Dosage & Administration
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Norvir Prescribing Information
- When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including contraindication information.
- NORVIR is contraindicated in patients with known hypersensitivity (e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome) to ritonavir or any of its ingredients.
- NORVIR is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions[see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
○ Alpha 1- Adrenoreceptor Antagonist : alfuzosin
○ Antianginal: ranolazine
○ Antiarrhythmics: amiodarone, dronedarone, flecainide, propafenone, quinidine
○ Antifungal: voriconazole
○ Anti-gout: colchicine
○ Antipsychotics: lurasidone, pimozide
○ Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine
○ GI Motility Agent: cisapride
○ HMG-CoA Reductase Inhibitors: lovastatin, simvastatin
○ Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide
○ PDE5 Inhibitor: sildenafil (Revatio®) when used for the treatment of pulmonary arterial hypertension
○ Sedative/Hypnotics: triazolam, orally administered midazolam - NORVIR is contraindicated with drugs that are potent CYP3A inducers where significantly reduced ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance[see Drug Interactions (7.2) and Clinical Pharmacology (12.3)].
○ Anticancer Agents: apalutamide
○ Herbal Products: St. John's Wort (hypericum perforatum)
- NORVIR is contraindicated in patients with known hypersensitivity to ritonavir (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome) or any of its ingredients
- Co-administration with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations may be associated with serious and/or life-threatening events
- Co-administration with drugs that significantly reduce ritonavir
Initiation of NORVIR, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving NORVIR, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of NORVIR, respectively. These interactions may lead to:
- Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.
- Clinically significant adverse reactions from greater exposures of NORVIR.
- Loss of therapeutic effect of NORVIR and possible development of resistance.
When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including important Warnings and Precautions.
See Table 3 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations
NORVIR tablets are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
NORVIR oral powder is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1 infection.
- Adult patients: 600 mg twice-day with meals ()2.000000000000000e+002Dosage Recommendations in AdultsRecommended Dosage for Treatment of HIV-1:
The recommended dosage of NORVIR is 600 mg twice daily by mouth to be taken with meals. Use of a dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels. NORVIR should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily. The maximum dose of 600 mg twice daily should not be exceeded upon completion of the titration
[see Dosage and Administration (2.5)]. - Pediatrics patients: The recommended twice daily dose for children greater than one month of age is based on body surface area and should not exceed 600 mg twice daily with meals ()2.000000000000000e+003Dosage Recommendations in Pediatric Patients
NORVIR must be used in combination with other antiretroviral agents
[see Dosage and Administration(2)]. The recommended dosage of NORVIR in pediatric patients older than 1 month is 350 to 400 mg per m2twice daily by mouth to be taken with meals and should not exceed 600 mg twice daily. NORVIR should be started at 250 mg per m2twice daily and increased at 2 to 3 day intervals by 50 mg per m2twice daily. If patients do not tolerate 400 mg per m2twice daily due to adverse events, the highest tolerated dose may be used for maintenance therapy in combination with other antiretroviral agents, however, alternative therapy should be considered[see Dosage and Administration (2.5)]. - NORVIR oral powder can only be used for dosing increments of 100 mg ()2.000000000000000e+004Preparation of Norvir Oral Powder
For details on the preparation and administration of NORVIR oral powder (see
Instructions for Use). NORVIR oral powder should only be used for dosing increments of 100 mg.Prepare the dose using the required number of packets. For example, use one packet for doses of 100 mg and two packets for doses of 200 mg. Pour and mix the entire contents of each packet over soft food or liquid. All of the powder mixed with soft food or liquid should be administered within 2 hours of preparation. If not administered within 2 hours of preparation, the mixture should be discarded and a new dose prepared.
The prescribed dose of NORVIR oral powder can be administered via a feeding tube after being mixed with water (see
Instructions for Use). Follow the instructions for the feeding tube to administer the medicine. - Instructions for Use should be followed for preparation and administration of NORVIR oral powder ()2.000000000000000e+004Preparation of Norvir Oral Powder
For details on the preparation and administration of NORVIR oral powder (see
Instructions for Use). NORVIR oral powder should only be used for dosing increments of 100 mg.Prepare the dose using the required number of packets. For example, use one packet for doses of 100 mg and two packets for doses of 200 mg. Pour and mix the entire contents of each packet over soft food or liquid. All of the powder mixed with soft food or liquid should be administered within 2 hours of preparation. If not administered within 2 hours of preparation, the mixture should be discarded and a new dose prepared.
The prescribed dose of NORVIR oral powder can be administered via a feeding tube after being mixed with water (see
Instructions for Use). Follow the instructions for the feeding tube to administer the medicine. - Dose modification for NORVIR is necessary when used with other protease inhibitors ()2.000000000000000e+005Dose Modification due to Drug Interaction
Dose reduction of NORVIR is necessary when used with other protease inhibitors: atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir.
Prescribers should consult the full prescribing information and clinical study information of these protease inhibitors if they are co-administered with a reduced dose of ritonavir
[see Warnings and Precautions(5.1), andDrug Interactions(7)].
- NORVIR Tablets
White film-coated ovaloid tablets debossed with the "a" logo and the code NK providing 100 mg ritonavir.
White film-coated ovaloid tablets debossed with “NK” on one side providing 100 mg ritonavir.
- NORVIR Oral Powder
Beige/pale yellow to yellow powder in child-resistant packet. Each packet contains 100 mg of ritonavir.
When co-administering NORVIR with other protease inhibitors, see the full prescribing information for the co-administered protease inhibitor including important information for use in special populations.
- When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including contraindication information.
- NORVIR is contraindicated in patients with known hypersensitivity (e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome) to ritonavir or any of its ingredients.
- NORVIR is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions [see Drug Interactions (7.1 Potential for NORVIR to Affect Other Drugs
Ritonavir is an inhibitor of cytochrome P450 3A (CYP3A) and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (greater than 3-fold) when co-administered with ritonavir. Thus, co-administration of NORVIR with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 3.
Ritonavir also inhibits CYP2D6 to a lesser extent. Co-administration of substrates of CYP2D6 with ritonavir could result in increases (up to 2-fold) in the AUC of the other agent, possibly requiring a proportional dosage reduction. Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase.
These examples are a guide and not considered a comprehensive list of all possible drugs that may interact with ritonavir. The healthcare provider should consult appropriate references for comprehensive information.
) and Clinical Pharmacology (12.3 PharmacokineticsThe pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-infected patients (CD4greater than or equal to 50 cells per μL). See Table 4 for ritonavir pharmacokinetic characteristics.
AbsorptionThe absolute bioavailability of ritonavir has not been determined. After a 100 mg tablet dose of NORVIR, peak concentrations of ritonavir were achieved approximately 3 hours and 4 hours after dosing under fasting conditions and moderate-fat (857 KCal; 31% fat, 13% protein, and 56% carbohydrate) meal, respectively.
After administration of a single 100 mg dose under fed conditions (approximately 600 Kcal, 30% calories from fat), NORVIR oral powder showed 23% higher exposure compared to the tablet.
Effect of Food on Oral AbsorptionThe bioavailability of NORVIR tablet and oral powder is decreased under fed conditions as compared to fasted conditions.
Following the administration of a 100 mg tablet dose of NORVIR, Cmaxand AUCinfof ritonavir were decreased by 21-23% under moderate fat (857 Kcal, 30% from fat) or high fat conditions (917 Kcal, 60% calories from fat) relative to fasting conditions.
Following the administration of a 100 mg dose of NORVIR oral powder, Cmaxand AUCinfof ritonavir were decreased by 23-49% under moderate fat (617 Kcal, 29% calories from fat) or high fat conditions (917 Kcal, 60% calories from fat) relative to fasting conditions.
MetabolismNearly all of the plasma radioactivity after a single oral 600 mg dose of14C-ritonavir oral solution (n = 5) was attributed to unchanged ritonavir. Five ritonavir metabolites have been identified in human urine and feces. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent drug; however, the concentrations of this metabolite in plasma are low.
In vitrostudies utilizing human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of M–2.EliminationIn a study of five subjects receiving a 600 mg dose of14C-ritonavir oral solution, 11.3 ± 2.8% of the dose was excreted into the urine, with 3.5 ± 1.8% of the dose excreted as unchanged parent drug. In that study, 86.4 ± 2.9% of the dose was excreted in the feces with 33.8 ± 10.8% of the dose excreted as unchanged parent drug. Upon multiple dosing, ritonavir accumulation is less than predicted from a single dose possibly due to a time and dose-related increase in clearance.
Table 4. Ritonavir Pharmacokinetic Characteristics ParameterNValues (Mean ± SD)Vβ/F‡ 91 0.41 ± 0.25 L/kg t½ 3 - 5 h CL/F SS† 10 8.8 ± 3.2 L/h CL/F‡ 91 4.6 ± 1.6 L/h CLR 62 < 0.1 L/h RBC/Plasma Ratio 0.14 Percent Bound* 98 to 99% † SS = steady state; patients taking ritonavir 600 mg q12h.
‡ Single ritonavir 600 mg dose.
* Primarily bound to human serum albumin and alpha-1 acid glycoprotein over the ritonavir concentration range of 0.01 to 30 µg/mL.Special PopulationsGender, Race and AgeNo age-related pharmacokinetic differences have been observed in adult patients (18 to 63 years). Ritonavir pharmacokinetics have not been studied in older patients.
A study of ritonavir pharmacokinetics in healthy males and females showed no statistically significant differences in the pharmacokinetics of ritonavir. Pharmacokinetic differences due to race have not been identified.
Pediatric PatientsSteady-state pharmacokinetics were evaluated in 37 HIV-infected patients ages 2 to 14 years receiving doses ranging from 250 mg per m2twice-daily to 400 mg per m2twice-daily in PACTG Study 310, and in 41 HIV-infected patients ages 1 month to 2 years at doses of 350 and 450 mg per m2twice-daily in PACTG Study 345. Across dose groups, ritonavir steady-state oral clearance (CL/F/m2) was approximately 1.5 to 1.7 times faster in pediatric patients than in adult subjects. Ritonavir concentrations obtained after 350 to 400 mg per m2twice-daily in pediatric patients greater than 2 years were comparable to those obtained in adults receiving 600 mg (approximately 330 mg per m2) twice-daily. The following observations were seen regarding ritonavir concentrations after administration with 350 or 450 mg per m2twice-daily in children less than 2 years of age. Higher ritonavir exposures were not evident with 450 mg per m2twice-daily compared to the 350 mg per m2twice-daily. Ritonavir trough concentrations were somewhat lower than those obtained in adults receiving 600 mg twice-daily. The area under the ritonavir plasma concentration time curve and trough concentrations obtained after administration with 350 or 450 mg per m2twice-daily in children less than 2 years were approximately 16% and 60% lower, respectively, than that obtained in adults receiving 600 mg twice daily.
Renal ImpairmentRitonavir pharmacokinetics have not been studied in patients with renal impairment, however, since renal clearance is negligible, a decrease in total body clearance is not expected in patients with renal impairment.
Hepatic ImpairmentDose-normalized steady-state ritonavir concentrations in subjects with mild hepatic impairment (400 mg twice-daily, n = 6) were similar to those in control subjects dosed with 500 mg twice-daily. Dose-normalized steady-state ritonavir exposures in subjects with moderate hepatic impairment (400 mg twice-daily, n= 6) were about 40% lower than those in subjects with normal hepatic function (500 mg twice-daily, n = 6). Protein binding of ritonavir was not statistically significantly affected by mild or moderately impaired hepatic function. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. However, health care providers should be aware of the potential for lower ritonavir concentrations in patients with moderate hepatic impairment and should monitor patient response carefully. Ritonavir has not been studied in patients with severe hepatic impairment.
PregnancyBased on evaluation of the published literature, ritonavir exposures are reduced during pregnancy relative to postpartum.
Drug Interactions[see also Contraindications(4), Warnings and Precautions(5.1),andDrug Interactions(7)]Table 5 and Table 6 summarize the effects on AUC and Cmax, with 95% confidence intervals (95% CI), of co-administration of ritonavir with a variety of drugs. For information about clinical recommendations see Table 3 in
Drug Interactions(7).Table 5. Drug Interactions - Pharmacokinetic Parameters for Ritonavir in the Presence of the Co-administered Drug Co-
administered
DrugDose of Co-
administered
Drug (mg)Dose of
NORVIR (mg)NAUC %
(95% CI)Cmax
(95% CI)Cmin
(95% CI)Clarithromycin 500 q12h,
4 d200 q8h,
4 d22 ↑ 12%
(2, 23%)↑ 15%
(2, 28%)↑ 14%
(-3, 36%)Didanosine 200 q12h,
4 d600 q12h,
4 d12 ↔ ↔ ↔ Fluconazole 400
single dose,
day 1;
200 daily,
4 d200 q6h,
4 d8 ↑ 12%
(5, 20%)↑ 15%
(7, 22%)↑ 14%
(0, 26%)Fluoxetine 30 q12h,
8 d600
single dose,
1 d16 ↑ 19%
(7, 34%)↔ ND Ketoconazole 200 daily,
7 d500 q12h,
10 d12 ↑ 18%
(-3, 52%)↑ 10%
(-11, 36%)ND Rifampin 600 or
300 daily,
10 d500 q12h,
20 d7, 9* ↓ 35%
(7, 55%)↓ 25%
(-5, 46%)↓ 49%
(-14, 91%)Voriconazole 400 q12h,
1 d;
then 200 q12h,
8 d400 q12h,
9 d↔ ↔ ND Zidovudine 200 q8h,
4 d300 q6h,
4 d10 ↔ ↔ ↔ ND=not determined Table 6. Drug Interactions - Pharmacokinetic Parameters for Co-administered Drug in the Presence of NORVIR Co-administered DrugDose of Co-administered Drug (mg)Dose of NORVIR (mg)NAUC % (95% CI)Cmax(95% CI)Cmin(95% CI)Alprazolam 1, single dose 500 q12h,
10 d12 ↓ 12%
(-5, 30%)↓ 16%
(5, 27%)ND Avanafil 50,
single dose600 q12h 146 ↑ 13-fold ↑ 2.4-fold ND Clarithromycin
14-OH clarithromycin metabolite500 q12h,
4 d200 q8h,
4 d22 ↑ 77%
(56, 103%)
↓ 100%↑ 31%
(15, 51%)
↓ 99%↑ 2.8-fold
(2.4, 3.3X)
↓ 100%Desipramine
2-OH desipramine
metabolite100,
single dose500 q12h,
12 d14 ↑ 145%
(103, 211%)
↓ 15%
(3, 26%)↑ 22%
(12, 35%)
↓ 67%
(62, 72%)ND
NDDidanosine 200 q12h,
4 d600 q12h,
4 d12 ↓ 13%
(0, 23%)↓ 16%
(5, 26%)↔ Ethinyl estradiol 50 µg
single dose500 q12h,
16 d23 ↓ 40%
(31, 49%)↓ 32%
(24, 39%)ND Fluticasone
propionate aqueous
nasal spray200 mcg qd,
7 d100 mg q12h,
7 d18 ↑ approximately 350-fold5 ↑ approximately 25-fold5 Indinavir1
Day 14
Day 15400 q12h,
15 d400 q12h,
15 d10 ↑ 6%
(-14, 29%)
↓ 7%
(-22, 28%)↓ 51%
(40, 61%)
↓ 62%
(52, 70%)↑ 4-fold
(2.8, 6.8X)
↑ 4-fold
(2.5, 6.5X)Ketoconazole 200 daily,
7 d500 q12h,
10 d12 ↑ 3.4-fold
(2.8, 4.3X)↑ 55%
(40, 72%)ND Meperidine
Normeperidine
metabolite50 oral
single dose500 q12h,
10 d8
6↓ 62%
(59, 65%)
↑ 47%
(-24, 345%)↓ 59%
(42, 72%)
↑ 87%
(42, 147%)ND
NDMethadone2 5, single dose 500 q12h,
15 d11 ↓ 36%
(16, 52%)↓ 38%
(28, 46%)ND Raltegravir 400,
single dose100 q12h,
16 d10 ↓ 16%
(-30, 1%)↓ 24%
(-45, 4%)↓ 1%
(-30, 40%)Rivaroxaban 10,
single dose
(days 0 and 7)600 q12h
(days
2 to 7)12 ↑ 150%
(130-170%)7↑ 60%
(40-70%)7ND Rifabutin
25-O-desacetyl
rifabutin
metabolite150 daily,
16 d500 q12h,
10 d5,
11*↑ 4-fold
(2.8, 6.1X)
↑ 38-fold
(28, 56X)↑ 2.5-fold
(1.9, 3.4X)
↑ 16-fold
(13, 20X)↑ 6-fold
(3.5, 18.3X)
↑ 181-fold
(ND)Sildenafil 100,
single dose500
twice daily,
8 d28 ↑ 11-fold ↑ 4-fold ND Simeprevir 200 mg qd,
7 d100 mg bid,
15 d12 ↑ 618%
(463%-815%)8↑370%
(284%-476%)8↑1335%
(929%-1901%)8Sulfamethoxazole3 800,
single dose500 q12h,
12 d15 ↓ 20%
(16, 23%)↔ ND Tadalafil 20 mg,
single dose200 mg q12h ↑ 124% ↔ ND Theophylline 3 mg/kg q8h,
15 d500 q12h,
10 d13, 11* ↓ 43%
(42, 45%)↓ 32%
(29, 34%)↓ 57%
(55, 59%)Trazodone 50 mg,
single dose200 mg q12h,
4 doses10 ↑ 2.4-fold ↑ 34% Trimethoprim3 160,
single dose500 q12h,
12 d15 ↑ 20%
(3, 43%)↔ ND Vardenafil 5 mg 600 q12h ↑ 49-fold ↑ 13-fold ND Voriconazole 400 q12h, 1 d;
then 200 q12h,
8 d400 q12h,
9 d↓ 82% ↓ 66% 400 q12h,
1 d;
then 200 q12h,
8 d100 q12h,
9 d↓ 39% ↓ 24% Warfarin
S-Warfarin
R-Warfarin5, single dose 400 q12h,
12d12 ↑ 9%
(-17, 44%)4
↓ 33%
(-38, -27%)4↓ 9%
(-16, -2%)4
↔ND
NDZidovudine 200 q8h,
4 d300 q6h,
4 d9 ↓ 25%
(15, 34%)↓ 27%
(4, 45%)ND ND=not determined
1 Ritonavir and indinavir were co-administered for 15 days; Day 14 doses were administered after a 15%-fat breakfast (757 Kcal) and 9%-fat evening snack (236 Kcal), and Day 15 doses were administered after a 15%-fat breakfast (757 Kcal) and 32%-fat dinner (815 Kcal). Indinavir Cminwas also increased 4-fold. Effects were assessed relative to an indinavir 800 mg q8h regimen under fasting conditions.
2 Effects were assessed on a dose-normalized comparison to a methadone 20 mg single dose.
3 Sulfamethoxazole and trimethoprim taken as single combination tablet.
4 90% CI presented for R- and S-warfarin AUC and Cmaxratios.
5 This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in plasma cortisol AUC.
6 For the reference arm: N=14 for Cmaxand AUC(0-inf), and for the test arm: N=13 for Cmaxand N=4 for AUC(0-inf).
7 90% CI presented for rivaroxaban
8 90% CI presented for simeprevir (change in exposure presented as percentage increase)
↑ Indicates increase, ↓ indicates decrease, ↔ indicates no change.
* Parallel group design; entries are subjects receiving combination and control regimens, respectively.)].
○ Alpha 1- Adrenoreceptor Antagonist : alfuzosin
○ Antianginal: ranolazine
○ Antiarrhythmics: amiodarone, dronedarone, flecainide, propafenone, quinidine
○ Antifungal: voriconazole
○ Anti-gout: colchicine
○ Antipsychotics: lurasidone, pimozide
○ Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine
○ GI Motility Agent: cisapride
○ HMG-CoA Reductase Inhibitors: lovastatin, simvastatin
○ Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide
○ PDE5 Inhibitor: sildenafil (Revatio®) when used for the treatment of pulmonary arterial hypertension
○ Sedative/Hypnotics: triazolam, orally administered midazolam - NORVIR is contraindicated with drugs that are potent CYP3A inducers where significantly reduced ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance [see Drug Interactions (7.2 Established and Other Potentially Significant Drug Interactions
Table 3 provides a list of established or potentially clinically significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction
[see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)]for magnitude of interaction.Table 3. Established and Other Potentially Significant Drug Interactions Concomitant Drug Class:Drug NameEffect on Concentration of Ritonavir or Concomitant DrugClinical CommentHIV-Antiviral AgentsHIV-1 Protease Inhibitor:
atazanavir
darunavir
fosamprenavir↑ amprenavir
↑ atazanavir
↑ darunavirSee the complete prescribing information for fosamprenavir, atazanavir, darunavir for details on co-administration with ritonavir. HIV-1 Protease Inhibitor:
indinavir↑ indinavir Appropriate doses for this combination, with respect to efficacy and safety, have not been established. HIV-1 Protease Inhibitor:
saquinavir↑ saquinavir See the complete prescribing information for saquinavir for details on co-administration of saquinavir and ritonavir.
Saquinavir/ritonavir in combination with rifampin is not recommended due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.HIV-1 Protease Inhibitor:
tipranavir↑ tipranavir See the complete prescribing information for tipranavir for details on co-administration of tipranavir and ritonavir. Non-Nucleoside Reverse Transcriptase Inhibitor:
delavirdine↑ ritonavir Appropriate doses of this combination with respect to safety and efficacy have not been established. HIV-1 CCR5 – antagonist: maraviroc ↑ maraviroc See the complete prescribing information for maraviroc for details on co-administration of maraviroc and ritonavir-containing protease inhibitors. Integrase Inhibitor:
raltegravir↓ raltegravir The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration. Other AgentsAlpha 1-
Adrenoreceptor
Antagonist:
alfuzosin↑ alfuzosin Contraindicated due to potential hypotension [see Contraindications(4)].Antianginal:
ranolazine↑ ranolazine Contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications(4)].Analgesics, Narcotic:
tramadol,
propoxyphene,
methadone,
fentanyl↑ analgesics
↓ methadone
↑ fentanylA dose decrease may be needed for these drugs when co-administered with ritonavir.
Dosage increase of methadone may be considered.
Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with NORVIR.Anesthetic:
meperidine↓ meperidine/ ↑ normeperidine (metabolite) Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures). Antiarrhythmics:
amiodarone,
dronedarone,
flecainide,
propafenone, quinidine↑ antiarrhythmics Contraindicated due to potential for cardiac arrhythmias [see Contraindications(4)].Antiarrhythmics:
disopyramide,
lidocaine, mexiletine↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available. Anticancer Agents:
abemaciclib,
apalutamide,
dasatinib,
encorafenib,
ibrutinib,
ivosidenib,
neratinib,
nilotinib,
venetoclax,
vinblastine,
vincristine↑ anticancer agents
↓ ritonavir#Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors [see Contraindications(4)].
Avoid co-administration of encorafenib or ivosidenib with NORVIR due to potential risk of serious adverse events such as QT interval prolongation. If co-administration of encorafenib with NORVIR cannot be avoided, modify dose as recommended in encorafenib USPI. If co-administration of ivosidenib with NORVIR cannot be avoided, reduce ivosidenib dose to 250 mg once daily.
Avoid use of neratinib, venetoclax or ibrutinib with NORVIR.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine.
Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as NORVIR. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.Anticoagulant:
warfarin↑↓ warfarin Initial frequent monitoring of the INR during ritonavir and warfarin co-administration is recommended. Anticoagulant:
rivaroxaban↑ rivaroxaban Avoid concomitant use of rivaroxaban and ritonavir. Co-administration of ritonavir and rivaroxaban may lead to risk of increased bleeding. Anticonvulsants:
carbamazepine, clonazepam, ethosuximide↑ anticonvulsants A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available. Anticonvulsants:
divalproex, lamotrigine, phenytoin↓ anticonvulsants A dose increase may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available. Antidepressants:
nefazodone,
selective serotonin
reuptake inhibitors
(SSRIs): e.g.
fluoxetine,
paroxetine,
tricyclics: e.g.
amitriptyline,
nortriptyline↑ antidepressants A dose decrease may be needed for these drugs when co-administered with ritonavir. Antidepressant:
bupropion↓ bupropion
↓ active metabolite, hydroxybupropionPatients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion. Antidepressant:
desipramine↑ desipramine Dosage reduction and concentration monitoring of desipramine is recommended. Antidepressant:
trazodone↑ trazodone Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and NORVIR. A lower dose of trazodone should be considered. Antiemetic:
dronabinol↑ dronabinol A dose decrease of dronabinol may be needed when co-administered with ritonavir. Antifungals:
ketoconazole
itraconazole
voriconazole↑ ketoconazole
↑ itraconazole
↓ voriconazoleHigh doses of ketoconazole or itraconazole (greater than 200 mg per day) are not recommended.
Co-administration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated due to the potential for loss of antifungal response[see Contraindications(4)]. Co-administration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.Anti-gout:
colchicine↑ colchicine Contraindicated due to potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment [see Contraindications(4)].For patients with normal renal or hepatic function:Treatment of gout flares-co-administration of colchicine in patients on ritonavir:0.6 mg (one tablet) for one dose, followed by 0.3 mg (half tablet) one hour later. Dose to be repeated no earlier than three days.Prophylaxis of gout flares-co-administration of colchicine in patients on ritonavir:If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on ritonavir:Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).Anti-infective:
clarithromycin↑ clarithromycin For patients with renal impairment, adjust clarithromycin dose as follows: - For patients with CLCR30 to 60 mL per min the dose of clarithromycin should be reduced by 50%.
- For patients with CLCRless than 30 mL per min the dose of clarithromycin should be decreased by 75%.
Antimycobacterial:
bedaquiline↑ bedaquiline Bedaquiline should only be used with ritonavir if the benefit of co-administration outweighs the risk. Antimycobacterial:
rifabutin↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg per day is recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be necessary. Antimycobacterial:
rifampin↓ ritonavir May lead to loss of virologic response. Alternate antimycobacterial agents such as rifabutin should be considered. Antiparasitic:
atovaquone↓ atovaquone Clinical significance is unknown; however, increase in atovaquone dose may be needed. Antiparasitic:
quinine↑ quinine A dose decrease of quinine may be needed when co-administered with ritonavir. Antipsychotics:
lurasidone
pimozide↑ lurasidone
↑ pimozideContraindicated due to potential for serious and/or life-threatening reactions [see Contraindications(4)].
Contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias[see Contraindications(4)].Antipsychotics:
perphenazine,
risperidone,
thioridazine↑ antipsychotics A dose decrease may be needed for these drugs when co-administered with ritonavir. Antipsychotics:
quetiapine↑ quetiapine Initiation of NORVIR in patients taking quetiapine:
Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.Initiation of quetiapine in patients taking NORVIR:
Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.β-Blockers:
metoprolol, timolol↑ beta-blockers Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir. Bronchodilator:
theophylline↓ theophylline Increased dosage of theophylline may be required; therapeutic monitoring should be considered. Calcium channel blockers:
diltiazem, nifedipine, verapamil↑ calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir. Digoxin ↑ digoxin Concomitant administration of ritonavir with digoxin may increase digoxin levels. Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels. Endothelin receptor antagonists: bosentan ↑ bosentan Co-administration of bosentan in patients on ritonavir:
In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.Co-administration of ritonavir in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir.
After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.GnRH Receptor
Antagonists:
elagolix↑ elagolix
↓ ritonavirConcomitant use of elagolix 200 mg twice daily and NORVIR for more than 1 month is not recommended due to potential risk of adverse events such as bone loss and hepatic transaminase elevations. Limit concomitant use of elagolix 150 mg once daily and NORVIR to 6 months. Ergot Derivatives:
dihydroergotamine,
ergotamine,
methylergonovine↑ ergot derivatives Contraindicated due to potential for acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications(4)].GI Motility Agent:
cisapride↑ cisapride Contraindicated due to potential for cardiac arrhythmias [see Contraindications(4)].Hepatitis C direct
acting antiviral:
glecaprevir/pibrentasvir
simeprevir
↑ glecaprevir
↑ pibrentasvir
↑simeprevirIt is not recommended to co-administer ritonavir with glecaprevir/pibrentasvir, or simeprevir. Herbal Products:
St. John's Wort
(hypericum
perforatum)↓ ritonavir Contraindicated due to potential for loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors [see Contraindications(4)].Lipid-modifying agents
HMG-CoA Reductase
Inhibitor:
lovastatin
simvastatin
atorvastatin
rosuvastatin
Microsomal
triglyceride
transfer protein
(MTTP)
Inhibitor:
lomitapide
↑ lovastatin
↑ simvastatin
↑ atorvastatin
↑ rosuvastatin
↑ lomitapide
Contraindicated due to potential for myopathy including rhabdomyolysis[see Contraindications(4)].
Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose.If NORVIR is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin.
Lomitapide is a sensitive substrate for CYP3A4 metabolism. CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold. Concomitant use of moderate or strong CYP3A4 inhibitors with lomitapide is contraindicated due to potential for hepatotoxicity[see Contraindications(4)].Immunosuppressants:
cyclosporine,
tacrolimus,
sirolimus
(rapamycin)↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir. Kinase Inhibitors:
fostamatinib(also see
anticancer agents
above)↑ fostamatinib
metabolite R406Monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required. Long-acting beta-adrenoceptor agonist: salmeterol ↑ salmeterol Concurrent administration of salmeterol and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. Oral Contraceptives or Patch Contraceptives:
ethinyl estradiol↓ ethinyl estradiol Alternate methods of contraception should be considered. PDE5 Inhibitors:
avanafil
sildenafil,
tadalafil,
vardenafil↑ avanafil
↑ sildenafil
↑ tadalafil
↑ vardenafilSildenafil when used for the treatment of pulmonary arterial hypertension (Revatio®) is contraindicated due to the potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope [see Contraindications(4)].
Do not use ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established.
Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Coadministration of ritonavir with these drugs may result in an increase in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes, and prolonged erection.
Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
Sildenafil (Revatio®) is contraindicated[see Contraindications(4)].
The following dose adjustments are recommended for use of tadalafil (Adcirca®) with ritonavir:Co-administration of ADCIRCA in patients on ritonavir:
In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.Co-administration of ritonavir in patients on ADCIRCA:
Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Use of PDE5 inhibitors for the treatment of erectile dysfunction:
It is recommended not to exceed the following doses:- Sildenafil: 25 mg every 48 hours
- Tadalafil: 10 mg every 72 hours
- Vardenafil: 2.5 mg every 72 hours
Use with increased monitoring for adverse events.Sedative/hypnotics:
buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem↑ sedative/hypnotics A dose decrease may be needed for these drugs when co-administered with ritonavir. Sedative/Hypnotics:
triazolam,
orally administered
midazolam↑ triazolam
↑ midazolamContraindicated due to potential for prolonged or increased sedation or respiratory depression [see Contraindications(4)].Sedative/hypnotics: Parenteral midazolam ↑ midazolam Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Stimulant:
methamphetamine↑ methamphetamine Use with caution. A dose decrease of methamphetamine may be needed when co-administered with ritonavir. Systemic/Inhaled/
Nasal/Ophthalmic
Corticosteroids:
e.g., betamethasone
budesonide
ciclesonide
dexamethasone
fluticasone
methylprednisolone
mometasone
prednisone
triamcinolone↑ glucocorticoids Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression.Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use. #refers to interaction with apalutamide. ) and Clinical Pharmacology (12.3 PharmacokineticsThe pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-infected patients (CD4greater than or equal to 50 cells per μL). See Table 4 for ritonavir pharmacokinetic characteristics.
AbsorptionThe absolute bioavailability of ritonavir has not been determined. After a 100 mg tablet dose of NORVIR, peak concentrations of ritonavir were achieved approximately 3 hours and 4 hours after dosing under fasting conditions and moderate-fat (857 KCal; 31% fat, 13% protein, and 56% carbohydrate) meal, respectively.
After administration of a single 100 mg dose under fed conditions (approximately 600 Kcal, 30% calories from fat), NORVIR oral powder showed 23% higher exposure compared to the tablet.
Effect of Food on Oral AbsorptionThe bioavailability of NORVIR tablet and oral powder is decreased under fed conditions as compared to fasted conditions.
Following the administration of a 100 mg tablet dose of NORVIR, Cmaxand AUCinfof ritonavir were decreased by 21-23% under moderate fat (857 Kcal, 30% from fat) or high fat conditions (917 Kcal, 60% calories from fat) relative to fasting conditions.
Following the administration of a 100 mg dose of NORVIR oral powder, Cmaxand AUCinfof ritonavir were decreased by 23-49% under moderate fat (617 Kcal, 29% calories from fat) or high fat conditions (917 Kcal, 60% calories from fat) relative to fasting conditions.
MetabolismNearly all of the plasma radioactivity after a single oral 600 mg dose of14C-ritonavir oral solution (n = 5) was attributed to unchanged ritonavir. Five ritonavir metabolites have been identified in human urine and feces. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent drug; however, the concentrations of this metabolite in plasma are low.
In vitrostudies utilizing human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of M–2.EliminationIn a study of five subjects receiving a 600 mg dose of14C-ritonavir oral solution, 11.3 ± 2.8% of the dose was excreted into the urine, with 3.5 ± 1.8% of the dose excreted as unchanged parent drug. In that study, 86.4 ± 2.9% of the dose was excreted in the feces with 33.8 ± 10.8% of the dose excreted as unchanged parent drug. Upon multiple dosing, ritonavir accumulation is less than predicted from a single dose possibly due to a time and dose-related increase in clearance.
Table 4. Ritonavir Pharmacokinetic Characteristics ParameterNValues (Mean ± SD)Vβ/F‡ 91 0.41 ± 0.25 L/kg t½ 3 - 5 h CL/F SS† 10 8.8 ± 3.2 L/h CL/F‡ 91 4.6 ± 1.6 L/h CLR 62 < 0.1 L/h RBC/Plasma Ratio 0.14 Percent Bound* 98 to 99% † SS = steady state; patients taking ritonavir 600 mg q12h.
‡ Single ritonavir 600 mg dose.
* Primarily bound to human serum albumin and alpha-1 acid glycoprotein over the ritonavir concentration range of 0.01 to 30 µg/mL.Special PopulationsGender, Race and AgeNo age-related pharmacokinetic differences have been observed in adult patients (18 to 63 years). Ritonavir pharmacokinetics have not been studied in older patients.
A study of ritonavir pharmacokinetics in healthy males and females showed no statistically significant differences in the pharmacokinetics of ritonavir. Pharmacokinetic differences due to race have not been identified.
Pediatric PatientsSteady-state pharmacokinetics were evaluated in 37 HIV-infected patients ages 2 to 14 years receiving doses ranging from 250 mg per m2twice-daily to 400 mg per m2twice-daily in PACTG Study 310, and in 41 HIV-infected patients ages 1 month to 2 years at doses of 350 and 450 mg per m2twice-daily in PACTG Study 345. Across dose groups, ritonavir steady-state oral clearance (CL/F/m2) was approximately 1.5 to 1.7 times faster in pediatric patients than in adult subjects. Ritonavir concentrations obtained after 350 to 400 mg per m2twice-daily in pediatric patients greater than 2 years were comparable to those obtained in adults receiving 600 mg (approximately 330 mg per m2) twice-daily. The following observations were seen regarding ritonavir concentrations after administration with 350 or 450 mg per m2twice-daily in children less than 2 years of age. Higher ritonavir exposures were not evident with 450 mg per m2twice-daily compared to the 350 mg per m2twice-daily. Ritonavir trough concentrations were somewhat lower than those obtained in adults receiving 600 mg twice-daily. The area under the ritonavir plasma concentration time curve and trough concentrations obtained after administration with 350 or 450 mg per m2twice-daily in children less than 2 years were approximately 16% and 60% lower, respectively, than that obtained in adults receiving 600 mg twice daily.
Renal ImpairmentRitonavir pharmacokinetics have not been studied in patients with renal impairment, however, since renal clearance is negligible, a decrease in total body clearance is not expected in patients with renal impairment.
Hepatic ImpairmentDose-normalized steady-state ritonavir concentrations in subjects with mild hepatic impairment (400 mg twice-daily, n = 6) were similar to those in control subjects dosed with 500 mg twice-daily. Dose-normalized steady-state ritonavir exposures in subjects with moderate hepatic impairment (400 mg twice-daily, n= 6) were about 40% lower than those in subjects with normal hepatic function (500 mg twice-daily, n = 6). Protein binding of ritonavir was not statistically significantly affected by mild or moderately impaired hepatic function. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. However, health care providers should be aware of the potential for lower ritonavir concentrations in patients with moderate hepatic impairment and should monitor patient response carefully. Ritonavir has not been studied in patients with severe hepatic impairment.
PregnancyBased on evaluation of the published literature, ritonavir exposures are reduced during pregnancy relative to postpartum.
Drug Interactions[see also Contraindications(4), Warnings and Precautions(5.1),andDrug Interactions(7)]Table 5 and Table 6 summarize the effects on AUC and Cmax, with 95% confidence intervals (95% CI), of co-administration of ritonavir with a variety of drugs. For information about clinical recommendations see Table 3 in
Drug Interactions(7).Table 5. Drug Interactions - Pharmacokinetic Parameters for Ritonavir in the Presence of the Co-administered Drug Co-
administered
DrugDose of Co-
administered
Drug (mg)Dose of
NORVIR (mg)NAUC %
(95% CI)Cmax
(95% CI)Cmin
(95% CI)Clarithromycin 500 q12h,
4 d200 q8h,
4 d22 ↑ 12%
(2, 23%)↑ 15%
(2, 28%)↑ 14%
(-3, 36%)Didanosine 200 q12h,
4 d600 q12h,
4 d12 ↔ ↔ ↔ Fluconazole 400
single dose,
day 1;
200 daily,
4 d200 q6h,
4 d8 ↑ 12%
(5, 20%)↑ 15%
(7, 22%)↑ 14%
(0, 26%)Fluoxetine 30 q12h,
8 d600
single dose,
1 d16 ↑ 19%
(7, 34%)↔ ND Ketoconazole 200 daily,
7 d500 q12h,
10 d12 ↑ 18%
(-3, 52%)↑ 10%
(-11, 36%)ND Rifampin 600 or
300 daily,
10 d500 q12h,
20 d7, 9* ↓ 35%
(7, 55%)↓ 25%
(-5, 46%)↓ 49%
(-14, 91%)Voriconazole 400 q12h,
1 d;
then 200 q12h,
8 d400 q12h,
9 d↔ ↔ ND Zidovudine 200 q8h,
4 d300 q6h,
4 d10 ↔ ↔ ↔ ND=not determined Table 6. Drug Interactions - Pharmacokinetic Parameters for Co-administered Drug in the Presence of NORVIR Co-administered DrugDose of Co-administered Drug (mg)Dose of NORVIR (mg)NAUC % (95% CI)Cmax(95% CI)Cmin(95% CI)Alprazolam 1, single dose 500 q12h,
10 d12 ↓ 12%
(-5, 30%)↓ 16%
(5, 27%)ND Avanafil 50,
single dose600 q12h 146 ↑ 13-fold ↑ 2.4-fold ND Clarithromycin
14-OH clarithromycin metabolite500 q12h,
4 d200 q8h,
4 d22 ↑ 77%
(56, 103%)
↓ 100%↑ 31%
(15, 51%)
↓ 99%↑ 2.8-fold
(2.4, 3.3X)
↓ 100%Desipramine
2-OH desipramine
metabolite100,
single dose500 q12h,
12 d14 ↑ 145%
(103, 211%)
↓ 15%
(3, 26%)↑ 22%
(12, 35%)
↓ 67%
(62, 72%)ND
NDDidanosine 200 q12h,
4 d600 q12h,
4 d12 ↓ 13%
(0, 23%)↓ 16%
(5, 26%)↔ Ethinyl estradiol 50 µg
single dose500 q12h,
16 d23 ↓ 40%
(31, 49%)↓ 32%
(24, 39%)ND Fluticasone
propionate aqueous
nasal spray200 mcg qd,
7 d100 mg q12h,
7 d18 ↑ approximately 350-fold5 ↑ approximately 25-fold5 Indinavir1
Day 14
Day 15400 q12h,
15 d400 q12h,
15 d10 ↑ 6%
(-14, 29%)
↓ 7%
(-22, 28%)↓ 51%
(40, 61%)
↓ 62%
(52, 70%)↑ 4-fold
(2.8, 6.8X)
↑ 4-fold
(2.5, 6.5X)Ketoconazole 200 daily,
7 d500 q12h,
10 d12 ↑ 3.4-fold
(2.8, 4.3X)↑ 55%
(40, 72%)ND Meperidine
Normeperidine
metabolite50 oral
single dose500 q12h,
10 d8
6↓ 62%
(59, 65%)
↑ 47%
(-24, 345%)↓ 59%
(42, 72%)
↑ 87%
(42, 147%)ND
NDMethadone2 5, single dose 500 q12h,
15 d11 ↓ 36%
(16, 52%)↓ 38%
(28, 46%)ND Raltegravir 400,
single dose100 q12h,
16 d10 ↓ 16%
(-30, 1%)↓ 24%
(-45, 4%)↓ 1%
(-30, 40%)Rivaroxaban 10,
single dose
(days 0 and 7)600 q12h
(days
2 to 7)12 ↑ 150%
(130-170%)7↑ 60%
(40-70%)7ND Rifabutin
25-O-desacetyl
rifabutin
metabolite150 daily,
16 d500 q12h,
10 d5,
11*↑ 4-fold
(2.8, 6.1X)
↑ 38-fold
(28, 56X)↑ 2.5-fold
(1.9, 3.4X)
↑ 16-fold
(13, 20X)↑ 6-fold
(3.5, 18.3X)
↑ 181-fold
(ND)Sildenafil 100,
single dose500
twice daily,
8 d28 ↑ 11-fold ↑ 4-fold ND Simeprevir 200 mg qd,
7 d100 mg bid,
15 d12 ↑ 618%
(463%-815%)8↑370%
(284%-476%)8↑1335%
(929%-1901%)8Sulfamethoxazole3 800,
single dose500 q12h,
12 d15 ↓ 20%
(16, 23%)↔ ND Tadalafil 20 mg,
single dose200 mg q12h ↑ 124% ↔ ND Theophylline 3 mg/kg q8h,
15 d500 q12h,
10 d13, 11* ↓ 43%
(42, 45%)↓ 32%
(29, 34%)↓ 57%
(55, 59%)Trazodone 50 mg,
single dose200 mg q12h,
4 doses10 ↑ 2.4-fold ↑ 34% Trimethoprim3 160,
single dose500 q12h,
12 d15 ↑ 20%
(3, 43%)↔ ND Vardenafil 5 mg 600 q12h ↑ 49-fold ↑ 13-fold ND Voriconazole 400 q12h, 1 d;
then 200 q12h,
8 d400 q12h,
9 d↓ 82% ↓ 66% 400 q12h,
1 d;
then 200 q12h,
8 d100 q12h,
9 d↓ 39% ↓ 24% Warfarin
S-Warfarin
R-Warfarin5, single dose 400 q12h,
12d12 ↑ 9%
(-17, 44%)4
↓ 33%
(-38, -27%)4↓ 9%
(-16, -2%)4
↔ND
NDZidovudine 200 q8h,
4 d300 q6h,
4 d9 ↓ 25%
(15, 34%)↓ 27%
(4, 45%)ND ND=not determined
1 Ritonavir and indinavir were co-administered for 15 days; Day 14 doses were administered after a 15%-fat breakfast (757 Kcal) and 9%-fat evening snack (236 Kcal), and Day 15 doses were administered after a 15%-fat breakfast (757 Kcal) and 32%-fat dinner (815 Kcal). Indinavir Cminwas also increased 4-fold. Effects were assessed relative to an indinavir 800 mg q8h regimen under fasting conditions.
2 Effects were assessed on a dose-normalized comparison to a methadone 20 mg single dose.
3 Sulfamethoxazole and trimethoprim taken as single combination tablet.
4 90% CI presented for R- and S-warfarin AUC and Cmaxratios.
5 This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in plasma cortisol AUC.
6 For the reference arm: N=14 for Cmaxand AUC(0-inf), and for the test arm: N=13 for Cmaxand N=4 for AUC(0-inf).
7 90% CI presented for rivaroxaban
8 90% CI presented for simeprevir (change in exposure presented as percentage increase)
↑ Indicates increase, ↓ indicates decrease, ↔ indicates no change.
* Parallel group design; entries are subjects receiving combination and control regimens, respectively.)].
○ Anticancer Agents: apalutamide
○ Herbal Products: St. John's Wort (hypericum perforatum) - For patients with CLCR30 to 60 mL per min the dose of clarithromycin should be reduced by 50%.