result in clinically important changes in protein binding of ritonavir.

Ritonavir crosses the placenta in rats. Low concentrations of the drug cross the placenta in humans.

Ritonavir is distributed into milk in rats; it is not known whether the drug is distributed into human milk.

Elimination

The metabolic fate of ritonavir has not been fully determined, but the drug is metabolized in the liver. Systemic clearance averages 8.8 L/hr in patients receiving ritonavir 600 mg every 12 hours or 4.6 L/hr in those receiving a single 600-mg dose. Renal clearance has been reported to be less than 0.1 L/hr. The plasma half-life of ritonavir in adults averages 3-5 hours. Preliminary results of pharmacokinetic studies in HIV-infected children 1 month to 14 years of age indicate that ritonavir clearance at steady-state is 1.5 times greater in these children than in adults.

Five ritonavir metabolites have been identified in human urine and feces. The isopropylthiazole oxidation metabolite (M2) appears to be the major metabolite. M2 (but not other metabolites) has antiviral activity similar to that of ritonavir; however, only very low concentrations of this metabolite are present in plasma. Other metabolites identified in vitro studies include a decarbamoylated metabolite (M1) and a product of N-dealkylation at the urea terminus (M11). Results of in vitro studies using human liver microsomes indicate that metabolism of ritonavir is mediated by P-450 CYP3A isoenzymes and, to a lesser extent, by CYP2D6; CYP3A contributes to the formation of the M1 and M11 metabolites and CYP3A and CYP2D6 contribute to the formation of M2.

Ritonavir is excreted principally in the feces, both as unchanged drug and metabolites. Following oral administration of 600 mg of radiolabeled ritonavir as the oral solution, 86.4% of the dose is excreted in feces (33.8% as unchanged drug) and 11.3% of the dose is excreted in urine (3.5% as unchanged drug).

Following continuous administration of ritonavir, plasma concentrations are lower than predicted from single-dose studies, presumably because of time- and dose-related increases in clearance.

Because ritonavir is metabolized in the liver and is highly protein bound, it is unlikely that substantial amounts of the drug would be removed from the body by hemodialysis or peritoneal dialysis.